Kevin M. Alexander, MD, FACC, FHFSA

All Publications

• Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial. Circulation Judge, D. P., Gillmore, J. D., Alexander, K. M., Ambardekar, A. V., Cappelli, F., Fontana, M., García-Pavía, P., Grodin, J. L., Grogan, M., Hanna, M., Masri, A., Nativi-Nicolau, J., Obici, L., Hvitfeldt Poulsen, S., Sarswat, N., Shah, K., Soman, P., Lystig, T., Cao, X., Wang, K., Pecoraro, M. L., Tamby, J. F., Katz, L., Sinha, U., Fox, J. C., Maurer, M. S. 2024

  Abstract

  In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE.Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42.Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model (P-value < 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42. Treatment effects for NT-proBNP and 6MWD also favored continuous acoramidis. Upon initiation of open-label acoramidis in the placebo-to-acoramidis arm there was a prompt increase in serum TTR. Quality of life assessed by KCCQ-OS was well preserved in continuous acoramidis participants compared with the placebo to acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation.Early initiation and continuous use of acoramidis in the ATTRibute-CM study through M42 of the ongoing OLE study was associated with sustained clinical benefits in a contemporary ATTR-CM cohort, with no clinically important safety issues newly identified.

  View details for DOI 10.1161/CIRCULATIONAHA.124.072771

  View details for PubMedID 39556242

• Should We Systematically Screen for the Amyloidogenic V142I Variant? Journal of cardiac failure Regan, J. A., Khouri, M. G., Olabisi, O. A., Alexander, K. M., Khan, S. S., Shah, S. H., Selvaraj, S. 2024

  View details for DOI 10.1016/j.cardfail.2024.08.055

  View details for PubMedID 39306232

• HF STATS 2024: Heart Failure Epidemiology and Outcomes Statistics An Updated 2024 Report from the Heart Failure Society of America. Journal of cardiac failure Bozkurt, B., Ahmad, T., Alexander, K., Baker, W. L., Bosak, K., Breathett, K., Carter, S., Drazner, M. H., Dunlay, S. M., Fonarow, G. C., Greene, S. J., Heidenreich, P., Ho, J. E., Hsich, E., Ibrahim, N. E., Jones, L. M., Khan, S. S., Khazanie, P., Koelling, T., Lee, C. S., Morris, A. A., Page, R. L., Pandey, A., Piano, M. R., Sandhu, A. T., Stehlik, J., Stevenson, L. W., Teerlink, J., Vest, A. R., Yancy, C., Ziaeian, B. 2024

  View details for DOI 10.1016/j.cardfail.2024.07.001

  View details for PubMedID 39322534

• Acoramidis achieves early reduction in cardiovascular death or hospitalization in transthyretin amyloid cardiomyopathy (ATTR-CM): results from the ATTRibute-CM clinical trial Alexander, K., Judge, D., Cappelli, F., Fontana, M., Garcia-Pavia, P., Grogan, M., Hanna, M., Masri, A., Maurer, M., Obici, L., Soman, P., Cao, X., Tamby, J., Siddhanti, S., Katz, L., Fox, J. C., Mahaffey, K. W. TAYLOR & FRANCIS LTD. 2024: S116-S117

  View details for Web of Science ID 001332706900164

• Characterization of ATTR amyloidosis by phenotype from claims data in the United States and Japan: preliminary results from the OverTTuRe Study Alexander, K., Alvarez, C. S., Pao, C., Wittbrodt, E., Kohsaka, S. TAYLOR & FRANCIS LTD. 2024: S79

  View details for Web of Science ID 001332706900110

• Quality of life of patients with variant and wild-type transthyretin amyloidosis Rebello, S., Hsu, K., Ber, J., Alexander, K., Polydefkis, M., Lovley, A., Lousada, I., Maurer, M. TAYLOR & FRANCIS LTD. 2024: S129-S130

  View details for Web of Science ID 001332706900184

• Higher risk of mortality in previously hospitalized patients: insights from ATTRibute-CM Masri, A., Emdin, M., Shah, K., Bhatt, K., Hanna, M., Johnstone, M., Khouri, M., Dasgupta, N. R., Akinboboye, O., Korczyk, D., Lam, K., Soman, P., Du, J., Tamby, J., Siddhanti, S., Katz, L., Fox, J. C., Alexander, K., Grogan, M. TAYLOR & FRANCIS LTD. 2024: S115

  View details for Web of Science ID 001332706900162

• Social determinants of health-related disparities in the diagnosis of transthyretin cardiac amyloidosis Pankratova, C., Chung, H., Crowley, A., Rava, A., Sienko, D., Boame, N., Swarup, S., Ebrahim, A., Alexander, K. TAYLOR & FRANCIS LTD. 2024: S152-S153

  View details for Web of Science ID 001332706900220

• Deciphering the pathogenesis of transthyretin cardiac amyloidosis in a humanized mouse model Wu, X., Cai, N., Jimenez, J., Evangelisti, A., Kitakata, H., Jha, A., Woo, J., Liao, R., Alexander, K. TAYLOR & FRANCIS LTD. 2024: S133

  View details for Web of Science ID 001332706900189

• Defining Disease Progression in ATTR Cardiac Amyloidosis: Keeping It Simple. Journal of the American College of Cardiology Alexander, K. M. 2024

  View details for DOI 10.1016/j.jacc.2024.02.024

  View details for PubMedID 38530685

• Outcomes with guideline-directed medical therapy and cardiac implantable electronic device therapies for patients with heart failure with reduced ejection fraction. Heart rhythm O2 Mignone, J. L., Alexander, K. M., Dobbles, M., Eberst, K., Fonarow, G. C., Ellenbogen, K. A. 2024; 5 (3): 168-173

  Abstract

  Limited real-world evidence exists for outcomes with contemporary guideline-directed medical therapy (GDMT) or GDMT with implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) therapy for patients with heart failure with reduced ejection fraction (HFrEF) and left ventricular ejection fraction (LVEF) ≤35%.The present study aimed to assess survival associated with GDMT or GDMT with ICD/CRT-D therapy.This retrospective observational study included real-world de-identified data from January 1, 2016, to December 19, 2023, from 24 U.S. institutions per participating institutional agreements (egnite Database; egnite, Inc.). Patients with a diagnosis of HFrEF and an echocardiographic study documenting LVEF ≤35% were included for analysis.Of 43,591 patients with eligible index event of LVEF ≤35%, prescription history through ≥1 year preindex, and no ICD/CRT-D therapy preindex, mean ± standard deviation age at index was 71.2 ± 13.2 years; 14,805 (34.0%) patients were female. At 24 months, an estimated 99.1% (95% confidence interval [CI] 99.0%-99.2%), 89.9% (95% CI 89.7%-90.1%), 54.8% (95% CI 54.4%-55.2%), and 17.2% (95% CI 16.9%-17.5%), had ≥1, 2, 3, or all 4 GDMT classes prescribed, respectively; an estimated 15.7% (95% CI 15.3%-16.1%) had device placement. Of those without a device, by 24 months, an estimated 45.1% (95% CI 44.4%-45.7%) had a documented LVEF >35%. Counts of GDMT classes prescribed as well as ICD/CRT-D device therapy were associated with lower mortality risk in this population, even after adjustment for patient age, sex, and comorbidities.Both GDMT classes prescribed and device therapy were independently associated with lower mortality risk, even in the presence of more GDMT options for this more contemporary population.

  View details for DOI 10.1016/j.hroo.2024.01.004

  View details for PubMedID 38560378

  View details for PubMedCentralID PMC10980920

• Almanac - Retrieval-Augmented Language Models for Clinical Medicine. NEJM AI Zakka, C., Shad, R., Chaurasia, A., Dalal, A. R., Kim, J. L., Moor, M., Fong, R., Phillips, C., Alexander, K., Ashley, E., Boyd, J., Boyd, K., Hirsch, K., Langlotz, C., Lee, R., Melia, J., Nelson, J., Sallam, K., Tullis, S., Vogelsong, M. A., Cunningham, J. P., Hiesinger, W. 2024; 1 (2)

  Abstract

  Large language models (LLMs) have recently shown impressive zero-shot capabilities, whereby they can use auxiliary data, without the availability of task-specific training examples, to complete a variety of natural language tasks, such as summarization, dialogue generation, and question answering. However, despite many promising applications of LLMs in clinical medicine, adoption of these models has been limited by their tendency to generate incorrect and sometimes even harmful statements.We tasked a panel of eight board-certified clinicians and two health care practitioners with evaluating Almanac, an LLM framework augmented with retrieval capabilities from curated medical resources for medical guideline and treatment recommendations. The panel compared responses from Almanac and standard LLMs (ChatGPT-4, Bing, and Bard) versus a novel data set of 314 clinical questions spanning nine medical specialties.Almanac showed a significant improvement in performance compared with the standard LLMs across axes of factuality, completeness, user preference, and adversarial safety.Our results show the potential for LLMs with access to domain-specific corpora to be effective in clinical decision-making. The findings also underscore the importance of carefully testing LLMs before deployment to mitigate their shortcomings. (Funded by the National Institutes of Health, National Heart, Lung, and Blood Institute.).

  View details for DOI 10.1056/aioa2300068

  View details for PubMedID 38343631

  View details for PubMedCentralID PMC10857783

• Healthcare Resource Utilization And Disease Burden In Patients With Transthyretin Amyloidosis With Cardiomyopathy: Results From The Amyloidosis Research Consortium Transthyretin Amyloidosis Burden Of Illness Study Rebello, S., Hsu, K., Berk, J., Alexander, K., Polydefkis, M., Gibbs, S., Lovley, A., Lousada, I., Maurer, M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2024: 145-146

  View details for Web of Science ID 001162343100065

• Impact Of Micro-education On Physician Knowledge, Competence, And Confidence Related To The Diagnosis And Treatment Of Transthyretin Cardiac Amyloidosis In Underserved Patient Populations Harris, M., O'Connor, A., Capparelli, C., Dillenburg, T., Gore, C., Alexander, K. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2024: 206

  View details for Web of Science ID 001162343100211

• Acoramidis Improves Clinical Outcomes In Transthyretin Amyloid Cardiomyopathy Patients Judge, D. P., Cappelli, F., Fontana, M., Garciapavia, P., Gibbs, S., Grogan, M., Hanna, M., Masri, A., Maurer, M. S., Obici, L., Soman, P., Alexander, K. M., Cao, X., Du, J., Lystig, T., Tamby, J., Siddhanti, S., Katz, L., Fox, J. C., Gillmore, J. D. LIPPINCOTT WILLIAMS & WILKINS. 2023: E303-E304

  View details for Web of Science ID 001297469300044

• TEMPORARY REMOVAL: Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. Journal of cardiac failure Bozkurt, B., Ahmad, T., Alexander, K., Baker, W. L., Bosak, K., Breathett, K., Fonarow, G. C., Heidenreich, P., Ho, J. E., Hsich, E., Ibrahim, N. E., Jones, L. M., Khan, S. S., Khazanie, P., Koelling, T., Krumholz, H. M., Khush, K. K., Lee, C., Morris, A. A., Page, R. 3., Pandey, A., Piano, M., Stehlik, J., Stevenson, L., Teerlink, J., Vaduganathan, M., Ziaeian, B. 2023

  Abstract

  The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

  View details for DOI 10.1016/j.cardfail.2023.07.006

  View details for PubMedID 37797885

• Exploring Race and Sex Differences in Cardiac Sarcoidosis: "Dispare" No More. Journal of cardiac failure Gupta, R., Bermudez, F., Alexander, K. M., Sheikh, F. H. 2023

  View details for DOI 10.1016/j.cardfail.2023.06.006

  View details for PubMedID 37354943

• Almanac: Retrieval-Augmented Language Models for Clinical Medicine. Research square Zakka, C., Chaurasia, A., Shad, R., Dalal, A. R., Kim, J. L., Moor, M., Alexander, K., Ashley, E., Boyd, J., Boyd, K., Hirsch, K., Langlotz, C., Nelson, J., Hiesinger, W. 2023

  Abstract

  Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n= 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings.

  View details for DOI 10.21203/rs.3.rs-2883198/v1

  View details for PubMedID 37205549

  View details for PubMedCentralID PMC10187428

• Implications of Extra-cardiac Disease in Patient Selection for Heart Transplantation: Considerations in Cardiac Amyloidosis. Cardiac failure review Punnoose, L. R., Siddiqi, H., Rosenthal, J., Kittleson, M., Witteles, R., Alexander, K. 2023; 9: e01

  Abstract

  Disease-modifying therapies in both light chain and transthyretin amyloidosis have improved patient functional status and survival. Conceivably, as heart failure may progress despite amyloid therapies, more patients may be considered for heart transplantation. In earlier eras, extra-cardiac amyloid deposits significantly reduced post-heart transplant patient survival and functional status compared to the non-amyloid population. In the modern era, transplant centres have reported improved outcomes in amyloidosis as patient selection has grown more stringent. Importantly, systematic candidate evaluation should assess the degree of extra-cardiac involvement, the effectiveness of disease-modifying therapies and downstream effects on patients' nutrition and frailty. This review outlines such an overall approach while also considering that organ-specific selection criteria may vary between individual transplant centres. A methodical approach to patient evaluation will promote better understanding of the prevalence and severity of extra-cardiac disease in amyloidosis patients referred for heart transplantation and of any disparities in decision outcomes in this population.

  View details for DOI 10.15420/cfr.2022.24

  View details for PubMedID 36891177

  View details for PubMedCentralID PMC9987512

• Nurturing Diverse Generations of the Medical Workforce for Success With Authenticity: An Association of Black Cardiologists' Roundtable. Circulation. Cardiovascular quality and outcomes Haynes, N. A., Johnson, M., Lewsey, S. C., Alexander, K. M., Anstey, D. E., Dillenburg, T., Njoroge, J. N., Gordon, D., Ofili, E. O., Yancy, C. W., Albert, M. A. 2023: e009032

  Abstract

  The COVID-19 pandemic exposed the consequences of systemic racism in the United States with Black, Hispanic, and other racial and ethnic diverse populations dying at disproportionately higher rates than White Americans. Addressing the social and health disparities amplified by COVID-19 requires in part restructuring of the healthcare system, particularly the diversity of the healthcare workforce to better reflect that of the US population. In January 2021, the Association of Black Cardiologists hosted a virtual roundtable designed to discuss key issues pertaining to medical workforce diversity and to identify strategies aimed at improving racial and ethnic diversity in medical school, graduate medical education, faculty, and leadership positions. The Nurturing Diverse Generations of the Medical Workforce for Success with Authenticity roundtable brought together diverse stakeholders and champions of diversity and inclusion to discuss innovative ideas, solutions, and opportunities to address workforce diversification.

  View details for DOI 10.1161/CIRCOUTCOMES.122.009032

  View details for PubMedID 36603043

• Effects of Body Mass Index on Presentation and Outcomes of COVID-19 among Heart Transplant and Left Ventricular Assist Device Patients: A Multi-Institutional Study. ASAIO journal (American Society for Artificial Internal Organs : 1992) Iyengar, A., Cohen, W., Han, J., Helmers, M., Kelly, J. J., Patrick, W., Moss, N., Molina, E. J., Sheikh, F. H., Houston, B. A., Tedford, R. J., Shore, S., Vorovich, E. E., Hsich, E. M., Bensitel, A., Alexander, K. M., Chaudhry, S., Vidula, H., Kilic, A., Genuardi, M. V., Birati, E. Y., Atluri, P. 2023; 69 (1): 43-49

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic continues to pose a significant threat to patients receiving advanced heart failure therapies. The current study was undertaken to better understand the relationship between obesity and outcomes of SARS-CoV-2 infection in patients with a left ventricular assist device (LVAD) or heart transplant. We performed a retrospective review of patients with a heart transplant or LVAD who presented to one of the participating 11 institutions between April 1 and November 30, 2020. Patients were grouped by body mass index (BMI) into obese (BMI ≥ 30 k/m2) and nonobese cohorts (BMI < 30kg/m2). Multivariable logistic regression models were used to estimate effects of obesity on outcomes of interest. Across all centers, 162 heart transplant and 81 LVAD patients were identified; 54 (33%) and 38 (47%) were obese, respectively. Obese patients tended to have more symptoms at presentation. No differences in rates of hospitalization or ICU admission were noted. Obese patients with LVADs were more likely to require mechanical ventilation (39% vs. 8%, p < 0.05). No differences in renal failure or secondary infection were noted. Mortality was similar among heart transplant patients (11% [obese] vs. 16% [nonobese], p = 0.628) and LVAD patients (12% vs. 15%, p = 1.0). BMI was not associated with increased adjusted odds of mortality, ICU admission, or mechanical ventilation (all p > 0.10). In summary, acute presentations of SARS-CoV-2 among heart transplant and LVAD recipients carry a significantly higher mortality than the general population, although BMI does not appear to impact this. Further studies on the longer-term effects of COVID-19 on this population are warranted.

  View details for DOI 10.1097/MAT.0000000000001801

  View details for PubMedID 36583770

• Prevalence, mutational spectrum and clinical implications of clonal hematopoiesis of indeterminate potential in plasma cell dyscrasias. Seminars in oncology Testa, S., Kumar, J., Goodell, A. J., Zehnder, J. L., Alexander, K. M., Sidana, S., Arai, S., Witteles, R. M., Liedtke, M. 2022

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is common both in healthy individuals and patients with hematological cancers. Recent studies have showed worse prognosis for patients with multiple myeloma (MM) and non-Hodgkin lymphoma undergoing stem cell transplant, that have concomitant presence of CHIP. Data regarding the clinical and biological role of CHIP in plasma cell dyscrasias (PCDs) is rapidly increasing. However, the prevalence and prognostic implication of CHIP in patients with MM outside of the transplant setting, and in those with other more indolent PCDs remains elusive. Here we explored the prevalence and clinical implications of CHIP detected through next-generation sequencing in 209 patients with PCDs including MM, light chain (AL) amyloidosis (ALA), monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM). To avoid attributing the mutations to the plasma cell clone, CHIP was defined as the presence of DNMT3A, TET2, or ASXL1 mutations in the peripheral blood or bone marrow (DTA-CH). The prevalence of DTA-CH was 19% in patients with PCDs, with no difference between each PCD. TET2 (23%) and DNMT3A (22%), were the most frequently mutated genes. DTA-CH correlated with older age in MM (P = .001) and MGUS/SMM (P = 0.0007), as well as with coronary artery disease or congestive heart failure in MM (P = .03). DTA-CH did not predict worse OS or PFS in either MM or ALA, nor it predict higher risk of progression to MM in patients with MGUS/SMM. Our results overall further elucidate the prevalence and mutational spectrum of CHIP in PCDs, providing more information regarding the clinical relevance of CHIP in this patient population.

  View details for DOI 10.1053/j.seminoncol.2022.11.001

  View details for PubMedID 36503855

• 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

• Proteotoxicity and Autophagy in Neurodegenerative and Cardiovascular Diseases Biochemistry of Apoptosis and Autophagy Alexander, K. M., Morgado, I., Liao, R. Springer. 2022; 1: 219-237
• Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review. Circulation. Genomic and precision medicine Chandrashekar, P., Alhuneafat, L., Mannello, M., Al-Rashdan, L., Kim, M. M., Dungu, J., Alexander, K., Masri, A. 2021: CIRCGEN121003356

  Abstract

  BACKGROUND: The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.METHODS: We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for 150 000 subjects.RESULTS: The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.CONCLUSION: The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.

  View details for DOI 10.1161/CIRCGEN.121.003356

  View details for PubMedID 34461737

• 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

• Coronavirus disease 2019 in heart transplant recipients: Risk factors, immunosuppression, and outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Genuardi, M. V., Moss, N., Najjar, S. S., Houston, B. A., Shore, S., Vorovich, E., Atluri, P., Molina, M., Chambers, S., Sharkoski, T., Hsich, E., Estep, J. D., Owens, A. T., Alexander, K. M., Chaudhry, S., Garcia-Cortes, R., Molina, E., Rodrigo, M., Wald, M. J., Margulies, K. B., Hanff, T. C., Zimmer, R., Kilic, A., Mclean, R., Vidula, H., Dodd, K., Blumberg, E. A., Mazurek, J. A., Goldberg, L. R., Alvarez-Garcia, J., Mancini, D., Teuteberg, J. J., Tedford, R. J., Birati, E. Y. 2021

  Abstract

  BACKGROUND: COVID-19 continues to inflict significant morbidity and mortality, particularly on patients with preexisting health conditions. The clinical course, outcomes, and significance of immunosuppression regimen in heart transplant recipients with COVID-19 remains unclear.METHODS: We included the first 99 heart transplant recipients at participating centers with COVID-19 and followed patients until resolution. We collected baseline information, symptoms, laboratory studies, vital signs, and outcomes for included patients. The association of immunosuppression regimens at baseline with severe disease were compared using logistic regression, adjusting for age and time since transplant.RESULTS: The median age was 60 years, 25% were female, and 44% were white. The median time post-transplant to infection was 5.6 years. Overall, 15% died, 64% required hospital admission, and 7% remained asymptomatic. During the course of illness, only 57% of patients had a fever, and gastrointestinal symptoms were common. Tachypnea, oxygen requirement, elevated creatinine and inflammatory markers were predictive of severe course. Age ≥ 60 was associated with higher risk of death and the use of the combination of calcineurin inhibitor, antimetabolite, and prednisone was associated with more severe disease compared to the combination of calcineurin inhibitor and antimetabolite alone (adjusted OR=7.3, 95% CI 1.8-36.2). Among hospitalized patients, 30% were treated for secondary infection, acute kidney injury was common and 17% required new renal replacement therapy.CONCLUSIONS: We present the largest study to date of heart transplant patients with COVID-19 showing common atypical presentations and a high case fatality rate of 24% among hospitalized patients and 16% among symptomatic patients.

  View details for DOI 10.1016/j.healun.2021.05.006

  View details for PubMedID 34140222

• MicroRNA-21 regulates right ventricular remodeling secondary to pulmonary arterial pressure overload. Journal of molecular and cellular cardiology Chang, W., Fisch, S., Dangwal, S., Mohebali, J., Fiedler, A. G., Chen, M., Hsu, C., Yang, Y., Qiu, Y., Alexander, K. M., Chen, F. Y., Liao, R. 2021

  Abstract

  Right ventricular (RV) function is a critical determinant of survival in patients with pulmonary arterial hypertension (PAH). While miR-21 is known to associate with vascular remodeling in small animal models of PAH, its role in RV remodeling in large animal models has not been characterized. Herein, we investigated the role of miR-21 in RV dysfunction using a sheep model of PAH secondary to pulmonary arterial constriction (PAC). RV structural and functional remodeling were examined using ultrasound imaging. Our results showed that post PAC, RV strain significantly decreased at the basal region compared with t the control. Moreover, such dysfunction was accompanied by increases in miR-21 levels. To determine the role of miR-21 in RV remodeling secondary to PAC, we investigated the molecular alteration secondary to phenylephrine induced hypertrophy and miR21 overexpression in vitro using neonatal rat ventricular myocytes (NRVMs). We found that overexpression of miR-21 in the setting of hypertrophic stimulation augmented only the expression of proteins critical for mitosis but not cytokinesis. Strikingly, this molecular alteration was associated with an eccentric cellular hypertrophic phenotype similar to what we observed in vivo PAC animal model in sheep. Importantly, this hypertrophic change was diminished upon suppressing miR-21 in NRVMs. Collectively, our in vitro and in vivo data demonstrate that miR-21 is a critical contributor in the development of RV dysfunction and could represent a novel therapeutic target for PAH associated RV dysfunction.

  View details for DOI 10.1016/j.yjmcc.2021.01.003

  View details for PubMedID 33548242

• Challenges and the innovations in the care of advanced heart failure patients during COVID-19. Heart failure reviews Yehya, A. n., Shah, K. S., Mitter, S. S., Ibrahim, N. E., Sperry, B. n., Shah, M. n., Chaudhry, S. P., Rajagopalan, N. n., Hernandez-Montfort, J. n., Mohan, R. n., Alexander, K. M., Sinha, S. n., Butler, J. n., Kittleson, M. M. 2021

  Abstract

  The COVID-19 pandemic underscored our healthcare system's unpreparedness to manage an unprecedented pandemic. Heart failure (HF) physicians from 14 different academic and private practice centers share their systems' challenges and innovations to care for patients with HF, heart transplantation, and patients on LVAD support during the COVID-19 pandemic. We discuss measures implemented to alleviate the fear in seeking care, ensure continued optimization of guideline directed medical therapy (GDMT), manage the heart transplant waiting list, continue essential outpatient monitoring of anticoagulation in LVAD patients and surveillance testing post-heart transplant, and prevent physician burnout. This collaborative work can build a foundation for better preparation in the face of future challenges.

  View details for DOI 10.1007/s10741-021-10074-0

  View details for PubMedID 33432419

• Transthyretin Cardiac Amyloidosis in the Elderly-Tip of a Heart Failure Iceberg? JAMA cardiology Alexander, K. M., Dorbala, S. 2021

  View details for DOI 10.1001/jamacardio.2020.4387

  View details for PubMedID 34037661

• Cardiac Amyloid Heart Disease in Racial/Ethnic Minorities: Focus on Transthyretin Amyloid Cardiomyopathy CARDIOVASCULAR DISEASE IN RACIAL AND ETHNIC MINORITY POPULATIONS, 2 EDITION Alexander, K. M., Maurer, M. S., Fergus, I. V., Ferdinand, K. C., Taylor, J., Rodriguez, C. J. 2021: 201-215

  View details for DOI 10.1007/978-3-030-81034-4_17

  View details for Web of Science ID 000868532600018

• Future Perspectives of Cardiovascular Biomarker Utilization in Cancer Survivors: A Scientific Statement From the American Heart Association. Circulation Zaha, V. G., Hayek, S. S., Alexander, K. M., Beckie, T. M., Hundley, W. G., Kondapalli, L., Ky, B., Leger, K. J., Meijers, W. C., Moslehi, J. J., Shah, S. H. 2021: CIR0000000000001032

  Abstract

  Improving cancer survival represents the most significant effect of precision medicine and personalized molecular and immunologic therapeutics. Cardiovascular health becomes henceforth a key determinant for the direction of overall outcomes after cancer. Comprehensive tissue diagnostic studies undoubtedly have been and continue to be at the core of the fight against cancer. Will a systemic approach integrating circulating blood-derived biomarkers, multimodality imaging technologies, strategic panomics, and real-time streams of digitized physiological data overcome the elusive cardiovascular tissue diagnosis in cardio-oncology? How can such a systemic approach be personalized for application in day-to-day clinical work, with diverse patient populations, cancer diagnoses, and therapies? To address such questions, this scientific statement approaches a broad definition of the biomarker concept. It summarizes the current literature on the utilization of a multitude of established cardiovascular biomarkers at the intersection with cancer. It identifies limitations and gaps of knowledge in the application of biomarkers to stratify the cardiovascular risk before cancer treatment, monitor cardiovascular health during cancer therapy, and detect latent cardiovascular damage in cancer survivors. Last, it highlights areas in biomarker discovery, validation, and clinical application for concerted efforts from funding agencies, scientists, and clinicians at the cardio-oncology nexus.

  View details for DOI 10.1161/CIR.0000000000001032

  View details for PubMedID 34753300

• Mistaken Identity: Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy JACC: CardioOncology Nguyen, A. T., Alexander, K. M. 2021; 3 (4): 594-597

  View details for DOI 10.1016/j.jaccao.2021.06.002

  View details for PubMedCentralID PMC8543088

• Electrocardiogram Characteristics and Prognostic Value in Light-Chain Amyloidosis: A Comparison With Cardiac Magnetic Resonance Imaging. Frontiers in cardiovascular medicine Guo, X., Chen, Z., Wan, K., Song, R., Yang, T., Xu, Y., Zhang, Q., Alexander, K. M., Han, Y., Chen, Y. 1800; 8: 751422

  Abstract

  Background: An electrocardiogram (ECG) is a simple and cheap non-invasive tool that shows various abnormalities and has prognostic value for patients with light-chain amyloidosis (AL). The present study aimed to explore the association between ECG characteristics and cardiac magnetic resonance (CMR)-detected amyloid burden and to investigate the prognostic value of ECG in AL amyloidosis. Methods: We prospectively enrolled 99 patients with AL amyloidosis (56 male patients; median age, 58 y). Detailed clinical information, 12-lead ECG, and CMR data were collected. All patients were followed up longitudinally, and the endpoint was all-cause mortality. ECG characteristics were analyzed and correlated with the degree of late gadolinium enhancement (LGE) and extracellular volume (ECV) by T1 mapping on CMR. The prognostic value of ECG characteristics was analyzed using Kaplan-Meier survival analysis and multivariate Cox regression. Results: During a median follow-up period of 33 months, 69 of the 99 patients died. Fragmented Q wave-R wave-S wave (QRS), pathological Q waves, the Sokolow index, QRS duration, and voltages were significantly associated with the extent of LGE, native T1, and ECV by CMR (p < 0.05). Fragmented QRS and Sokolow index showed independent prognostic value in AL amyloidosis (p = 0.001; p = 0.026, respectively). Fragmented QRS remained independent after adjusting for clinical values (hazard ratio: 2.034; 95% confidence interval: 1.148-3.603; p = 0.015). However, no ECG characteristics were independent predictors for prognosis in AL amyloidosis when LGE and ECV were included in the multivariate analysis. Conclusion: ECG abnormalities showed significant association with CMR indicators of amyloid burden. Fragmented QRS has an independent prognostic value in AL amyloidosis and could be used as an alternative marker when CMR is not available.

  View details for DOI 10.3389/fcvm.2021.751422

  View details for PubMedID 34938781

• Characteristics and Outcomes of COVID-19 in Patients on Left Ventricular Assist Device Support. Circulation. Heart failure Birati, E. Y., Najjar, S. S., Tedford, R. J., Houston, B. A., Shore, S. n., Vorovich, E. n., Atluri, P. n., Urgo, K. n., Molina, M. n., Chambers, S. n., Escobar, N. n., Hsich, E. n., Estep, J. D., Alexander, K. M., Teuteberg, J. J., Chaudhry, S. P., Ravichandran, A. n., DeVore, A. D., Margulies, K. B., Hanff, T. C., Zimmer, R. n., Kilic, A. n., Wald, J. W., Vidula, H. n., Martens, J. n., Blumberg, E. A., Mazurek, J. A., Owens, A. T., Goldberg, L. R., Alvarez-Garcia, J. n., Mancini, D. M., Moss, N. n., Genuardi, M. V. 2021: CIRCHEARTFAILURE120007957

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic continues to afflict millions of people worldwide. Patients with end-stage heart failure and left ventricular assist devices (LVADs) may be at risk for severe COVID-19 given a high prevalence of complex comorbidities and functional impaired immunity. The objective of this study is to describe the clinical characteristics and outcomes of COVID-19 in patients with end-stage heart failure and durable LVADs.The Trans-CoV-VAD registry is a multi-center registry of LVAD and cardiac transplant patients in the United States with confirmed COVID-19. Patient characteristics, exposure history, presentation, laboratory data, course, and clinical outcomes were collected by participating institutions and reviewed by a central data repository. This report represents the participation of the first 9 centers to report LVAD data into the registry.A total of 40 patients were included in this cohort. The median age was 56 years (interquartile range, 46-68), 14 (35%) were women, and 21 (52%) were Black. Among the most common presenting symptoms were cough (41%), fever, and fatigue (both 38%). A total of 18% were asymptomatic at diagnosis. Only 43% of the patients reported either subjective or measured fever during the entire course of illness. Over half (60%) required hospitalization, and 8 patients (20%) died, often after lengthy hospitalizations.We present the largest case series of LVAD patients with COVID-19 to date. Understanding these characteristics is essential in an effort to improve the outcome of this complex patient population.

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.007957

  View details for PubMedID 33813838

• Decoding the Nanoenvironment in Cardiac Amyloidosis Through Proteomics JACC: CARDIOONCOLOGY Alexander, K. M., Jha, A., Liao, R. 2020; 2 (4): 644–46

  View details for DOI 10.1016/j.jaccao.2020.10.002

  View details for Web of Science ID 000613114700013

• High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function. Journal of visualized experiments : JoVE Evangelisti, A., Schimmel, K., Joshi, S., Shah, K., Fisch, S., Alexander, K. M., Liao, R., Morgado, I. 2020

  Abstract

  The zebrafish (Danio rerio) has become a very popular model organism in cardiovascular research, including human cardiac diseases, largely due to its embryonic transparency, genetic tractability, and amenity to rapid, high-throughput studies. However, the loss of transparency limits heart function analysis at the adult stage, which complicates modeling of age-related heart conditions. To overcome such limitations, high-frequency ultrasound echocardiography in zebrafish is emerging as a viable option. Here, we present a detailed protocol to assess cardiac function in adult zebrafish by non-invasive echocardiography using high-frequency ultrasound. The method allows visualization and analysis of zebrafish heart dimension and quantification of important functional parameters, including heart rate, stroke volume, cardiac output, and ejection fraction. In this method, the fish are anesthetized and kept underwater and can be recovered after the procedure. Although high-frequency ultrasound is an expensive technology, the same imaging platform can be used for different species (e.g., murine and zebrafish) by adapting different transducers. Zebrafish echocardiography is a robust method for cardiac phenotyping, useful in the validation and characterization of disease models, particularly late-onset diseases; drug screens; and studies of heart injury, recovery, and regenerative capacity.

  View details for DOI 10.3791/60976

  View details for PubMedID 32225163

• 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

• Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction. Circulation Schimmel, K. n., Jung, M. n., Foinquinos, A. n., San José, G. n., Beaumont, J. n., Bock, K. n., Grote-Levi, L. n., Xiao, K. n., Bär, C. n., Pfanne, A. n., Just, A. n., Zimmer, K. n., Ngoy, S. n., López, B. n., Ravassa, S. n., Samolovac, S. n., Janssen-Peters, H. n., Remke, J. n., Scherf, K. n., Dangwal, S. n., Piccoli, M. T., Kleemiss, F. n., Kreutzer, F. P., Kenneweg, F. n., Leonardy, J. n., Hobuß, L. n., Santer, L. n., Do, Q. T., Geffers, R. n., Braesen, J. H., Schmitz, J. n., Brandenberger, C. n., Müller, D. N., Wilck, N. n., Kaever, V. n., Bähre, H. n., Batkai, S. n., Fiedler, J. n., Alexander, K. M., Wertheim, B. M., Fisch, S. n., Liao, R. n., Diez, J. n., González, A. n., Thum, T. n. 2020

  Abstract

  Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis. Methods: Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression. In vitro findings were confirmed in vivo, using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing. Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective anti-fibrotic molecules both in vitro and in vivo leading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds. Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

  View details for DOI 10.1161/CIRCULATIONAHA.119.042559

  View details for PubMedID 31948273

• Pulling at the heart: COVID-19, race/ethnicity and ongoing disparities. Nature reviews. Cardiology Chin-Hong, P. n., Alexander, K. M., Haynes, N. n., Albert, M. A. 2020

  View details for DOI 10.1038/s41569-020-0416-6

  View details for PubMedID 32732989

• Serum high-density lipoprotein cholesterol serves as a prognostic marker for light-chain cardiac amyloidosis. International journal of cardiology Yang, T. n., Wan, K. n., Song, R. n., Guo, X. n., Xu, Y. n., Wang, J. n., Zhang, Q. n., Alexander, K. M., Liao, R. n., Chen, Y. n. 2020

  Abstract

  Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM.In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C < 40 mg/dL and HDL-C ≥ 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C.Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy.HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis.

  View details for DOI 10.1016/j.ijcard.2020.10.034

  View details for PubMedID 33080283

• Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis. Current cardiology reports Joshi, S. n., Evangelisti, A. n., Liao, R. n., Alexander, K. M. 2020; 22 (1): 1

  Abstract

  Cardiac regeneration has received much attention as a possible means to treat various forms of cardiac injury. This review will explore the field of cardiac regeneration by highlighting the existing animal models, describing the involved molecular pathways, and discussing attempts to harness cardiac regeneration to treat cardiomyopathies.Light chain cardiac amyloidosis is a degenerative disease characterized by progressive heart failure due to amyloid fibril deposition and light chain-mediated cardiotoxicity. Recent findings in a zebrafish model of light chain amyloidosis suggest that cardiac regenerative confers a protective effect against this disease. Cardiac regeneration remains an intriguing potential tool for treating cardiovascular disease. Degenerative diseases, such as light chain cardiac amyloidosis, may be particularly suited for therapeutic interventions that target cardiac regeneration. Further studies are needed to translate preclinical findings for cardiac regeneration into effective therapies.

  View details for DOI 10.1007/s11886-020-1252-3

  View details for PubMedID 31932992

• Recipe for Success in Transthyretin Cardiomyopathy: Monoclonal Protein Rule Out, SPECT Imaging, and Genetic Testing. JACC. Cardiovascular imaging Alexander, K. M., Masri, A. n. 2020

  View details for DOI 10.1016/j.jcmg.2020.09.009

  View details for PubMedID 33221210

• Advances in the Diagnosis and Management of Transthyretin Amyloid Cardiomyopathy Curr Treat Options Cardio Med Spencer-Bonilla, G., Alexander, K. M., Witteles, R. M. 2020; 22 (45)
• 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

• 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

• Gene Signatures to Distinguish Amyloid Cardiomyopathy Risk in Multiple Myeloma Patients Jha, A., Morgado, I., Lee, D. J., Alexander, K., Tsai, C., Schimmel, K., Ward, J., Witteles, R., Liedtke, M., Liao, R., Dangwal, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800441

• Prenatal Exposure of Cigarette Smoke Impacts Cardiac Regeneration Schimmel, K., Morgado, I., Tsai, C., Evangelisti, A., Fisch, S., Ngoy, S., Lee, D., Dangwal, S., Alexander, K., Ward, J. E., Liao, R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800423

• 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

• Trends and causes of hospitalizations in patients with amyloidosis. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis Patil, N. n., Arora, S. n., Qamar, A. n., Strassle, P. D., Alexander, K. M., Fatima, A. n., Maurer, M. S., Grodin, J. L., Pandey, A. n. 2019: 1–2

  View details for DOI 10.1080/13506129.2019.1618261

  View details for PubMedID 31172802

• 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

• Mortality from Heart Failure and Dementia in the United States: CDC WONDER 1999-2016. Journal of cardiac failure Vuong, J. T., Jacob, S. A., Alexander, K. M., Singh, A., Liao, R., Desai, A. S., Dorbala, S. 2018

  Abstract

  Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual healthcare expenditure. With the aging of the United States population, and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of our study are to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals.This is a retrospective study using National Vital Statistics Data from 1999-2016 provided by the Centers for Disease Control and ICD-10 codes for heart failure and dementia defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed by heart failure and dementia totaled 214,706 and comprised 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age-adjusted mortality rates (per 1,000,000 person-years): 38.67, 95% CI: 38.47-38.87 vs. 32.90, 95% CI: 32.65-33.15, p<0.001. Whites were affected more than Blacks, with age-adjusted mortality rates (per 1,000,000 person-years): 38.00, 95% CI: 37.83-38.16 vs. 31.06, 95% CI: 30.54-31.59, p<0.001. However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16, p<0.001).This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years, Whites, and women.

  View details for DOI 10.1016/j.cardfail.2018.11.012

  View details for PubMedID 30471348

• Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine: The ROPA-DOP Trial. JACC. Heart failure Sharma, K., Vaishnav, J., Kalathiya, R., Hu, J. R., Miller, J., Shah, N., Hill, T., Sharp, M., Tsao, A., Alexander, K. M., Gupta, R., Montemayor, K., Kovell, L., Chasler, J. E., Lee, Y. J., Fine, D. M., Kass, D. A., Weiss, R. G., Thiemann, D. R., Ndumele, C. E., Schulman, S. P., Russell, S. D. 2018

  Abstract

  This study sought to compare a continuous infusion diuretic strategy versus an intermittent bolus diuretic strategy, with the addition of low-dose dopamine (3 μg/kg/min) in the treatment of hospitalized patients with heart failure with preserved ejection fraction (HFpEF).HFpEF patients are susceptible to development of worsening renal function (WRF) when hospitalized with acute heart failure; however, inpatient treatment strategies to achieve safe and effective diuresis in HFpEF patients have not been studied to date.In a prospective, randomized, clinical trial, 90 HFpEF patients hospitalized with acute heart failure were randomized within 24 h of admission to 1 of 4 treatments: 1) intravenous bolus furosemide administered every 12 h; 2) continuous infusion furosemide; 3) intermittent bolus furosemide with low-dose dopamine; and 4) continuous infusion furosemide with low-dose dopamine. The primary endpoint was percent change in creatinine from baseline to 72 h. Linear and logistic regression analyses with tests for interactions between diuretic and dopamine strategies were performed.Compared to intermittent bolus strategy, the continuous infusion strategy was associated with higher percent increase in creatinine (continuous infusion: 16.01%; 95% confidence interval [CI]: 8.58% to 23.45% vs. intermittent bolus: 4.62%; 95% CI: -1.15% to 10.39%; p = 0.02). Low-dose dopamine had no significant effect on percent change in creatinine (low-dose dopamine: 12.79%; 95% CI: 5.66% to 19.92%, vs. no-dopamine: 8.03%; 95% CI: 1.44% to 14.62%; p = 0.33). Continuous infusion was also associated with greater risk of WRF than intermittent bolus (odds ratio [OR]: 4.32; 95% CI: 1.26 to 14.74; p = 0.02); no differences in WRF risk were seen with low-dose dopamine. No significant interaction was seen between diuretic strategy and low-dose dopamine (p > 0.10).In HFpEF patients hospitalized with acute heart failure, low-dose dopamine had no significant impact on renal function, and a continuous infusion diuretic strategy was associated with renal impairment. (Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction [ROPA-DOP]; NCT01901809).

  View details for DOI 10.1016/j.jchf.2018.04.008

  View details for PubMedID 30098962

• Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis. JAMA cardiology Alexander, K. M., Orav, J., Singh, A., Jacob, S. A., Menon, A., Padera, R. F., Kijewski, M. F., Liao, R., Di Carli, M. F., Laubach, J. P., Falk, R. H., Dorbala, S. 2018

  Abstract

  Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.Region of residence.Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.

  View details for DOI 10.1001/jamacardio.2018.2093

  View details for PubMedID 30046835

• True, true unrelated? Coexistence of Waldenstrom's macroglobulinemia and cardiac transthyretin Amyloidosis. Haematologica Singh, A., Geller, H. I., Alexander, K. M., Padera, R. F., Mitchell, R. N., Dorbala, S., Castillo, J. J., Falk, R. H. 2018

  View details for DOI 10.3324/haematol.2018.190405

  View details for PubMedID 29674499

• Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors Encyclopedia of Cardiovascular Research and Medicine Alexander, K. M., Nayor, M. 2018: 446–455

  View details for DOI https://doi.org/10.1016/B978-0-12-809657-4.64288-6

• Novel pharmacotherapies for cardiac amyloidosis. Pharmacology & therapeutics Alexander, K. M., Singh, A., Falk, R. H. 2017; 180: 129-138

  Abstract

  Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis.

  View details for DOI 10.1016/j.pharmthera.2017.06.011

  View details for PubMedID 28648829

  View details for PubMedCentralID PMC5832446

• Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis. JAMA Geller, H. I., Singh, A., Alexander, K. M., Mirto, T. M., Falk, R. H. 2017; 318 (10): 962-963

  View details for DOI 10.1001/jama.2017.9236

  View details for PubMedID 28898370

  View details for PubMedCentralID PMC5818850

• Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation. Cellular signalling Watson, L. J., Alexander, K. M., Mohan, M. L., Bowman, A. L., Mangmool, S., Xiao, K., Naga Prasad, S. V., Rockman, H. A. 2016; 28 (10): 1580-1592

  Abstract

  β2-Adrenergic receptors (β2AR) transactivate epidermal growth factor receptors (EGFR) through formation of a β2AR-EGFR complex that requires activation of Src to mediate signaling. Here, we show that both lipid and protein kinase activities of the bifunctional phosphoinositide 3-kinase (PI3K) enzyme are required for β2AR-stimulated EGFR transactivation. Mechanistically, the generation of phosphatidylinositol (3,4,5)-tris-phosphate (PIP3) by the lipid kinase function stabilizes β2AR-EGFR complexes while the protein kinase activity of PI3K regulates Src activation by direct phosphorylation. The protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation. This newly identified function for PI3K, whereby Src is a substrate for the protein kinase activity of PI3K, is of importance since Src plays a key role in pathological and physiological signaling.

  View details for DOI 10.1016/j.cellsig.2016.05.006

  View details for PubMedID 27169346

  View details for PubMedCentralID PMC4980165

• AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. Journal of the American College of Cardiology Falk, R. H., Alexander, K. M., Liao, R., Dorbala, S. 2016; 68 (12): 1323-1341

  Abstract

  The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease. The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel approaches to the diagnosis and treatment of cardiac amyloidosis are discussed, with particular reference to AL amyloidosis in the heart.

  View details for DOI 10.1016/j.jacc.2016.06.053

  View details for PubMedID 27634125

• V122I TTR Cardiac Amyloidosis in Patients of African Descent: Recognizing a Missed Disease or the Dog That Didn't Bark? CIRCULATION-HEART FAILURE Alexander, K. M., Falk, R. H. 2016; 9 (9)

  View details for DOI 10.1161/CIRCHEARTFAILURE.116.003489

  View details for Web of Science ID 000384460800011

  View details for PubMedID 27618856

• Grim Messenger: Virchow's Node Presenting with Virchow's Triad AMERICAN JOURNAL OF MEDICINE Alexander, K. M., Vaduganathan, M., Qamar, A., Gerhard-Herman, M. D. 2016; 129 (9): 948-951

  View details for DOI 10.1016/j.amjmed.2016.05.009

  View details for Web of Science ID 000382309900036

  View details for PubMedID 27267288

• Response by Alexander et al to Letters Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain" CIRCULATION Alexander, K. M., Veillet-Chowdhury, M. R., Macintyre, C. J., Loscalzo, J., Bhatt, D. L. 2016; 134 (4): E22-E23

  View details for DOI 10.1161/CIRCULATIONAHA.116.023204

  View details for Web of Science ID 000380136700003

  View details for PubMedID 27462059

• Utility of multimodality imaging in myopericarditis with aortitis. Journal of nuclear cardiology Qamar, A., Veeranna, V., Fatima, A., Alexander, K. M., Di Carli, M. F., Bonaca, M. P., Steigner, M., Dorbala, S. 2016: -?

  View details for PubMedID 27174190

• A Shocking Development in a Young Male Athlete With Chest Pain CIRCULATION Alexander, K. M., Veillet-Chowdhury, M. R., Macintyre, C. J., Loscalzo, J., Bhatt, D. L. 2016; 133 (8): 756-763

  View details for DOI 10.1161/CIRCULATIONAHA.115.019127

  View details for Web of Science ID 000371490400009

  View details for PubMedID 26903018

• Myocarditis and Pericarditis Infectious Diseases Emergencies Alexander, K. Oxford University Press. 2016: 103–106
• Mechanical circulatory support for advanced heart failure. Current treatment options in cardiovascular medicine Patel, C. B., Alexander, K. M., Rogers, J. G. 2010; 12 (6): 549-565

  Abstract

  Both acute and chronic systolic heart failure can progress to an advanced phase, resulting in stage D heart failure and even cardiogenic shock. Despite significant progress in the treatment of systolic heart failure using medical and device therapies, this terminal phase continues to be prevalent and associated with unacceptably high morbidity and mortality. Given the inability to offer cardiac transplantation to the majority of those presenting with advanced heart failure, alternative strategies for cardiac replacement therapy are often required. Although there has been interest in using mechanical devices to support the circulation since the advent of cardiopulmonary bypass, it is only in the past 20 years that ventricular assist devices (VAD) have become viable options for therapy. Indeed, we are now entering an era where circulatory assist devices are being used not only to temporarily support patients with post-cardiotomy shock, but also as a long-term treatment in ambulatory heart failure patients. Furthermore, we are now able to utilize data from multicenter trials and registries to guide treatment decisions. These data have clearly shown that VADs improve survival and quality of life in patients with advanced heart failure when implanted as a temporary measure (bridge to recovery and bridge to transplant) or as long-term support (destination therapy). However, with a growing heart failure population there is much work to be done to improve VAD technology, patient selection, post-implantation management, and to define the optimal role for assist devices in the management of systolic heart failure. We are also in the nascent stages of fully understanding the impact of mechanical support on the failing myocardium, and developing research methodologies to study novel therapies in tandem with VADs to facilitate ventricular recovery. These important questions are currently being addressed in ongoing clinical trials, registry analyses, and translational research endeavors.

  View details for DOI 10.1007/s11936-010-0093-6

  View details for PubMedID 21063932

• A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus Envelope Glycoprotein Trimer JOURNAL OF VIROLOGY Xiang, S., Finzi, A., Pacheco, B., Alexander, K., Yuan, W., Rizzuto, C., Huang, C., Kwong, P. D., Sodroski, J. 2010; 84 (7): 3147-3161

  Abstract

  Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 beta2, beta19, beta20, and beta21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

  View details for DOI 10.1128/JVI.02587-09

  View details for Web of Science ID 000275307400002

  View details for PubMedID 20089638

  View details for PubMedCentralID PMC2838131