Ronald Witteles

All Publications

• Avoiding Catastrophe: Understanding Free Light Chain Testing in the Evaluation of ATTR Amyloidosis. Circulation. Heart failure Witteles, R. M., Liedtke, M. 2021: CIRCHEARTFAILURE120008225

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.008225

  View details for PubMedID 33736459

• Global Longitudinal Strain in Cardio-Oncology. Journal of the American College of Cardiology Moslehi, J. J., Witteles, R. M. 2021; 77 (4): 402–4

  View details for DOI 10.1016/j.jacc.2020.12.014

  View details for PubMedID 33509396

• Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. European journal of heart failure Damy, T., Garcia-Pavia, P., Hanna, M., Judge, D. P., Merlini, G., Gundapaneni, B., Patterson, T. A., Riley, S., Schwartz, J. H., Sultan, M. B., Witteles, R. 2020

  Abstract

  AIMS: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.METHODS AND RESULTS: In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80mg, 20mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80mg or 20mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80mg (P =0.0030) and 20mg (P=0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80mg (Cox hazards model [95% CI]: 0.690 [0.487-0.979], P=0.0378) and 20mg (0.715 [0.450-1.137], P=0.1564). The mean (SE) change in NT-proBNP from baseline to Month 30 was -1170.51 (587.31), P=0.0468 with tafamidis 80mg vs. 20mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80mg vs 20mg (0.700 [0.501-0.979], P=0.0374). Incidence of adverse events in both tafamidis doses were comparable to placebo.CONCLUSION: Tafamidis, both 80mg and 20mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data, and the lack of dose-related safety concerns, support tafamidis 80mg as the optimal dose. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2027

  View details for PubMedID 33070419

• Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor JACC: CARDIOONCOLOGY Waliany, S., Sainani, K. L., Park, L. S., Zhang, C., Srinivas, S., Witteles, R. M. 2019; 1 (1): 24–36

  View details for DOI 10.1016/j.jaccao.2019.08.012

  View details for Web of Science ID 000613113100004

• AL Amyloidosis for the Cardiologist and Oncologist Epidemiology, Diagnosis, and Management JACC: CARDIOONCOLOGY Witteles, R. M., Liedtke, M. 2019; 1 (1): 117–30

  View details for DOI 10.1016/j.jaccao.2019.08.002

  View details for Web of Science ID 000613113100016

• Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC. Heart failure Witteles, R. M., Bokhari, S., Damy, T., Elliott, P. M., Falk, R. H., Fine, N. M., Gospodinova, M., Obici, L., Rapezzi, C., Garcia-Pavia, P. 2019

  Abstract

  Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here we propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure.

  View details for DOI 10.1016/j.jchf.2019.04.010

  View details for PubMedID 31302046

• Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients With Cardiac Sarcoidosis JOURNAL OF CARDIAC FAILURE Ning, N., Guo, H., Iagaru, A., Mittra, E., Fowler, M., Witteles, R. 2019; 25 (4): 307–11

  View details for DOI 10.1016/j.cardfail.2019.02.018

  View details for Web of Science ID 000466060500013

• A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K. n., Liedtke, M. n., Tuzovic, M. n., Haddad, F. n., Kobayashi, Y. n., Lafayette, R. n., Fowler, M. B., Arai, S. n., Schrier, S. n., Witteles, R. M. 2019

  Abstract

  The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

  View details for DOI 10.1016/j.jchf.2019.07.007

  View details for PubMedID 31606365

• Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis. Circulation. Heart failure Maurer, M. S., Bokhari, S. n., Damy, T. n., Dorbala, S. n., Drachman, B. M., Fontana, M. n., Grogan, M. n., Kristen, A. V., Lousada, I. n., Nativi-Nicolau, J. n., Cristina Quarta, C. n., Rapezzi, C. n., Ruberg, F. L., Witteles, R. n., Merlini, G. n. 2019; 12 (9): e006075

  Abstract

  Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006075

  View details for PubMedID 31480867

• Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy NEW ENGLAND JOURNAL OF MEDICINE Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018; 379 (11): 1007–16

  View details for DOI 10.1056/NEJMoa1805689

  View details for Web of Science ID 000444501600005

• The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? Academic medicine Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534-1539

  Abstract

  The medical student performance evaluation (MSPE), a letter summarizing academic performance, is included in each medical student's residency application. The extent to which medical schools follow Association of American Medical Colleges (AAMC) recommendations for comparative and transparent data is not known. This study's purpose was to describe the content, interpretability, and transparency of MSPEs.This cross-sectional study examined one randomly selected MSPE from every Liaison Committee on Medical Education-accredited U.S. medical school from which at least one student applied to the Stanford University internal medical residency program during the 2013-2014 application cycle. The authors described the number, distribution, and range of key words and clerkship grades used in the MSPEs and the proportions of schools with missing or incomplete data.The sample included MSPEs from 117 (89%) of 131 medical schools. Sixty schools (51%) provided complete information about clerkship grade and key word distributions. Ninety-six (82%) provided comparative data for clerkship grades, and 71 (61%) provided complete key word data. Key words describing overall performance were extremely heterogeneous, with a total of 72 used and great variation in the assignment of the top designation (median: 24% of students; range: 1%-60%). There was also great variation in the proportion of students awarded the top internal medicine clerkship grade (median: 29%; range: 2%-90%).The MSPE is a critical component of residency applications, yet data contained within MSPEs are incomplete and variable. Approximately half of U.S. medical schools do not follow AAMC guidelines for MSPEs.

  View details for PubMedID 26703411

• Changing outcomes after heart transplantation in patients with amyloid cardiomyopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Davis, M. K., Lee, P. H., Witteles, R. M. 2015; 34 (5): 658-666

  Abstract

  Amyloid cardiomyopathy (ACM) is associated with a poor prognosis. Previous reports have suggested unfavorable post-heart transplant (HT) survival in this population compared with other HT recipients.Data from the United Network for Organ Sharing (UNOS) registry were used to study outcomes among ACM patients undergoing HT in the modern era (Era 2, 2008 to 2013) as compared with the historical era (Era 1, 1987 to 2007).One hundred eighty-eight ACM patients underwent primary single-organ HT. Ninety-seven patients (51.6%) were transplanted in Era 1 and 91 (48.4%) in Era 2. ACM patients undergoing HT in Era 2 were older (p < 0.0001), had higher body mass index (p = 0.008) and longer ischemic times (p = 0.02), and were more likely to be African-American (p < 0.0001), UNOS Status 1A (p < 0.0001), male (p = 0.01) and highly sensitized (p < 0.0001) compared with those in Era 1. Compared with patients with other etiologies of restrictive cardiomyopathy (RCM; n = 339 in Era 1, n = 164 in Era 2), adjusted hazard ratios (HRs) for post-HT mortality of ACM were 2.08 (p < 0.0001) in Era 1 and 1.22 (p = not statistically significant) in Era 2. Adjusted HRs for mortality of ACM vs all other diagnoses (n = 36,334 in Era 1, n = 9,225 in Era 2) were 1.84 (p < 0.0001) in Era 1 and 1.38 (p = NS) in Era 2. Although post-HT survival did not change with time among non-ACM RCM patients, post-HT mortality was lower in Era 2 compared with Era 1 among ACM patients (HR 0.49, p = 0.03).Although historically associated with inferior survival, post-HT outcomes in ACM patients in the modern era are now approaching those of non-ACM patients. Changes in patients' demographics suggest that this may be related to improved patient selection, including an increased proportion of patients with transthyretin ACM. HT should be considered for appropriate candidates with ACM.

  View details for DOI 10.1016/j.healun.2014.09.006

  View details for PubMedID 25444369

• Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

  Abstract

  We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

  View details for DOI 10.1111/ajt.13025

  View details for PubMedID 25648766

• Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

  View details for DOI 10.1016/j.hrthm.2013.10.026

  View details for PubMedID 24121001

• Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Heidenreich, P. A., Lin, S., Knowles, J. W., Perez, M., Maddox, T. M., Ho, M. P., Rumsfeld, J. S., Sahay, A., Massie, B. M., Tsai, T. T., Witteles, R. M. 2013; 6 (6): 687-693

  Abstract

  Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.

  View details for DOI 10.1161/CIRCOUTCOMES.113.000199

  View details for Web of Science ID 000330362400017

  View details for PubMedID 24192569

• Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned? JOURNAL OF CLINICAL ONCOLOGY Witteles, R. M., Telli, M. 2012; 30 (16): 1916-1918

  View details for DOI 10.1200/JCO.2011.40.4012

  View details for Web of Science ID 000304596800010

  View details for PubMedID 22454419

• Use and overuse of left ventriculography AMERICAN HEART JOURNAL Witteles, R. M., Knowles, J. W., Perez, M., Morris, W. M., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. 2012; 163 (4): 617-?

  Abstract

  Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.

  View details for DOI 10.1016/j.ahj.2011.12.018

  View details for PubMedID 22520528

• Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

  Abstract

  Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

  View details for DOI 10.1016/j.healun.2011.09.010

  View details for PubMedID 22051505

• Chemotherapy-Associated Cardiotoxicity: How Often Does it Really Occur and How Can it Be Prevented? HEART FAILURE CLINICS Witteles, R. M., Fowler, M. B., Telli, M. L. 2011; 7 (3): 333-?

  Abstract

  Cardiotoxicity remains the limiting factor for many forms of cancer therapy and is the focus of growing research and clinical emphasis. This article outlines the current clinical evidence for left ventricular dysfunction and heart failure for the two most important classes of cardiotoxic chemotherapeutic agents, examines the potential pitfalls that have led to underestimated rates of left ventricular dysfunction from these agents, and reviews strategies for screening for and providing prophylaxis against chemotherapy-associated left ventricular dysfunction.

  View details for DOI 10.1016/j.hfc.2011.03.005

  View details for PubMedID 21749885

• Radiation Therapy for Breast Cancer Buyer Beware JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M. 2011; 57 (4): 453-454

  View details for DOI 10.1016/j.jacc.2010.08.637

  View details for Web of Science ID 000286376500011

  View details for PubMedID 21251586

• Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies Are Clinicians Responding Optimally? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yoon, G. J., Telli, M. L., Kao, D. P., Matsuda, K. Y., Carlson, R. W., Witteles, R. M. 2010; 56 (20): 1644-1650

  Abstract

  The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines.Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines.Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations.Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation.Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.

  View details for DOI 10.1016/j.jacc.2010.07.023

  View details for PubMedID 21050974

• Heart Failure in Hispanics JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vivo, R. P., Krim, S. R., Cevik, C., Witteles, R. M. 2009; 53 (14): 1167-1175

  Abstract

  Although large-scale heart failure (HF) studies in Hispanic Americans are lacking, some compelling data indicate that they are a particularly vulnerable population and underscore the need for further research. Hispanics comprise the largest and fastest-growing ethnic group in the U.S., in whom the impact of this burgeoning public health problem may be magnified. Current data show that Hispanics with HF are more likely to be younger and underinsured than non-Hispanic whites. They have higher rates of readmissions but have lower in-hospital and short-term mortality rates. Epidemiologic studies demonstrate that Hispanics have excessive rates of diabetes, obesity, dyslipidemia, and metabolic syndrome. Although hypertension and ischemic heart disease are established risk factors in this ethnic group, it may be considered that insulin resistance plays a significant role in the pathogenesis of HF in Hispanics, accounting for their inordinate cardiometabolic risk burden and the growing evidence of novel metabolic risk factors for HF. Hispanics encounter multiple barriers to health care influenced by socioeconomic, linguistic, and cultural factors that, in turn, have an adverse impact on disease prognosis. Recognition of predominant risk factors and health care disparities in this population is crucial to tailoring appropriate management strategies. This review summarizes epidemiologic and clinical data on Hispanics with HF, details risk factors and health care impediments, and presents an agenda for future investigation.

  View details for DOI 10.1016/j.jacc.2008.12.037

  View details for Web of Science ID 000264724500001

  View details for PubMedID 19341856

• Clinical problem-solving. Fool's Gold. New England journal of medicine Leeper, N. J., Dhaliwal, G., Saint, S., Witteles, R. M. 2008; 359 (19): 2035-2041

  View details for DOI 10.1056/NEJMcps0802668

  View details for PubMedID 18987372

• Insulin-resistant cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Fowler, M. B. 2008; 51 (2): 93-102

  Abstract

  Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.

  View details for DOI 10.1016/j.jacc.2007.10.021

  View details for PubMedID 18191731

• Impact of nesiritide on renal function in patients with acute decompensated failure an pre-existing renal dysfunction - A randomized, double-blind, placebo-controlled clinical trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Kao, D., Christopherson, D., Matsuda, K., Vagelos, R. H., Schreiber, D., Fowler, M. B. 2007; 50 (19): 1835-1840

  Abstract

  Our purpose was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure and baseline renal dysfunction.Although nesiritide is approved for the treatment of acute decompensated heart failure, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue.Consecutive patients with acute decompensated heart failure and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive nesiritide (0.01 microg/kg/min with or without a 2-microg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by > or =20% and change in serum creatinine.Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (-0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%).In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with acute decompensated heart failure. (BNP-CARDS trial; http://www.clinicaltrials.gov/ct/show/NCT00186329?order=1; NCT00186329).

  View details for DOI 10.1016/j.jacc.2007.03.071

  View details for PubMedID 17980248

• Cardiomyopathy of insulin resistance. Heart failure clinics Witteles, R. M., Fowler, M. B. 2006; 2 (1): 13-23

  View details for PubMedID 17386873

• Insulin resistance in idiopathic dilated cardiomyopathy - A possible etiologic link JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Tang, W. H., Jamali, A. H., Chu, J. W., Reaven, G. M., Fowler, M. B. 2004; 44 (1): 78-81

  Abstract

  This study was designed to quantify the prevalence of abnormal glucose tolerance and insulin resistance in patients with idiopathic dilated cardiomyopathy (IDCM).Insulin resistance is an independent risk factor for mortality in patients with heart failure (HF) and is a known risk factor for ischemic cardiomyopathy. Though potential physiologic links between insulin resistance and HF have been hypothesized, the relationship between insulin resistance and IDCM remains unclear.A total of 230 consecutive patients from a university HF clinic were screened for IDCM, the absence of diabetes mellitus, and the lack of significant co-morbid conditions. Oral glucose tolerance tests were performed in the 43 patients with IDCM who met these criteria, and their plasma glucose and insulin responses were compared with those of 40 healthy volunteers, matched for age, gender, and body mass index.Plasma glucose responses were higher during the oral glucose tolerance tests in patients with IDCM (p < 0.01), associated with significantly higher plasma insulin concentrations following the oral glucose challenge (p < 0.01). In addition, abnormalities of glucose tolerance were significantly (p < 0.05) more common in patients with IDCM (49% vs. 23%).Insulin resistance and abnormal glucose tolerance are more prevalent in patients with IDCM and represent potentially reversible metabolic derangements in these individuals.

  View details for DOI 10.1016/j.jacc.2004.03.037

  View details for PubMedID 15234411

• Constrictive Pericarditis Revealing Rare Case of ALH Amyloidosis With Underlying Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia). JACC. Case reports Ho, V. V., O'Sullivan, J. W., Collins, W. J., Ozdalga, E., Bell, C. F., Shah, N. D., Krishnam, M. S., Ozawa, M. G., Witteles, R. M. 2022; 4 (5): 271-275

  Abstract

  We present a case of pericardial amyloidosis with associated lymphoplasmacytic lymphoma in a patient with chronic worsening shortness of breath and cough. This case highlights the wide variation in the presentation of cardiac amyloidosis, and the rare occurrence of clinically significant light-chain and heavy-chain amyloidosis in the pericardium.(Level of Difficulty: Advanced.).

  View details for DOI 10.1016/j.jaccas.2022.01.007

  View details for PubMedID 35257101

• High-Throughput Precision Phenotyping of Left Ventricular Hypertrophy With Cardiovascular Deep Learning. JAMA cardiology Duffy, G., Cheng, P. P., Yuan, N., He, B., Kwan, A. C., Shun-Shin, M. J., Alexander, K. M., Ebinger, J., Lungren, M. P., Rader, F., Liang, D. H., Schnittger, I., Ashley, E. A., Zou, J. Y., Patel, J., Witteles, R., Cheng, S., Ouyang, D. 2022

  Abstract

  Importance: Early detection and characterization of increased left ventricular (LV) wall thickness can markedly impact patient care but is limited by under-recognition of hypertrophy, measurement error and variability, and difficulty differentiating causes of increased wall thickness, such as hypertrophy, cardiomyopathy, and cardiac amyloidosis.Objective: To assess the accuracy of a deep learning workflow in quantifying ventricular hypertrophy and predicting the cause of increased LV wall thickness.Design, Settings, and Participants: This cohort study included physician-curated cohorts from the Stanford Amyloid Center and Cedars-Sinai Medical Center (CSMC) Advanced Heart Disease Clinic for cardiac amyloidosis and the Stanford Center for Inherited Cardiovascular Disease and the CSMC Hypertrophic Cardiomyopathy Clinic for hypertrophic cardiomyopathy from January 1, 2008, to December 31, 2020. The deep learning algorithm was trained and tested on retrospectively obtained independent echocardiogram videos from Stanford Healthcare, CSMC, and the Unity Imaging Collaborative.Main Outcomes and Measures: The main outcome was the accuracy of the deep learning algorithm in measuring left ventricular dimensions and identifying patients with increased LV wall thickness diagnosed with hypertrophic cardiomyopathy and cardiac amyloidosis.Results: The study included 23 745 patients: 12 001 from Stanford Health Care (6509 [54.2%] female; mean [SD] age, 61.6 [17.4] years) and 1309 from CSMC (808 [61.7%] female; mean [SD] age, 62.8 [17.2] years) with parasternal long-axis videos and 8084 from Stanford Health Care (4201 [54.0%] female; mean [SD] age, 69.1 [16.8] years) and 2351 from CSMS (6509 [54.2%] female; mean [SD] age, 69.6 [14.7] years) with apical 4-chamber videos. The deep learning algorithm accurately measured intraventricular wall thickness (mean absolute error [MAE], 1.2 mm; 95% CI, 1.1-1.3 mm), LV diameter (MAE, 2.4 mm; 95% CI, 2.2-2.6 mm), and posterior wall thickness (MAE, 1.4 mm; 95% CI, 1.2-1.5 mm) and classified cardiac amyloidosis (area under the curve [AUC], 0.83) and hypertrophic cardiomyopathy (AUC, 0.98) separately from other causes of LV hypertrophy. In external data sets from independent domestic and international health care systems, the deep learning algorithm accurately quantified ventricular parameters (domestic: R2, 0.96; international: R2, 0.90). For the domestic data set, the MAE was 1.7 mm (95% CI, 1.6-1.8 mm) for intraventricular septum thickness, 3.8 mm (95% CI, 3.5-4.0 mm) for LV internal dimension, and 1.8 mm (95% CI, 1.7-2.0 mm) for LV posterior wall thickness. For the international data set, the MAE was 1.7 mm (95% CI, 1.5-2.0 mm) for intraventricular septum thickness, 2.9 mm (95% CI, 2.4-3.3 mm) for LV internal dimension, and 2.3 mm (95% CI, 1.9-2.7 mm) for LV posterior wall thickness. The deep learning algorithm accurately detected cardiac amyloidosis (AUC, 0.79) and hypertrophic cardiomyopathy (AUC, 0.89) in the domestic external validation site.Conclusions and Relevance: In this cohort study, the deep learning model accurately identified subtle changes in LV wall geometric measurements and the causes of hypertrophy. Unlike with human experts, the deep learning workflow is fully automated, allowing for reproducible, precise measurements, and may provide a foundation for precision diagnosis of cardiac hypertrophy.

  View details for DOI 10.1001/jamacardio.2021.6059

  View details for PubMedID 35195663

• Developing Therapy for Transthyretin Amyloidosis. The American journal of medicine Campbell, C. M., Zhang, K., Lenihan, D. J., Witteles, R. 1800

  Abstract

  Transthyretin amyloidosis (ATTR) is an under-recognized cause of cardiomyopathy and neuropathy. Until recently, there were limited therapeutic options for ATTR. However, new therapeutics including tafamidis, patisiran, and inotersen increase both quality and length of life of patients with ATTR. This review details the chronological development of ATTR therapies through landmark clinical trials. In addition, we discuss emerging ATTR therapies including improvements in drug delivery methods, antibodies to break-down deposited amyloid fibrils, and gene-editing. ATTR is a prime example of how an understanding of the pathophysiological basis of disease can lead to effective therapies. The future of ATTR therapy is bright with every reason to believe outcomes will continue to improve.

  View details for DOI 10.1016/j.amjmed.2022.01.002

  View details for PubMedID 35077703

• The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity JACC: CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629–634

  View details for DOI 10.1016/j.jaccao.2022.08.012

• Ibrutinib-associated atrial fibrillation treatment with catheter ablation. HeartRhythm case reports Kapoor, R., Fazal, M., Cheng, P., Witteles, R., Rhee, J., Baykaner, T. 2021; 7 (11): 713-716

  View details for DOI 10.1016/j.hrcr.2021.08.003

  View details for PubMedID 34820264

• Misconceptions and Facts About Cardiac Amyloidosis. The American journal of cardiology Nguyen, F. D., Rodriguez Rivera, M., Krittanawong, C., Witteles, R., Lenihan, D. J. 2021

  Abstract

  Cardiac amyloidosis is an important clinical entity associated with significant morbidity and mortality. Although the signs and symptoms can be apparent early in the disease course, diagnoses are often made late because of inadequate recognition. A diagnosis of cardiac amyloidosis requires careful scrutiny of a patient's symptoms, an electrocardiogram, and imaging studies, including echocardiography and magnetic resonance imaging. Further evaluation is required through the measurement of serum and urine light chains and the use of bone scintigraphy imaging to differentiate transthyretin amyloidosis from light-chain cardiac amyloidosis. The available treatments have expanded tremendously in recent years and have improved outcomes in the population with this disorder. Thus, it has become increasingly important to diagnose cardiac amyloidosis and provide timely therapies. This article will clarify the various misconceptions about cardiac amyloidosis and provide a framework for primary care providers to better identify this disease in their practice.

  View details for DOI 10.1016/j.amjcard.2021.08.045

  View details for PubMedID 34610875

• Graded renal response criteria and revised renal progression criteria for light chain (AL) amyloidosis Muchtar, E., Wisniowski, B., Palladini, G., Milani, P., Merlini, G., Schonland, S., Veelkan, K., Hegenbart, U., Dispenzieri, A., Kumar, S., Leung, N., Kastritis, E., Dimopoulos, M., Liedtke, M., Witteles, R., Sanchorawala, V., Szalat, R., Landau, H., Lentzsch, S., Blade, J., Cibeira, M. T., Cohen, O., Foard, D., Wechalekar, A., Gertz, M. CIG MEDIA GROUP, LP. 2021: S23-S24

  View details for Web of Science ID 000717640800037

• Graded cardiac response criteria for AL amyloidosis: the impact of depth of cardiac response on survival Muchtar, E. Y., Dispenzieri, A., Wisniowski, B., Palladini, G., Milani, P., Merlini, G., Schonland, S., Veelkan, K., Hegenbart, U., Kumar, S., Kastritis, E., Dimopoulos, M., Liedtke, M., Witteles, R., Sanchorawala, V., Szalat, R., Landau, H., Lentzsch, S., Coltoff, A., Blade, J., Cibeira, M., Cohen, O., Foard, D., Wechalekar, A., Gertz, M. CIG MEDIA GROUP, LP. 2021: S24-S25

  View details for Web of Science ID 000717640800039

• Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Waliany, S., Zhu, H., Wakelee, H., Padda, S. K., Das, M., Ramchandran, K., Myall, N. J., Chen, T., Witteles, R. M., Neal, J. W. 2021

  Abstract

  INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.

  View details for DOI 10.1016/j.jtho.2021.07.030

  View details for PubMedID 34418561

• Corrigendum to 'TNF-alpha Inhibition for the Treatment of Cardiac Sarcoidosis' Seminars in Arthritis and Rheumatism. 2020 Jun;50(3):546-552. Seminars in arthritis and rheumatism Baker, M. C., Sheth, K., Witteles, R., Genovese, M. C., Shoor, S., Simard, J. F. 2021

  View details for DOI 10.1016/j.semarthrit.2021.05.009

  View details for PubMedID 34172273

• Racial and Ethnic Disparities in Cardio-Oncology A Call to Action JACC: CARDIOONCOLOGY Fazal, M., Malisa, J., Rhee, J., Witteles, R. M., Rodriguez, F. 2021; 3 (2): 201-204

  View details for DOI 10.1016/j.jaccao.2021.05.001

  View details for Web of Science ID 000662265700003

• Racial and Ethnic Disparities in Transthyretin Cardiac Amyloidosis. Current cardiovascular risk reports Spencer-Bonilla, G., Njoroge, J. N., Pearson, K., Witteles, R. M., Aras, M. A., Alexander, K. M. 2021; 15 (6)

  Abstract

  Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening disease that disproportionately affects older adults and people of African descent. This review discusses current knowledge regarding racial and ethnic disparities in the diagnosis and management of ATTR-CM.Historically, ATTR-CM was thought to be a rare cause of heart failure. Recent evidence has shown that ATTR-CM is more common among older adults, men, and people of African descent. In addition, significant geographic variation exists in the identification of amyloid cardiomyopathy. Despite the high burden of ATTR-CM among Black individuals, most clinical data for ATTR-CM are from North America and Europe. Moreover, only a minority of clinical trial participants thus far have been Black patients. In addition to racial differences, socioeconomic disparities may be further compounded by the potentially prohibitive cost and limited accessibility of disease-modifying ATTR therapies.ATTR-CM is an important cause of heart failure that disproportionately affects people of African descent. Efforts to promote earlier identification of ATTR-CM in general practice will likely improve clinical outcomes for all groups. Future trials should strive to enroll a higher proportion of Black patients. Furthermore, enhanced efforts are warranted to improve treatment accessibility among racial and ethnic minority groups that may be more likely to be affected by ATTR-CM.

  View details for DOI 10.1007/s12170-021-00670-y

  View details for PubMedID 35280930

  View details for PubMedCentralID PMC8916707

• Racial and Ethnic Disparities in Cardio-Oncology: A Call to Action. JACC. CardioOncology Fazal, M., Malisa, J., Rhee, J. W., Witteles, R. M., Rodriguez, F. 2021; 3 (2): 201-204

  View details for DOI 10.1016/j.jaccao.2021.05.001

  View details for PubMedID 34308372

  View details for PubMedCentralID PMC8301207

• Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC. CardioOncology Waliany, S., Neal, J. W., Reddy, S., Wakelee, H., Shah, S. A., Srinivas, S., Padda, S. K., Fan, A. C., Colevas, A. D., Wu, S. M., Witteles, R. M., Zhu, H. 2021; 3 (1): 137–39

  View details for DOI 10.1016/j.jaccao.2021.01.004

  View details for PubMedID 33796869

• Racial and Ethnic Disparities in Transthyretin Cardiac Amyloidosis Curr Cardiovasc Risk Rep Spencer-Bonilla, G., Njoroge, J. N., Pearson, K., Witteles, R. M., Aras, M. A., Alexander, K. M. 2021

  View details for DOI 10.1007/s12170-021-00670-y

• Cardiac Transplantation and Mechanical Circulatory Support in Amyloidosis. JACC. CardioOncology Witteles, R. M. 2021; 3 (4): 516-521

  View details for DOI 10.1016/j.jaccao.2021.05.007

  View details for PubMedID 34729523

  View details for PubMedCentralID PMC8543081

• Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey. JACC. CardioOncology Nativi-Nicolau, J., Siu, A., Dispenzieri, A., Maurer, M. S., Rapezzi, C., Kristen, A. V., Garcia-Pavia, P., LoRusso, S., Waddington-Cruz, M., Lairez, O., Witteles, R., Chapman, D., Amass, L., Grogan, M. 2021; 3 (4): 537-546

  Abstract

  Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations.This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS.Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy.There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015-2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%).In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745).

  View details for DOI 10.1016/j.jaccao.2021.08.009

  View details for PubMedID 34729526

  View details for PubMedCentralID PMC8543133

• Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury: Insights Into the SENECA Trial. JACC. CardioOncology O'Brien, C. G., Ozen, M. O., Ikeda, G., Vaskova, E., Jung, J. H., Bayardo, N., Santoso, M. R., Shi, L., Wahlquist, C., Jiang, Z., Jung, Y., Zeng, Y., Egan, E., Sinclair, R., Gee, A., Witteles, R., Mercola, M., Svensson, K. J., Demirci, U., Yang, P. C. 2021; 3 (3): 428-440

  Abstract

  Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification.The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients.Patient-specific iCMs were injured with 1 μmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system.iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy.L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs.

  View details for DOI 10.1016/j.jaccao.2021.05.006

  View details for PubMedID 34604804

  View details for PubMedCentralID PMC8463733

• Arrhythmia Patterns in Patients on Ibrutinib. Frontiers in cardiovascular medicine Fazal, M., Kapoor, R., Cheng, P., Rogers, A. J., Narayan, S. M., Wang, P., Witteles, R. M., Perino, A. C., Baykaner, T., Rhee, J. 1800; 8: 792310

  Abstract

  Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor (TKI) used primarily in the treatment of hematologic malignancies, has been associated with increased incidence of atrial fibrillation (AF), with limited data on its association with other tachyarrhythmias. There are limited reports that comprehensively analyze atrial and ventricular arrhythmia (VA) burden in patients on ibrutinib. We hypothesized that long-term event monitors could reveal a high burden of atrial and VAs in patients on ibrutinib. Methods: A retrospective data analysis at a single center using electronic medical records database search tools and individual chart review was conducted to identify consecutive patients who had event monitors while on ibrutinib therapy. Results: Seventy-two patients were included in the analysis with a mean age of 76.9 ± 9.9 years and 13 patients (18%) had a diagnosis of AF prior to the ibrutinib therapy. During ibrutinib therapy, most common arrhythmias documented were non-AF supraventricular tachycardia (n = 32, 44.4%), AF (n = 32, 44%), and non-sustained ventricular tachycardia (n = 31, 43%). Thirteen (18%) patients had >1% premature atrial contraction burden; 16 (22.2%) patients had >1% premature ventricular contraction burden. In 25% of the patients, ibrutinib was held because of arrhythmias. Overall 8.3% of patients were started on antiarrhythmic drugs during ibrutinib therapy to manage these arrhythmias. Conclusions: In this large dataset of ambulatory cardiac monitors on patients treated with ibrutinib, we report a high prevalence of atrial and VAs, with a high incidence of treatment interruption secondary to arrhythmias and related symptoms. Further research is warranted to optimize strategies to diagnose, monitor, and manage ibrutinib-related arrhythmias.

  View details for DOI 10.3389/fcvm.2021.792310

  View details for PubMedID 35047578

• Functional Capacity, Health-related Quality-of-life and Cardiac Biomarker Improvement with Tafamidis in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) Hanna, M., Fine, N., Stewart, M., Gundapaneni, B., Sultan, M. B., Witteles, R. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S65

  View details for Web of Science ID 000579889600171

• Temporal Trends of Wild-type Attr Amyloidosis in the Transthyretin Amyloidosis Outcomes Survey Nativi-Nicolau, J., Siu, A., Dispenzieri, A., Maurer, M. S., Rapezzi, C., Kristen, A., Garcia-Pavia, P., LoRusso, S., Waddington-Cruz, M., Lairez, O., Witteles, R., Chapman, D., Rill, D., Kiszko, J., Amass, L., Grogan, M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S82

  View details for Web of Science ID 000579889600216

• REPLY: Should We Be for ASCT? If Yes, Then When? JACC-HEART FAILURE Witteles, R. M., Barrett, C. D. 2020; 8 (8): 696–97

  View details for DOI 10.1016/j.jchf.2020.05.008

  View details for Web of Science ID 000555602900015

  View details for PubMedID 32731950

• Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Zhu, H., Lee, D., Sarah, W., Galdos, F. X., D'Addabbo, J., Fowler, M. B., Reddy, S., Heather, W., Neal, J. W., Witteles, R., Maecker, H. T., Davis, M., Nguyen, P. K., Wu, S. M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.350

  View details for Web of Science ID 000606541500116

• Cardiac Scintigraphy With Technetium-99m-Labeled Bone -Seeking Tracers for Suspected Amyloidosis JACC Review Topic of the Week JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hanna, M., Ruberg, F. L., Maurer, M. S., Dispenzieri, A., Dorbala, S., Falk, R. H., Hoffman, J., Jaber, W., Soman, P., Witteles, R. M., Grogan, M. 2020; 75 (22): 2851–62

  View details for Web of Science ID 000539419300012

• Cardiac Scintigraphy With Technetium-99m-Labeled Bone-Seeking Tracers for Suspected Amyloidosis: JACC Review Topic of the Week. Journal of the American College of Cardiology Hanna, M., Ruberg, F. L., Maurer, M. S., Dispenzieri, A., Dorbala, S., Falk, R. H., Hoffman, J., Jaber, W., Soman, P., Witteles, R. M., Grogan, M. 2020; 75 (22): 2851–62

  Abstract

  Technetium-labeled cardiac scintigraphy (i.e., Tc-PYP scan) has been repurposed for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Validated in cohorts of patients with heart failure and echocardiographic and/or cardiac magnetic resonance imaging findings suggestive of cardiac amyloidosis, cardiac scintigraphy can confirm the diagnosis of ATTR-CM only when combined with blood and urine testing to exclude a monoclonal protein. Multisocietal guidelines support the nonbiopsy diagnosis of ATTR-CM using cardiac scintigraphy, yet emphasize its use in the appropriate clinical context and the crucial need to rule out light chain amyloid cardiomyopathy. Although increased awareness of ATTR-CM and the advent of effective therapy have led to rapid adoption of diagnostic scintigraphy, there is heterogeneity in adherence to consensus guidelines. This perspective outlines clinical scenarios wherein findings on technetium-labeled cardiac scintigraphy have been misinterpreted, reviews causes of false-negative and false-positive results, and provides strategies to avoid costly and potentially fatal misdiagnoses.

  View details for DOI 10.1016/j.jacc.2020.04.022

  View details for PubMedID 32498813

• Correction to: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response. Current cardiology reports Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5): 36

  Abstract

  It has been pointed out that the second paragraph of the section "Treatments for SARS-CoV-2 Infection" contains an error. The original article has been corrected.

  View details for DOI 10.1007/s11886-020-01302-4

  View details for PubMedID 32405913

• A pilot study of F-18-FSPG SiPM-based PET/CT in patients referred for exclusion of active cardiac sarcoidosis and negative or non-diagnostic F-18-FDG PET/CT Duan, H., Hatami, N., Baratto, L., Davidzon, G., Aparici, C., Gambhir, S., Koglin, N., Witteles, R., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501539

• Portable Ultrasound Device Usage and Learning Outcomes Among Internal Medicine Trainees: A Parallel-Group Randomized Trial. Journal of hospital medicine Kumar, A., Weng, Y., Wang, L., Bentley, J., Almli, M., Hom, J., Witteles, R., Ahuja, N., Kugler, J. 2020; 15 (2): e1–e6

  Abstract

  BACKGROUND: Little is known about how to effectively train residents with point-of-care ultrasonography (POCUS) despite increasing usage.OBJECTIVE: This study aimed to assess whether handheld ultrasound devices (HUDs), alongside a year-long lecture series, improved trainee image interpretation skills with POCUS.METHODS: Internal medicine intern physicians (N = 149) at a single academic institution from 2016 to 2018 participated in the study. The 2017 interns (n = 47) were randomized 1:1 to receive personal HUDs (n = 24) for patient care vs no-HUDs (n = 23). All 2017 interns received a repeated lecture series regarding cardiac, thoracic, and abdominal POCUS. Interns were assessed on their ability to interpret POCUS images of normal/abnormal findings. The primary outcome was the difference in end-of-the-year assessment scores between interns randomized to receive HUDs vs not. Secondary outcomes included trainee scores after repeating lectures and confidence with POCUS. Intern scores were also compared with historical (2016, N = 50) and contemporaneous (2018, N = 52) controls who received no lectures.RESULTS: Interns randomized to HUDs did not have significantly higher image interpretation scores (median HUD score: 0.84 vs no-HUD score: 0.84; P = .86). However, HUD interns felt more confident in their abilities. The 2017 cohort had higher scores (median 0.84), compared with the 2016 historical control (median 0.71; P = .001) and 2018 contemporaneous control (median 0.48; P < .001). Assessment scores improved after first-time exposure to the lecture series, while repeated lectures did not improve scores.CONCLUSIONS: Despite feeling more confident, personalized HUDs did not improve interns' POCUS-related knowledge or interpretive ability. Repeated lecture exposure without further opportunities for deliberate practice may not be beneficial for mastering POCUS.

  View details for DOI 10.12788/jhm.3351

  View details for PubMedID 32118565

• Bone Scintigraphy Imaging for Transthyretin Cardiac Amyloidosis: Still Much to Learn. JACC. Cardiovascular imaging Alexander, K. M., Witteles, R. M. 2020

  View details for DOI 10.1016/j.jcmg.2019.11.011

  View details for PubMedID 31954652

• Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC family practice Gertz, M. n., Adams, D. n., Ando, Y. n., Beirão, J. M., Bokhari, S. n., Coelho, T. n., Comenzo, R. L., Damy, T. n., Dorbala, S. n., Drachman, B. M., Fontana, M. n., Gillmore, J. D., Grogan, M. n., Hawkins, P. N., Lousada, I. n., Kristen, A. V., Ruberg, F. L., Suhr, O. B., Maurer, M. S., Nativi-Nicolau, J. n., Quarta, C. C., Rapezzi, C. n., Witteles, R. n., Merlini, G. n. 2020; 21 (1): 198

  Abstract

  Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms.These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central.The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy.A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

  View details for DOI 10.1186/s12875-020-01252-4

  View details for PubMedID 32967612

• Letter regarding the article 'Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study'. European journal of heart failure Damy, T. n., Sultan, M. B., Witteles, R. n. 2020

  View details for DOI 10.1002/ejhf.2074

  View details for PubMedID 33340199

• Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a Position Statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. European journal of heart failure Lyon, A. R., Dent, S. n., Stanway, S. n., Earl, H. n., Brezden-Masley, C. n., Cohen-Solal, A. n., Tocchetti, C. G., Moslehi, J. n., Groarke, J. D., Bergler-Klein, J. n., Khoo, V. n., Tan, L. L., Anker, M. S., von Haehling, S. n., Maack, C. n., Pudil, R. n., Barac, A. n., Thavendirnathan, P. n., Ky, B. n., Neilan, T. G., Belenkov, Y. n., Rosen, S. D., Iakobishvili, Z. n., Sverdlov, A. L., Hajjar, L. A., Macedo, A. V., Manisty, C. n., Ciardiello, F. n., Farmakis, D. n., De Boer, R. A., Skouri, H. n., Suter, T. M., Cardinale, D. n., Witteles, R. M., Fradley, M. G., Herrmann, J. n., Cornell, R. F., Wechelaker, A. n., Mauro, M. J., Milojkovic, D. n., de Lavallade, H. n., Ruschitzka, F. n., Coats, A. J., Seferovic, P. M., Chioncel, O. n., Thum, T. n., Bauersachs, J. n., Andres, M. S., Wright, D. J., López-Fernández, T. n., Plummer, C. n., Lenihan, D. n. 2020

  Abstract

  This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.1920

  View details for PubMedID 32463967

• Organ responses with daratumumab therapy in previously treated AL amyloidosis. Blood advances Chung, A. n., Kaufman, G. P., Sidana, S. n., Eckhert, E. n., Schrier, S. L., Lafayette, R. A., Arai, S. n., Witteles, R. M., Liedtke, M. n. 2020; 4 (3): 458–66

  Abstract

  Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

  View details for DOI 10.1182/bloodadvances.2019000776

  View details for PubMedID 32027745

• Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response Curr Cardiol Rep Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5)

  View details for DOI 10.1007/s11886-020-01292-3

• Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020

  Abstract

  The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

  View details for DOI 10.1016/j.jchf.2019.12.013

  View details for PubMedID 32387068

• Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty. Current cardiology reports Cheng, P. n., Zhu, H. n., Witteles, R. M., Wu, J. C., Quertermous, T. n., Wu, S. M., Rhee, J. W. 2020; 22 (5): 34

  Abstract

  COronaVirus Disease 2019 (COVID-19) has spread at unprecedented speed and scale into a global pandemic with cardiovascular risk factors and complications emerging as important disease modifiers. We aim to review available clinical and biomedical literature on cardiovascular risks of COVID-19.SARS-CoV2, the virus responsible for COVID-19, enters the cell via ACE2 expressed in select organs. Emerging epidemiological evidence suggest cardiovascular risk factors are associated with increased disease severity and mortality in COVID-19 patients. Patients with a more severe form of COVID-19 are also more likely to develop cardiac complications such as myocardial injury and arrhythmia. The true incidence of and mechanism underlying these events remain elusive. Cardiovascular diseases appear intricately linked with COVID-19, with cardiac complications contributing to the elevated morbidity/mortality of COVID-19. Robust epidemiologic and biologic studies are urgently needed to better understand the mechanism underlying these associations to develop better therapies.

  View details for DOI 10.1007/s11886-020-01293-2

  View details for PubMedID 32350632

• Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure. Annual review of pharmacology and toxicology Waliany, S. n., Lee, D. n., Witteles, R. M., Neal, J. W., Nguyen, P. n., Davis, M. M., Salem, J. E., Wu, S. M., Moslehi, J. J., Zhu, H. n. 2020

  Abstract

  Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by lowering barriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pharmtox-010919-023451

  View details for PubMedID 32776859

• Long-Term Safety and Efficacy of AG10 in Patients With Transthyretin Amyloid Cardiomyopathy (ATTR-CM): Interim Analysis of the Ongoing Phase 2 Open-Label Extension Study Judge, D., Heitner, S. B., Falk, R. H., Grogan, M., Jacoby, D. L., Maurer, M. S., Selby, V. N., Shah, S. J., Witteles, R., Katz, L., Rao, S., Sinha, U., Fox, J. LIPPINCOTT WILLIAMS & WILKINS. 2019: E966–E967

  View details for Web of Science ID 000508228600009

• Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis Chung, A., Kaufman, G. P., Sidana, S., Eckhert, E., Schrier, S., Arai, S., Lafayette, R., Witteles, R., Liedtke, M. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-122152

  View details for Web of Science ID 000577160403100

• Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses Chung, A., Kaufman, G. P., Sidana, S., Iberri, D., Eckhert, E., Schrier, S., Lafayette, R., Arai, S., Witteles, R., Liedtke, M. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124981

  View details for Web of Science ID 000577160403156

• Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias. Cardiology clinics Alexander, K. M., Evangelisti, A., Witteles, R. M. 2019; 37 (4): 487–95

  Abstract

  Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management.

  View details for DOI 10.1016/j.ccl.2019.07.013

  View details for PubMedID 31587789

• Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor. JACC. CardioOncology Waliany, S., Sainani, K. L., Park, L. S., Zhang, C. A., Srinivas, S., Witteles, R. M. 2019; 1 (1): 24-36

  Abstract

  This study quantified the change in blood pressure (BP) during antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy, compared BPs between TKIs, and analyzed change in BP during antihypertensive therapy.TKIs targeting VEGF are associated with hypertension. The absolute change in BP during anti-VEGF TKI treatment is not well characterized outside clinical trials.A retrospective single-center study included patients with metastatic renal cell carcinoma who received anti-VEGF TKIs between 2007 and 2018. Mixed models analyzed 3,088 BPs measured at oncology clinics.In 228 patients (baseline systolic blood pressure [SBP] 130.2 ± 16.3 mm Hg, diastolic blood pressure [DBP] 76.8 ± 9.3 mm Hg), anti-VEGF TKIs were associated with mean increases in SBP of 8.5 mm Hg (p < 0.0001) and DBP of 6.7 mm Hg (p <0.0001). Of the anti-VEGF TKIs evaluated, axitinib was associated with the greatest BP increase, with an increase in SBP of 12.6 mm Hg (p < 0.0001) and in DBP of 10.3 mm Hg (p < 0.0001) relative to baseline. In pairwise comparisons between agents, axitinib was associated with greater SBPs than cabozantinib by 8.4 mm Hg (p = 0.004) and pazopanib by 5.1 mm Hg (p = 0.01). Subsequent anti-VEGF TKI courses were associated with small increases in DBP, but not SBP, relative to the first course. During anti-VEGF TKI therapy, calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest BP reductions, with decreases in SBP of 5.6 mm Hg (p < 0.0001) and 9.9 mm Hg (p = 0.007), respectively.Anti-VEGF TKIs are associated with increased BP; greatest increases are observed with axitinib. Calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest reductions in BP.

  View details for DOI 10.1016/j.jaccao.2019.08.012

  View details for PubMedID 34396159

  View details for PubMedCentralID PMC8352203

• AL Amyloidosis for the Cardiologist and Oncologist: Epidemiology, Diagnosis, and Management. JACC. CardioOncology Witteles, R. M., Liedtke, M. 2019; 1 (1): 117-130

  Abstract

  AL amyloidosis results from clonal production of immunoglobulin light chains, most commonly arising from a clonal plasma cell disorder. Once considered a nearly uniformly fatal disease, prognosis has improved markedly over the past 15 years, predominantly because of advances in light chain suppressive therapies. Cardiac deposition of amyloid fibrils is common, and the severity of cardiac involvement remains the primary driver of prognosis. Improvements in chemotherapy/immunotherapy have prompted a reassessment of the role of advanced cardiac therapies previously considered contraindicated in most patients, including the role of implantable cardioverter-defibrillators and cardiac transplantation. This state-of-the-art review highlights the current state of the field, including diagnosis, prognosis, and hematologic- and cardiac-specific therapies.

  View details for DOI 10.1016/j.jaccao.2019.08.002

  View details for PubMedID 34396169

  View details for PubMedCentralID PMC8352106

• Human-induced Pluripotent Stem Cell-derived Cardiomyocytes as a Model for Trastuzumab-Induced Cardiac Dysfunction Kitani, T., Ong, S., Lam, C. K., Rhee, J., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800463

• Efficacy and Safety of Tafamidis Doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) Hanna, M., Damy, T., Garcia-Pavia, P., Judge, D. P., Merlini, G., Maurer, M. S., Gundapaneni, B., Patterson, T. A., Schwartz, J. H., Sultan, M. B., Witteles, R. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2019: S77–S78

  View details for DOI 10.1016/j.cardfail.2019.07.220

  View details for Web of Science ID 000482698000206

• Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Judge, D. P., Heitner, S. B., Falk, R. H., Maurer, M. S., Shah, S. J., Witteles, R. M., Grogan, M., Selby, V. N., Jacoby, D., Hanna, M., Nativi-Nicolau, J., Patel, J., Rao, S., Sinha, U., Turtle, C. W., Fox, J. C. 2019; 74 (3): 285–95

  View details for DOI 10.1016/j.jacc.2019.03.012

  View details for Web of Science ID 000475459800003

• Grading cardiac response in AL amyloidosis: implications for relapse and survival BRITISH JOURNAL OF HAEMATOLOGY Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2019; 186 (1): 144–46

  View details for DOI 10.1111/bjh.15717

  View details for Web of Science ID 000472576700020

• Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer CIRCULATION Kitani, T., Ong, S., Lam, C., Rhee, J., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. 2019; 139 (21): 2451–65

  View details for DOI 10.1161/CIRCULATIONAHA.118.037357

  View details for Web of Science ID 000469018300014

• Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. Journal of the American College of Cardiology Judge, D. P., Falk, R. H., Maurer, M. S., Shah, S. J., Witteles, R. M., Grogan, M., Selby, V. N., Jacoby, D., Hanna, M., Nativi-Nicolau, J., Patel, J., Rao, S., Sinha, U., Turtle, C. W., Fox, J. C., Heitner, S. B. 2019

  Abstract

  BACKGROUND: Transthyretin (TTR) amyloidosis (ATTR) is an under-diagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for ATTR cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.OBJECTIVES: This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.METHODS: ATTR-CM, NYHA Class II-III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400mg, 800mg or placebo bid for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR and two established ex vivo assays (Fluorescent Probe Exclusion [FPE] and Western blot).RESULTS: AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by FPE of 92 ± 10% (mean±SD) at trough and 96 ± 9% at peak (both p<10-12 vs placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 mg and 800 mg respectively (both p<0.0001 vs placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects.CONCLUSIONS: AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A Phase 3 trial is planned.

  View details for PubMedID 30885685

• Doxycycline and Ursodiol for ATTR Amyloidosis: Not Ready for Prime Time JOURNAL OF CARDIAC FAILURE Witteles, R. M. 2019; 25 (3): 154–55

  View details for DOI 10.1016/j.cardfail.2019.01.014

  View details for Web of Science ID 000462807400003

• REPLY: Increasingly Recognized Role of Right Ventricle Assessment in Cardiac Amyloidosis JACC-HEART FAILURE Amsallem, M., Witteles, R., Haddad, F. 2019; 7 (3): 279–80

  View details for DOI 10.1016/j.jchf.2018.12.010

  View details for Web of Science ID 000460037600017

  View details for PubMedID 30819389

• Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients with Cardiac Sarcoidosis. Journal of cardiac failure Ning, N., Guo, H. H., Iagaru, A., Mittra, E., Fowler, M., Witteles, R. 2019

  Abstract

  BACKGROUND: Cardiac fluorodeoxyglucose positron emission tomography (FDG-PET) has emerged as a standard imaging modality for the diagnosis of cardiac sarcoidosis (CS); however, there is a scarcity of data on the use of serial FDG-PET to guide immunosuppressive therapy.OBJECTIVES: To report our experience in using serial FDG-PET for the diagnosis and management of patients with CS, focusing on its utility in ongoing immunosuppression management.METHODS: We studied consecutive patients with CS managed at Stanford University from 2010-2017. We evaluated our experience in using FDG-PET for diagnosis and guidance of immunosuppressive therapy titration in CS.RESULTS: Among 34 patients diagnosed with CS, 16 (47%), 12 (35%) and 14 (41%) patients presented with heart block, heart failure and ventricular arrhythmias, respectively. FDG-PET proved beneficial in the initial diagnosis in 21 (62%) patients. 128 FDG-PET scans were performed (median 3/patient). Ninety-four (73%) FDG-PET scans resulted in a change in therapy, with 42 (33%) FDG-PET scans instrumental for tapering prednisone. Among patients who were initiated on prednisone, the mean dose of prednisone at one year was 9.5 mg/day. Over a median follow-up of 2.3 years, 48% of patients were successfully weaned off of prednisone completely, and 20% were weaned to a maintenance dosage of 5-10 mg/day. During the follow-up period, transplant-free survival was 88%.CONCLUSIONS: The use of serial cardiac FDG-PET for the diagnosis and management of CS was critical for guiding immunosuppression management and resulted in low chronic steroid doses and good disease control within one year of diagnosis.

  View details for PubMedID 30825644

• Doxycycline and Ursodiol for ATTR Amyloidosis: Not Ready for Prime Time. Journal of cardiac failure Witteles, R. 2019

  View details for PubMedID 30726714

• Management of Cardiac Amyloidosis: Do's and Don'ts. The Canadian journal of cardiology Alexander, K. M., Witteles, R. M. 2019

  Abstract

  Cardiac amyloidosis is a potentially deadly disease characterized by progressive infiltration of amyloid fibrils, and it is increasingly recognized as an underdiagnosed but important cause of heart failure. Given its unique pathogenesis, there are key differences in the management of cardiac amyloidosis compared with other forms of heart failure. Moreover, the 2 common forms of cardiac amyloidosis, transthyretin and light-chain amyloidosis, are distinct entities with varying clinical manifestations and prognoses, leading to the need for tailored approaches to management. In the past decade, there have been many significant advances in the diagnosis and treatment of both forms of cardiac amyloidosis. For example, in selected cases, transthyretin cardiac amyloidosis can be diagnosed noninvasively with the use of bone scintigraphy imaging, avoiding the need for a biopsy. Effective, more targeted therapies have been developed for both transthyretin and light-chain amyloidosis. However, these treatments are much more effective in early stages of disease before significant end-organ amyloid deposition has occurred. Consequently, it is increasingly imperative that clinicians aggressively screen at-risk groups, identify early signs of disease, and initiate treatment. Finally, once thought to be ill advised, heart transplantation should be considered in carefully selected patients with end-stage cardiac amyloidosis, because transplant outcomes in these patients is now similar to other those for other cardiomyopathies. Given these and other recent changes in clinical practice, this article discusses several key considerations for the clinical care of patients with cardiac amyloidosis.

  View details for DOI 10.1016/j.cjca.2019.10.032

  View details for PubMedID 32033795

• TNF-alpha inhibition for the treatment of cardiac sarcoidosis. Seminars in arthritis and rheumatism Baker, M. C., Sheth, K. n., Witteles, R. n., Genovese, M. C., Shoor, S. n., Simard, J. F. 2019

  Abstract

  Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used for treating refractory cardiac sarcoidosis. There is a theoretical risk, however, that these therapies can worsen heart failure, and reports on efficacy and safety are lacking.We conducted a retrospective review of all cardiac sarcoidosis patients seen at Stanford University from 2009 to 2018. Data were collected on patient demographics, diagnostic testing, and treatment outcomes.We identified 77 cardiac sarcoidosis patients, of which 20 (26%) received TNF-α inhibitor treatment. The majority were treated for progressive heart failure or tachyarrhythmia, along with worsening imaging findings. All TNF-α inhibitor treated patients demonstrated meaningful benefit, as assessed by changes in advanced imaging, echocardiographic measures of cardiac function, and prednisone use.A large cohort (n = 77) of cardiac sarcoidosis patients has been treated at Stanford University. Roughly one-fourth of these patients (n = 20) received TNF-α inhibitors. Of these patients, none had worsening heart failure and all saw clinical benefit. These results help support the use of TNF-α inhibitors for the treatment of cardiac sarcoidosis based on real-world evidence and highlight the need for future prospective studies.

  View details for DOI 10.1016/j.semarthrit.2019.11.004

  View details for PubMedID 31806154

• Thrombophilia testing in the inpatient setting: impact of an educational intervention. BMC medical informatics and decision making Kwang, H. n., Mou, E. n., Richman, I. n., Kumar, A. n., Berube, C. n., Kaimal, R. n., Ahuja, N. n., Harman, S. n., Johnson, T. n., Shah, N. n., Witteles, R. n., Harrington, R. n., Shieh, L. n., Hom, J. n. 2019; 19 (1): 167

  Abstract

  Thrombophilia testing is frequently ordered in the inpatient setting despite its limited impact on clinical decision-making and unreliable results in the setting of acute thrombosis or ongoing anticoagulation. We sought to determine the effect of an educational intervention in reducing inappropriate thrombophilia testing for hospitalized patients.During the 2014 academic year, we implemented an educational intervention with a phase implementation design for Internal Medicine interns at Stanford University Hospital. The educational session covering epidemiology, appropriate thrombophilia evaluation and clinical rationale behind these recommendations. Their ordering behavior was compared with a contemporaneous control (non-medicine and private services) and a historical control (interns from prior academic year). From the analyzed data, we determined the proportion of inappropriate thrombophilia testing of each group. Logistic generalized estimating equations were used to estimate odds ratios for inappropriate thrombophilia testing associated with the intervention.Of 2151 orders included, 934 were deemed inappropriate (43.4%). The two intervention groups placed 147 orders. A pooled analysis of ordering practices by intervention groups revealed a trend toward reduction of inappropriate ordering (p = 0.053). By the end of the study, the intervention groups had significantly lower rates of inappropriate testing compared to historical or contemporaneous controls.A brief educational intervention was associated with a trend toward reduction in inappropriate thrombophilia testing. These findings suggest that focused education on thrombophilia testing can positively impact inpatient ordering practices.

  View details for DOI 10.1186/s12911-019-0889-6

  View details for PubMedID 31429747

• Genomics in medicine: a novel elective rotation for internal medicine residents. Postgraduate medical journal Geng, L. N., Kohler, J. N., Levonian, P. n., Bernstein, J. A., Ford, J. M., Ahuja, N. n., Witteles, R. n., Hom, J. n., Wheeler, M. n. 2019

  Abstract

  It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in 'Genomic Medicine and Undiagnosed Diseases' for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

  View details for DOI 10.1136/postgradmedj-2018-136355

  View details for PubMedID 31439813

• Human Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Breast Cancer Patients. Circulation Kitani, T. n., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A. n., Ma, N. n., Tian, L. n., Lee, J. n., Telli, M. L., Witteles, R. M., Sharma, A. n., Sayed, N. n., Wu, J. C. 2019

  Abstract

  Molecular targeted chemotherapies have been shown to significantly improve cancer patient outcomes, but often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype compared to cardiotoxicity induced by conventional chemotherapies.We employed the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing (RNA-seq) to further examine the effect of trastuzumab on iPSC-CMs. We also generated iPSCs from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro using patient-specific iPSC-CMs.We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-seq and subsequent functional analysis revealed mitochondrial dysfunction and altered cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment, compared to iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. Importantly, metabolic modulation with AMPK activators could avert the adverse effects induced by trastuzumab.Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

  View details for PubMedID 30866650

• Emerging Therapies for Transthyretin Cardiac Amyloidosis. Current treatment options in cardiovascular medicine Alexander, K. M., Evangelisti, A. n., Witteles, R. M. 2019; 21 (8): 40

  Abstract

  Transthyretin cardiac amyloidosis is an underdiagnosed, undertreated disease which is associated with significant morbidity and mortality. This review will discuss the recent advancements in novel therapies for transthyretin amyloidosis.In recent phase 3 clinical trials, transthyretin stabilizers (tafamidis) and transthyretin silencers (patisiran and inotersen) have proven to be effective therapies for various forms of transthyretin amyloidosis. Understanding the recent and upcoming clinical trials for transthyretin amyloidosis will be important for improving the management of this challenging disease.

  View details for DOI 10.1007/s11936-019-0743-2

  View details for PubMedID 31309347

• Grading cardiac response in AL amyloidosis: implications for relapse and survival. British journal of haematology Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2018

  View details for PubMedID 30569572

• Safety, Tolerability and Transthyretin Stabilization by AG10: A Phase 2, Randomized, Double-blind, Placebo-controlled Clinical Trial in Patients with Transthyretin Amyloid Cardiomyopathy and NYHA Class II/III Heart Failure Judge, D. P., Falk, R., Grogan, M., Heitner, S. B., Jacoby, D., Maurer, M., Selby, V. N., Shah, S. J., Witteles, R. M., Hanna, M., Patel, J., Nativi-Nicolau, J., Rao, S., Sinha, U., Fox, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2018: E770

  View details for Web of Science ID 000453713500038

• Graded Cardiac Response Correlates with Relapse and Survival in AL Amyloidosis Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113577

  View details for Web of Science ID 000454842804139

• Efficacy of Tafamidis in Transthyretin Amyloid Cardiomyopathy in the ATTR-ACT Trial: Sensitivity Analyses Further Support the Primary Results Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P., Merlini, G., Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Gottlieb, S. S., Berk, J. L., Lenihan, D. J., Hoffman, J. E., Hummel, S. L., Velazquez, E. J., Patterson, T. A., Sultan, M. B., Rapezzi, C. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2018: 813

  View details for DOI 10.1016/j.cardfail.2018.11.008

  View details for Web of Science ID 000452937400019

• Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. The New England journal of medicine Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018

  Abstract

  Background Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. Conclusions In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

  View details for PubMedID 30145929

• 18F-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition. EJNMMI research Baratto, L., Park, S. Y., Hatami, N., Gulaka, P., Vasanawala, S., Yohannan, T. K., Herfkens, R., Witteles, R., Iagaru, A. 2018; 8 (1): 66

  Abstract

  BACKGROUND: Florbetaben, a 18F-labeled stilbene derivative (Neuraceq, formerly known as BAY-949172), is a diagnostic radiopharmaceutical developed to visualize beta-amyloid plaques in the brain. Here, we report a pilot study evaluating patients with suspected cardiac amyloidosis for systemic extent of disease.METHODS: We prospectively enrolled nine patients, 61-86year old (mean±SD 69.4±8.6), referred from the cardiac amyloid clinic. First, dynamic imaging of the heart was acquired immediately after injection of 222-318.2MBq (mean±SD 270.1±33.3) of 18F-florbetaben using the GE SIGNA PET/MRI. This was followed by a whole-body PET/MRI scan 60-146.4min (mean±SD 98±33.4) after injection. Cardiac MRI sequences included ECG-triggered cine SSFP, T2-weighted, and late gadolinium-enhanced imaging. Whole-body MRI sequences included MRAC and axial T1-weighted imaging.RESULTS: High early uptake and delayed high uptake in the left ventricle correlated with amyloid deposition in five patients, while low uptake on early and delayed cardiac imaging was noted in four patients. Cardiac function measurements were successfully obtained in all participants. Areas of increased abnormal 18F-florbetaben accumulation were noted on delayed whole-body imaging in the bone marrow (seven patients), stomach (diffuse in five patients and focal in one patient), brain (five patients), salivary glands (three patients), tongue (three patients), spleen (three patients), skeletal muscles (three patients), ocular muscles (two patients), thyroid (two patients), pleura (two patients), kidneys (two patients), and lungs (two patients).CONCLUSIONS: Whole-body 18F-florbetaben PET/MRI is promising for localization of systemic amyloid deposition. This technique may provide important structural and functional information regarding the organs involved by disease, with potential to guide biopsy and evaluate response to treatment.TRIAL REGISTRATION: Clinicaltrials.gov registration: NCT03119558 .

  View details for PubMedID 30043115

• F-18-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition EJNMMI RESEARCH Baratto, L., Park, S., Hatami, N., Gulaka, P., Vasanawala, S., Yohannan, T., Herfkens, R., Witteles, R., Iagaru, A. 2018; 8

  View details for DOI 10.1186/s13550-018-0425-1

  View details for Web of Science ID 000439657200001

• SERIAL CARDIAC FDG-PET IN THE DIAGNOSIS AND THERAPEUTIC GUIDANCE OF PATIENTS WITH CARDIAC SARCOIDOSIS: A STANFORD EXPERIENCE Ning, N., Guo, H. H., Jagaru, A., Mittra, E., Fowler, M., Witteles, R. ELSEVIER SCIENCE INC. 2018: 1690

  View details for DOI 10.1016/S0735-1097(18)32231-9

  View details for Web of Science ID 000429659703340

• Atrial Septal Defect as Unexpected Cause of Pulmonary Artery Hypertension TEXAS HEART INSTITUTE JOURNAL Parikh, R., Boyd, J., Lee, D. P., Witteles, R. 2018; 45 (1): 42–44

  Abstract

  Methamphetamine abuse is an increasingly prevalent cause of pulmonary artery hypertension in the United States. Conversely, an atrial septal defect rarely presents late as pulmonary artery hypertension. We present the case of a 44-year-old methamphetamine abuser who had a 3-month history of worsening fatigue and near-syncope. She had elevated cardiac enzyme levels and right-sided heart strain. Angiographic findings suggested methamphetamine-induced pulmonary artery hypertension; however, we later heard S2 irregularities that raised suspicion of an atrial septal defect. Ultimately, the diagnosis was pulmonary artery hypertension and a large secundum atrial septal defect with left-to-right flow. One year after defect closure, the patient was asymptomatic. In addition to discussing this unexpected case of a secundum atrial septal defect masquerading as methamphetamine-induced pulmonary artery hypertension, we briefly review the natural history of atrial septal defects and emphasize the importance of thorough examination in avoiding diagnostic anchoring bias.

  View details for DOI 10.14503/THIJ-17-6208

  View details for Web of Science ID 000426402700011

  View details for PubMedID 29556152

  View details for PubMedCentralID PMC5832086

• A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback POSTGRADUATE MEDICAL JOURNAL Hom, J., Kumar, A., Evans, K. H., Svec, D., Richman, I., Fang, D., Smeraglio, A., Holubar, M., Johnson, T., Shah, N., Renault, C., Ahuja, N., Witteles, R., Harman, S., Shieh, L. 2017; 93 (1106): 725–29

  View details for DOI 10.1136/postgradmedj-2016-134617

  View details for Web of Science ID 000416160200005

• Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor A Case Report PANCREAS Gerson, J. N., Witteles, R. M., Chang, D. T., Beygui, R. E., Iagaru, A. H., Kunz, P. L. 2017; 46 (10): 1381–85

  Abstract

  Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.

  View details for PubMedID 29040196

• Epidemiology and Clinical Implications of Gastrointestinal Symptoms in Systemic Amyloidosis Yen, T., Chen, F., Witteles, R., Liedtke, M., Nguyen, L. NATURE PUBLISHING GROUP. 2017: S240

  View details for Web of Science ID 000439259001037

• Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis BLOOD Kaufman, G. P., Schrier, S. L., Lafayette, R. A., Arai, S., Witteles, R. M., Liedtke, M. 2017; 130 (7): 900–902

  Abstract

  The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

  View details for PubMedID 28615223

• WHOLE HEART OF THE MATTER Parikh, R., Boyd, J., Lee, D., Witteles, R. ELSEVIER SCIENCE INC. 2017: 2411

  View details for Web of Science ID 000397342303333

• A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback. Postgraduate medical journal Hom, J. n., Kumar, A. n., Evans, K. H., Svec, D. n., Richman, I. n., Fang, D. n., Smeraglio, A. n., Holubar, M. n., Johnson, T. n., Shah, N. n., Renault, C. n., Ahuja, N. n., Witteles, R. n., Harman, S. n., Shieh, L. n. 2017

  Abstract

  Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns.Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self-reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments.The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001).We successfully implemented a novel high value care curriculum that specifically targets intern physicians.

  View details for PubMedID 28663352

• Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M. n., Kobayashi, Y. n., Wheeler, M. n., Barrett, C. n., Liedtke, M. n., Lafayette, R. n., Schrier, S. n., Haddad, F. n., Witteles, R. n. 2017; 120 (8): 1381–86

  Abstract

  Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

  View details for PubMedID 28844519

• A 15-year review of the Stanford Internal Medicine Residency Program: predictors of resident satisfaction and dissatisfaction ADVANCES IN MEDICAL EDUCATION AND PRACTICE Kahn, J. S., Witteles, R. M., Mahaffey, K. W., Desai, S. A., Ozdalga, E., Heidenreich, P. A. 2017; 8: 559–66

  Abstract

  Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment.We surveyed former IM residents from the training program held during the years 2000-2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience.Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (±4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers.The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences.

  View details for PubMedID 28814910

• Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab Kaufman, G., Witteles, R., Wheeler, M., Ulloa, P., Lugtu, M., Arai, S., Schrier, S., Lafayette, R., Liedtke, M. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452505077

• Prevalence and Financial Impact of Inappropriate Thrombophilia Testing in the Inpatient Hospital Setting: A Retrospective Analysis Mou, E., Kwang, H., Hom, J., Shieh, L., Ahuja, N., Harman, S., Johnson, T., Kumar, A., Shah, N., Witteles, R., Berube, C. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452508066

• The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? ACADEMIC MEDICINE Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534–39

  View details for DOI 10.1097/ACM.0000000000001034

  View details for Web of Science ID 000387208300024

• Accreditation Council for Graduate Medical Education (ACGME) Milestones-Time for a Revolt? JAMA internal medicine Witteles, R. M., Verghese, A. 2016; 176 (11): 1599-1600

  View details for DOI 10.1001/jamainternmed.2016.5552

  View details for PubMedID 27668812

• A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 2016; 11 (9): 646-649

  Abstract

  The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.

  View details for DOI 10.1002/jhm.2590

  View details for PubMedID 27079160

• Patient Outcomes when Housestaff Exceed 80 Hours per Week. American journal of medicine Ouyang, D., Chen, J. H., Krishnan, G., Hom, J., Witteles, R., Chi, J. 2016; 129 (9): 993-999 e1

  Abstract

  It has been posited that high workload and long work hours for trainees could affect the quality and efficiency of patient care. Duty hour restrictions seek to balance patient care and resident education by limiting resident work hours. Through a retrospective cohort study, we investigate whether patient care on an inpatient general medicine service at a large academic medical center is impacted when housestaff work greater than eighty hours per week METHODS: We identified all admissions to a housestaff-run general medicine service between June 25, 2013 and June 29, 2014. Each hospitalization was classified by whether or not the patient was admitted by housestaff who have worked more than eighty hours a week during their hospitalization. Housestaff computer activity and duty hours were calculated by institutional electronic heath record audit, as well as length of stay and a composite of in-hospital mortality, ICU transfer rate, and 30-day readmission rate.We identified 4,767 hospitalizations by 3,450 unique patients; of which 40.9% of hospitalizations were managed by housestaff who worked more than eighty hours that week during their hospitalization. There was a significantly higher rate of the composite outcome (19.2% vs. 16.7%, p = 0.031) for patients admitted by housestaff working more than eighty hours a week during their hospitalization. We found a statistically significant higher length of stay (5.12 vs. 4.66 days, p = 0.048) and rate of ICU transfer (3.18% vs. 2.38%, p = 0.029). There was no statistically significant difference in 30-day readmission rate (13.7% vs. 12.8%, p = 0.395), or in-hospital mortality rate (3.18% vs. 2.42%, p = 0.115).There was no correlation with team census on admission and patient outcomes.Patients taken care of by housestaff working more than eighty hours a week had increased length of stay and number of ICU transfers. There was no association between resident work-hours and patient in-hospital mortality or 30-day readmission rate.

  View details for DOI 10.1016/j.amjmed.2016.03.023

  View details for PubMedID 27103047

• Genotype and Phenotype of Transthyretin Cardiac Amyloidosis THAOS (Transthyretin Amyloid Outcome Survey) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Maurer, M. S., Hanna, M., Grogan, M., Dispenzieri, A., Witteles, R., Drachman, B., Judge, D. P., Lenihan, D. J., Gottlieb, S. S., Shah, S. J., Steidley, D. E., Ventura, H., Murali, S., Silver, M. A., Jacoby, D., Fedson, S., Hummel, S. L., Kristen, A. V., Damy, T., Plante-Bordeneuve, V., Coelho, T., Mundayat, R., Suhr, O. B., Cruz, M. W., Rapezzi, C. 2016; 68 (2): 161-172

  Abstract

  Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

  View details for DOI 10.1016/j.jacc.2016.03.596

  View details for Web of Science ID 000379123800005

  View details for PubMedCentralID PMC4940135

• Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). Journal of the American College of Cardiology Maurer, M. S., Hanna, M., Grogan, M., Dispenzieri, A., Witteles, R., Drachman, B., Judge, D. P., Lenihan, D. J., Gottlieb, S. S., Shah, S. J., Steidley, D. E., Ventura, H., Murali, S., Silver, M. A., Jacoby, D., Fedson, S., Hummel, S. L., Kristen, A. V., Damy, T., Planté-Bordeneuve, V., Coelho, T., Mundayat, R., Suhr, O. B., Waddington Cruz, M., Rapezzi, C. 2016; 68 (2): 161-172

  Abstract

  Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

  View details for DOI 10.1016/j.jacc.2016.03.596

  View details for PubMedID 27386769

  View details for PubMedCentralID PMC4940135

• Biomarkers as Predictors of Cardiac Toxicity From Targeted Cancer Therapies JOURNAL OF CARDIAC FAILURE Witteles, R. M. 2016; 22 (6): 459-464

  Abstract

  Cardiac biomarkers have been extensively investigated as early detectors of cardiac toxicity from cancer therapies. Whereas the role of biomarkers in monitoring anthracycline toxicity is generally well understood, substantial uncertainty remains regarding their role in monitoring newer targeted cancer therapies.This review article examines all major published studies using cardiac troponins and/or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in monitoring for cardiac toxicity with trastuzumab, tyrosine kinase inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. There is substantial variability among studies regarding biomarker assays used, sensitivity of the assays, and definitions of abnormal results. In general, troponin I predicts early but not late cardiac events when trastuzumab is administered after anthracyclines, but troponin increases likely reflect anthracycline injury rather than trastuzumab injury. NT-proBNP detects cardiac toxicity with tyrosine kinase inhibitors and mTOR inhibitors, but not independently from echocardiography.Troponin I can serve as a marker for susceptibility to cardiac toxicity during early trastuzumab treatment in patients who have received recent anthracyclines. NT-proBNP can serve as a useful marker of cardiac toxicity in patients treated with tyrosine kinase inhibitors or mTOR inhibitors if echocardiographic screening is not being used.

  View details for DOI 10.1016/j.cardfail.2016.03.016

  View details for PubMedID 27038641

• Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556

  Abstract

  Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

  View details for DOI 10.1038/nm.4087

  View details for PubMedID 27089514

• Response to Letter Regarding Article, "Myocardial Protection During Cardiotoxic Chemotherapy" CIRCULATION Witteles, R. M., Bosch, X. 2016; 133 (15): E598

  View details for PubMedID 27067094

• Myocardial Protection During Cardiotoxic Chemotherapy CIRCULATION Witteles, R. M., Bosch, X. 2015; 132 (19): 1835–45

  View details for PubMedID 26553713

• FROM PALPITATIONS TO CARDIOVASCULAR COLLAPSE: THE STORY OF A PHEOCHROMOCYTOMA Flint, K. M., Witteles, R. ELSEVIER SCIENCE INC. 2015: A618

  View details for DOI 10.1016/S0735-1097(15)60618-0

  View details for Web of Science ID 000375328800619

• Radiation-induced heart disease: an under-recognized entity? Current treatment options in cardiovascular medicine Davis, M., Witteles, R. M. 2014; 16 (6): 317-?

  Abstract

  Radiation-induced heart disease (RIHD) represents a spectrum of cardiovascular disease in patients who have undergone mediastinal, thoracic, or breast radiotherapy (RT). RIHD may involve any cardiac structure and is a major cause of morbidity and mortality in cancer survivors. While large cohort studies have demonstrated that symptomatic RIHD is a common late finding in this population, the incidence of asymptomatic disease is likely to be even higher. Long-term follow-up with regular screening for RIHD plays an important role in the management of cancer survivors who have undergone RT. Aggressive modification of traditional cardiovascular risk factors such as hypertension, dyslipidemia, and cigarette smoking is essential in patients at risk for RIHD, as these have been shown to potentiate the risks of radiation. In patients with symptomatic RIHD, medical and/or percutaneous therapies are often preferable to surgical interventions in view of the increased surgical risk associated with radiation damage to surrounding tissues. Percutaneous revascularization should generally be favored over surgical revascularization. Transcatheter valve replacements have not been widely used in this population but may offer an alternative to high-risk surgical valve procedures. Pericardiectomy is usually associated with extremely poor short-term and long-term outcomes in patients with RIHD and should be avoided in most cases. Heart transplantation is also higher risk in patients with RIHD than in patients with other etiologies of heart failure, but may be considered in young patients without other comorbidities.

  View details for DOI 10.1007/s11936-014-0317-2

  View details for PubMedID 24756471

• Reply to "heart failure and breast cancer: emerging controversies regarding some cardioprotective strategies". Journal of cardiac failure Witteles, R. M., Thakur, A. 2014; 20 (6): 457-?

  View details for DOI 10.1016/j.cardfail.2014.04.015

  View details for PubMedID 24747785

• Cancer therapy-induced left ventricular dysfunction: interventions and prognosis. Journal of cardiac failure Thakur, A., Witteles, R. M. 2014; 20 (3): 155-158

  Abstract

  For multiple chemotherapeutics, cardiotoxicity is dose limiting and can lead to substantial morbidity and mortality. Early cardiac intervention has the potential to positively affect clinical course.We reviewed 247 consecutive patients referred to the Stanford cardiology clinic for cancer therapy-associated cardiac abnormalities from 2004 to 2012. A comprehensive review of records was performed, with documentation of baseline characteristics, cardiac imaging, medications, and clinical course. Seventy-nine patients who had left ventricular ejection fraction (LVEF) declines temporally associated with cancer therapy were included. The most common malignancies were breast (46%) and hematologic (35%); 71% of the patients were female, and overall mean age was 52 years. The primary cancer therapeutics associated with LVEF decline included anthracyclines, trastuzumab, and tyrosine kinase inhibitors. The mean LVEF was 60% before cancer therapy and 40% after cancer therapy. The most common cardiac interventions included beta-blockers (84%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (83%). Mean LVEF after cardiac intervention rose to 53%; 77% of patients had LVEF recovery to ≥50%, and 68% of these patients had recovery within 6 months of starting cardiac therapy; 76% of patients were able to continue their planned cancer therapy.With appropriate cardiac intervention, the majority of patients with LVEF decline from cancer therapy can achieve LVEF recovery and complete their cancer therapy.

  View details for DOI 10.1016/j.cardfail.2013.12.018

  View details for PubMedID 24378722

• Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

  Abstract

  Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

  View details for DOI 10.3324/haematol.2013.084574

  View details for PubMedID 23716538

• Chemotherapy-Induced Left Ventricular Dysfunction: Interventions and Prognosis Thakur, A., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2013: S86–S87

  View details for DOI 10.1016/j.cardfail.2013.06.277

  View details for Web of Science ID 000323142500253

• AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997

  Abstract

  The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

  View details for DOI 10.1073/pnas.1300761110

  View details for Web of Science ID 000320930100085

  View details for PubMedID 23716704

• The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

  Abstract

  The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

  View details for DOI 10.1111/bjh.12269

  View details for PubMedID 23432783

• Development of a reproducible FDG PET/CT cardiac imaging protocol for the evaluation of cardiac sarcoidosis Kulm, J., Mittra, E., Guo, H., Witteles, R., Quon, A. SOC NUCLEAR MEDICINE INC. 2013

  View details for Web of Science ID 000209478700154

• Cardiac Testing to Manage Cardiovascular Risk in Cancer Patients SEMINARS IN ONCOLOGY Davis, M., Witteles, R. M. 2013; 40 (2): 147-155

  Abstract

  Cardiovascular toxicity is one of the most feared complications of cancer treatment. Recent advances in oncologic therapies have resulted in improved cancer outcomes but also a new set of cardiovascular adverse effects. Common toxicities include left ventricular dysfunction/heart failure, hypertension, and myocardial ischemia. Accurate risk stratification allows avoidance of potentially harmful treatments in those patients at greatest risk while maintaining the ability to deliver high doses of effective therapies to the lower-risk population. Cardiac investigations, including echocardiography, nuclear imaging, magnetic resonance imaging, biomarker measurement, blood pressure monitoring, electrocardiography, stress testing, and invasive angiography, can help to risk-stratify selected patients. In this review, common complications are discussed in terms of the factors used to identify patients with elevated risk, the monitoring strategies available, and selected interventions that have been used to modify outcomes in patients identified as being at high risk for cardiac complications of cancer treatment.

  View details for DOI 10.1053/j.seminoncol.2013.01.003

  View details for PubMedID 23540740

• The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients. JACC. Heart failure Hall, P. S., Harshman, L. C., Srinivas, S., Witteles, R. M. 2013; 1 (1): 72-78

  Abstract

  The purpose of this study was to document the incidence and extent of cardiovascular toxicity among advanced renal cell carcinoma patients treated with newer targeted cancer agents.The potential for targeted cancer agents to induce cardiovascular toxicity has been increasingly recognized, but the overall incidence and extent of toxicity have not been well characterized. Early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.The incidence of hypertension, left ventricular dysfunction, and heart failure was assessed for all advanced renal cell carcinoma patients treated with targeted therapies at our institution between 2004 and 2011. Grading was performed according to the Common Terminology Criteria for Adverse Events version 4.0.Cardiovascular toxicity developed in 116 of 159 patients (73%), including 52 of 159 patients (33%) when hypertension was excluded. Toxicity varied from occurrences of asymptomatic drops in left ventricular ejection fraction to rises in N-terminal-pro-B-type natriuretic peptide to severe heart failure. The tyrosine kinase inhibitor sunitinib was the agent most frequently used, with 66 of 101 sunitinib-treated patients (65%) developing a form of cardiovascular toxicity, including 32 of 101 patients (32%), excluding hypertension. Other VEGF inhibitors such as bevacizumab, sorafenib, and pazopanib also elicited significant cardiovascular toxicity with incidences ranging from 51% to 68%.The frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies are high.

  View details for DOI 10.1016/j.jchf.2012.09.001

  View details for PubMedID 24621801

• The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JACC-HEART FAILURE Hall, P. S., Harshman, L. C., Srinivas, S., Witteles, R. M. 2013; 1 (1): 72-78

  Abstract

  The purpose of this study was to document the incidence and extent of cardiovascular toxicity among advanced renal cell carcinoma patients treated with newer targeted cancer agents.The potential for targeted cancer agents to induce cardiovascular toxicity has been increasingly recognized, but the overall incidence and extent of toxicity have not been well characterized. Early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.The incidence of hypertension, left ventricular dysfunction, and heart failure was assessed for all advanced renal cell carcinoma patients treated with targeted therapies at our institution between 2004 and 2011. Grading was performed according to the Common Terminology Criteria for Adverse Events version 4.0.Cardiovascular toxicity developed in 116 of 159 patients (73%), including 52 of 159 patients (33%) when hypertension was excluded. Toxicity varied from occurrences of asymptomatic drops in left ventricular ejection fraction to rises in N-terminal-pro-B-type natriuretic peptide to severe heart failure. The tyrosine kinase inhibitor sunitinib was the agent most frequently used, with 66 of 101 sunitinib-treated patients (65%) developing a form of cardiovascular toxicity, including 32 of 101 patients (32%), excluding hypertension. Other VEGF inhibitors such as bevacizumab, sorafenib, and pazopanib also elicited significant cardiovascular toxicity with incidences ranging from 51% to 68%.The frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies are high.

  View details for DOI 10.1016/j.jchf.2012.09.001

  View details for Web of Science ID 000209535300010

• Broken Heart Syndrome (Takotsubo Cardiomyopathy) Triggered by Acute Mania: A Review and Case Report PSYCHOSOMATICS Maldonado, J. R., Pajouhi, P., Witteles, R. 2013; 54 (1): 74-79

  View details for PubMedID 22795622

• Capecitabine-Induced Chest Pain Relieved by Diltiazem AMERICAN JOURNAL OF CARDIOLOGY Ambrosy, A. P., Kunz, P. L., Fisher, G. A., Witteles, R. M. 2012; 110 (11): 1623-1626

  Abstract

  Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed.

  View details for DOI 10.1016/j.amjcard.2012.07.026

  View details for PubMedID 22939579

• Dipeptidyl Peptidase 4 Inhibition Increases Myocardial Glucose Uptake in Nonischemic Cardiomyopathy JOURNAL OF CARDIAC FAILURE Witteles, R. M., Keu, K. V., Quon, A., Tavana, H., Fowler, M. B. 2012; 18 (10): 804-809

  Abstract

  Glucose and fatty acids comprise the primary substrates for myocardial energy metabolism. The normal myocardium switches toward glucose metabolism in the setting of stress; the inability to affect such a switch is a fundamental mechanism behind "diabetic" or "insulin-resistant" cardiomyopathy. The purpose of this mechanistic study was to evaluate the effects of treatment with the dipeptidyl peptidase (DPP) 4 inhibitor sitagliptin on myocardial glucose uptake in patients with nonischemic cardiomyopathy.Twelve nondiabetic subjects with nonischemic cardiomyopathy underwent metabolic testing and assessment of myocardial glucose uptake by (18)F-fluorodeoxyglucose positron-emission tomographic/computerized tomographic imaging at baseline and after 4 weeks of sitagliptin therapy. Sitagliptin therapy resulted in a significant increase in myocardial glucose uptake (19% increase; P = .04). Although most patients had at least a slight increase in glucose uptake, there was an overall bimodal response, with 6 patients ("responders") demonstrating large increases (>20%) in glucose uptake and 6 patients ("nonresponders") demonstrating <5% increases or slight decreases. Triglyceride-high-density lipoprotein ratios significantly dropped in the 6 responders compared with the 6 nonresponders (P < .02).Therapy with the DPP-4 inhibitor sitagliptin results in increased myocardial glucose uptake in nondiabetic patients with nonischemic cardiomyopathy.

  View details for DOI 10.1016/j.cardfail.2012.07.009

  View details for PubMedID 23040117

• Therapy With a DPP-4 Inhibitor Increases Myocardial Glucose Uptake in Nonischemic Cardiomyopathy Witteles, R. M., Keu, K. V., Quon, A., Tavana, H., Fowler, M. B. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2012: S10

  View details for DOI 10.1016/j.cardfail.2012.06.030

  View details for Web of Science ID 000307679700027

• Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Hall, P. S., Witteles, R., Srinivas, S., Harshman, L. C. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803091

• More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

  View details for PubMedID 22652951

• Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45–S46

  View details for Web of Science ID 000293938700145

• Treating Asymptomatic Chemotherapy-Induced Cardiac Dysfunction A Chance That Cardiologists and Oncologists Should Not Miss Reply JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Yoon, G., Telli, M., Kao, D. P., Matsuda, K. Y., Carlson, R. W. 2011; 57 (17): 1790-1791

  View details for DOI 10.1016/j.jacc.2011.01.016

  View details for Web of Science ID 000289715600015

• OVERUSE OF LEFT VENTRICULOGRAPHY 60th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) / I2 Summit / ACCF/Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology Witteles, R., Knowles, J. W., Perez, M., Morris, W. H., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. ELSEVIER SCIENCE INC. 2011: E1289–E1289

  View details for Web of Science ID 000291695101292

• Trastuzumab-Related Cardiac Dysfunction JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Telli, M. L., Witteles, R. M. 2011; 9 (2): 243-249

  Abstract

  The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long-term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today.

  View details for PubMedID 21310845

• Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial LANCET Esler, M. D., Krum, H., Sobotka, P. A., Schlaich, M. P., Schmieder, R. E., Boehm, M., Mahfoud, F., Sievert, H., Wunderlich, N., Rump, L. C., Vonend, O., Uder, M., Lobo, M., Caulfield, M., Erglis, A., Azizi, M., Sapoval, M., Thambar, S., Persu, A., Renkin, J., Schunkert, H., Weil, J., Hoppe, U. C., Walton, T., Scheinert, D., Binder, T., Januszewicz, A., Witkowski, A., Ruilope, L. M., Whitbourn, R., Bruck, H., Downes, M., Luescher, T. F., Jardine, A. G., Webster, M. W., Zeller, T., Sadowski, J., Bartus, K., Straley, C. A., Barman, N. C., Lee, D. P., Witteles, R. M., Bhalla, V., Massaro, J. M. 2010; 376 (9756): 1903-1909

  Abstract

  Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension.In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433.106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment.Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients.Ardian.

  View details for DOI 10.1016/S0140-6736(10)62039-9

  View details for Web of Science ID 000285439800031

  View details for PubMedID 21093036

• A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Afghahi, A., Witteles, W., Witteles, R., Liedtke, M., Lafayette, R., Arai, S., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 810–11

  View details for Web of Science ID 000289662202170

• AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions. Witteles, W., Witteles, R., Liedtke, M., Arai, S., Lafayette, R., George, T. I., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 1649

  View details for Web of Science ID 000289662204464

• Overdiagnosis of Left Ventricular Noncompaction 14th Annual Scientific Meeting of the Heart-Failure-Society-of-America Singh, G. D., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: S107–S107

  View details for Web of Science ID 000281501800352

• Measurement Precision in the Optimization of Cardiac Resynchronization Therapy CIRCULATION-HEART FAILURE Turcott, R. G., Witteles, R. M., Wang, P. J., Vagelos, R. H., Fowler, M. B., Ashley, E. A. 2010; 3 (3): 395-404

  Abstract

  Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, the precision of their estimates and the ramifications of an imprecise estimate have not been characterized previously.An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchrony were obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62%-82%). In contrast, impedance cardiography yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values.Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings and a misinterpretation of observed changes over time. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization data in the majority of patients.

  View details for DOI 10.1161/CIRCHEARTFAILURE.109.900076

  View details for PubMedID 20176716

• Rosiglitazone Increases Myocardial Glucose Metabolism in Insulin-Resistant Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kao, D. P., Witteles, R. M., Quon, A., Wu, J. C., Gambhir, S. S., Fowler, M. B. 2010; 55 (9): 926-927

  View details for DOI 10.1016/j.jacc.2009.08.085

  View details for Web of Science ID 000274865100015

  View details for PubMedID 20185047

• Nesiritide, Heart Failure, and Renal Dysfunction: Irrational Exuberance or Throwing the Baby out with the Bathwater Editorial to: "Impact of Nesiritide on Renal Function and Mortality in Patients Suffering from Heart Failure" by Dontas et al. CARDIOVASCULAR DRUGS AND THERAPY Witteles, R. M. 2009; 23 (3): 183-186

  View details for DOI 10.1007/s10557-009-6169-4

  View details for Web of Science ID 000268200100001

  View details for PubMedID 19353257

• Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: Are clinicians responding appropriately? 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Telli, M. L., Yoon, G., Kao, D., Matsuda, K., Witteles, R. M. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606606146

• Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies: Are Clinicians Responding Appropriately? 58th Annual Scientific Session of the American-College-of-Cardiology Yoon, G., Telli, M., Kao, D., Matsuda, K., Witteles, R. ELSEVIER SCIENCE INC. 2009: A173–A173

  View details for Web of Science ID 000263864200721

• Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate ANNALS OF ONCOLOGY Telli, M. L., Witteles, R. M., Fisher, G. A., Srinivas, S. 2008; 19 (9): 1613-1618

  Abstract

  In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

  View details for DOI 10.1093/annonc/mdn168

  View details for Web of Science ID 000259505400015

  View details for PubMedID 18436521

• Impedance cardiography is superior to echocardiographic methods for pacing interval optimization Turcott, R. G., Witteles, R. M., Wang, P. J., Vagelos, R. H., Fowler, M. B., Ashley, E. A. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2008: S65

  View details for Web of Science ID 000258565100208

• Insulin resistance in chronic heart failure - Reply JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Fowler, M. B. 2008; 52 (3): 239-240

  View details for DOI 10.1016/j.jacc.2008.04.017

  View details for Web of Science ID 000257474400012

• Independent AV/VV pacing optimization requires operation along mechanical AV delay isochrones Turcott, R. G., Witteles, R., Wang, P. J., Ashley, E. A. ELSEVIER SCIENCE INC. 2008: A21

  View details for Web of Science ID 000253997100088

• Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

  View details for DOI 10.1080/10428190701861702

  View details for Web of Science ID 000253513300029

  View details for PubMedID 18297538

• Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma Leukemia and Lymphoma Kohrt H, Logan A, Temmins C, Witteles R, Liedtke M, Medeiros B 2008; 49: 581-585
• Trastuzumab cardiotoxicity: Clinical management of asymptomatic declines in left ventricular function The American Journal of Hematology/Oncology Telli ML, Witteles RM, Hunt SA, Carlson RW, Guardino AE 2008; 7 (1): 38-41
• Reversibility of trastuzumab cardiotoxicity: Is the concept alive and well? Reply JOURNAL OF CLINICAL ONCOLOGY Telli, M. L., Carlson, R. W., Guardino, A. E., Hunt, S. A., Witteles, R. M. 2007; 25 (34): 5533-5534

  View details for DOI 10.1200/JCO.2007.14.1036

  View details for Web of Science ID 000253885700032

• Nesiritide does not cause renal dysfunction in acute decompensated heart failure: A randomized, double-blind, placebo-controlled clinical trial Witteles, R. M., Kao, D., Vagelos, R., Christopherson, D., Matsuda, K., Schreiber, D., Fowler, M. B. ELSEVIER SCIENCE INC. 2007: 63A

  View details for Web of Science ID 000244651800260

• Reversibility of trastuzumab cardiotoxicity: Is the concept alive and well? Journal of Clinical Oncology Telli ML, Carlson RW, Guardino AE, Hunt SA, Witteles RM. 2007; 25 (34): 5533-5534
• Premature ventricular contractions causing pacemaker-mediated tachycardia: A failure of postventricular atrial refractory period after premature ventricular contraction extension? HEART RHYTHM Witteles, R., Engel, G., Wang, P. J., Al-Ahmad, A. 2005; 2 (12): 1389-1390

  View details for DOI 10.1016/j.hrthm.2005.08.023

  View details for PubMedID 16360099

• B-type natriuretic peptide is effective therapy before care ANNALS OF INTERNAL MEDICINE Witteles, R., Matsuda, K., Fowler, M. B. 2004; 141 (11): 895

  View details for DOI 10.7326/0003-4819-141-11-200412070-00032

  View details for Web of Science ID 000225530700027

  View details for PubMedID 15583244

• B-type natriuretic peptide is effective therapy before cardiac transplantation Annals of Internal Medicine Witteles R, Matsuda K, Fowler MB 2004; 141 (11): 895
• High prevalence of impaired glucose metabolism in patients with idiopathic dilated cardiomyopathy Jamali, A. H., Witteles, R. M., Tang, W. H., Chu, J. W., Reaven, G. M., Fowler, M. B. ELSEVIER SCIENCE INC. 2002: 181A–181A

  View details for Web of Science ID 000174106700803

• Neuroendocrine tumors of the pancreas The Practice of General Surgery Buell J, Witteles RM, Koka MLR, Sugg SL, Kaplan EL 2002: 1083-1093
• Parathyroid carcinoma Surgery of the thyroid and parathyroid glands Witteles RM, Straus FH, Koka MLR, Kaplan EL 2002: 46.1-46.13
• Adult-onset nesidioblastosis causing hypoglycemia: An important clinical entity and continuing treatment dilemma Archives of Surgery Witteles RM, Straus II FH, Sugg SL, Koka MR, Costa EA, Kaplan EL 2001; 136 (6): 656-663
• Episodic hypertension associated with sitting on hard surfaces Journal of General Internal Medicine Witteles RM 2001; 16: 70
• A new provocative test for the diagnosis of pheochromocytoma? American Journal of Anesthesiology Witteles R, Roizen MF 2001; 28: 446-447
• Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice Archives of Internal Medicine Witteles RM, Kaplan EL, Roizen MF 2000; 160 (16): 2521-2524
• Safe and cost-effective preoperative preparation of patients with pheochromocytoma Anesthesia and Analgesia Witteles RM, Kaplan EL, Roizen MF 2000; 91 (2): 302-304