Dr. Alexander is an advanced heart failure-trained cardiologist. He is also an Assistant Professor of Cardiovascular Medicine at Stanford University School of Medicine.
Dr. Alexander specializes in the management of advanced heart failure and transplant cases, seeing a wide range of patients. He also has an active research laboratory, studying various forms of heart failure.
Dr. Alexander has expertise in diagnosing and treating transthyretin cardiac amyloidosis, a critical yet underdiagnosed cause of heart failure among African Americans and the elderly. He is conducting extensive research to enhance our understanding of this condition, with grant support from the National Institutes of Health and American Heart Association, among other sources.
- Heart Failure
- Heart Transplantation
- Mechanical Circulatory Support
- Cardiovascular Disease
Honors & Awards
Sarnoff Cardiovascular Research Fellowship, Sarnoff Cardiovascular Foundation (2009-2011)
Gertrude M and Ezra M. Eisen Prize for Cardiovascular Research, University of Pennsylvania (2011)
ASPIRE Transthyretin Amyloidosis Competitive Research Grant, Pfizer (2017)
Carl Storm Underrepresented Minority Fellowship, Gordon Research Conference (2017)
Thomas W. Smith Fellowship in Heart Failure, Brigham and Women’s Hospital (2017)
Loan Repayment Program Award, National Institutes of Health (2017-2019, 2019-2020)
Presidential Travel Award, International Society of Amyloidosis (2018)
Fellow, American College of Cardiology (2019-)
Harold Amos Medical Faculty Development Program Award, American Heart Association (2019-2023)
Stanford KL2 Mentored Career Development Program Award, National Institutes of Health (2020-2022)
Fellow, Heart Failure Society of America (2021-)
Boards, Advisory Committees, Professional Organizations
Member, Alumni Committee, Sarnoff Cardiovascular Research Foundation (2017 - 2019)
Co-Chair, Diversity and Inclusion Committee, California Chapter, American College of Cardiology (2018 - Present)
Editorial Board, Circulation Research (2019 - Present)
Member, BCVS Early Career Committee, American Heart Association (2020 - Present)
Member, Scientific Advisory and Coordinating Committee, American Heart Association (2021 - Present)
Board Certification: American Board of Internal Medicine, Heart Transplant (2020)
Board Certification, American Board of Internal Medicine, Advanced Heart Failure and Transplant Cardiology (2020)
Board Certification, American Board of Internal Medicine, Cardiovascular Disease (2017)
Board Certification, American Board of Internal Medicine, Internal Medicine (2014)
Fellowship, Stanford Health Care, Advanced Heart Failure and Transplant Cardiology (2019)
Fellowship, Brigham and Women's Hospital, Cardiovascular Medicine (2017)
Residency, Johns Hopkins Hospital, Internal Medicine (2014)
M.D., University of Pennsylvania (2011)
B.S., Yale University, Molecular Biophysics and Biochemistry (2006)
CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC). For more information, please visit https://www.cardio-ttransform.com.
Daratumumab-SC for Highly Sensitized Patients Awaiting Heart Transplantation
The purpose of this study is to test whether Daratumumab-SC, a drug that eliminates antibody-producing plasma cells, can effectively lower the level of preformed antibodies in patients awaiting heart transplantation. These preformed antibodies limit the number of donor hearts that are compatible for the patients. If Daratumumab-SC can effectively remove preformed, donor-specific antibodies, then highly allosensitized patients will have more compatible hearts available to them, potentially decreasing transplant waitlist time and reducing mortality.
HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy
This study will evaluate the efficacy and safety of vutrisiran 25 mg administered subcutaneously (SC) once every 3 months (q3M) compared to placebo in patients with ATTR amyloidosis with cardiomyopathy.
MitraClip REPAIR MR Study
The objective of this randomized controlled trial (RCT) is to compare the clinical outcome of MitraClip™ device versus surgical repair in patients with severe primary MR who are at moderate surgical risk and whose mitral valve has been determined to be suitable for correction by MV repair surgery by the cardiac surgeon on the local site heart team.
High-Throughput Precision Phenotyping of Left Ventricular Hypertrophy With Cardiovascular Deep Learning.
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 Springer. 2022; 1: 219-237
Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review.
Circulation. Genomic and precision medicine
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
2021; 15 (6)
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
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
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
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
- Cardiac Amyloid Heart Disease in Racial/Ethnic Minorities: Focus on Transthyretin Amyloid Cardiomyopathy CARDIOVASCULAR DISEASE IN RACIAL AND ETHNIC MINORITY POPULATIONS, 2 EDITION 2021: 201-215
Future Perspectives of Cardiovascular Biomarker Utilization in Cancer Survivors: A Scientific Statement From the American Heart Association.
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
Electrocardiogram Characteristics and Prognostic Value in Light-Chain Amyloidosis: A Comparison With Cardiac Magnetic Resonance Imaging.
Frontiers in cardiovascular medicine
1800; 8: 751422
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
- Transthyretin Cardiac Amyloidosis in the Elderly-Tip of a Heart Failure Iceberg? JAMA cardiology 2021
- Mistaken Identity: Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy JACC: CardioOncology 2021; 3 (4): 594-597
Characteristics and Outcomes of COVID-19 in Patients on Left Ventricular Assist Device Support.
Circulation. Heart failure
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 2020; 2 (4): 644–46
High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function.
Journal of visualized experiments : JoVE
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 2020
Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation.
JACC. Heart failure
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
- Pulling at the heart: COVID-19, race/ethnicity and ongoing disparities. Nature reviews. Cardiology 2020
Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis.
Current cardiology reports
2020; 22 (1): 1
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 2020
- Advances in the Diagnosis and Management of Transthyretin Amyloid Cardiomyopathy Curr Treat Options Cardio Med 2020; 22 (45)
Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.
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
Serum high-density lipoprotein cholesterol serves as a prognostic marker for light-chain cardiac amyloidosis.
International journal of cardiology
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
Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias.
2019; 37 (4): 487–95
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
Prenatal Exposure of Cigarette Smoke Impacts Cardiac Regeneration
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000511467800423
Gene Signatures to Distinguish Amyloid Cardiomyopathy Risk in Multiple Myeloma Patients
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000511467800441
Emerging Therapies for Transthyretin Cardiac Amyloidosis.
Current treatment options in cardiovascular medicine
2019; 21 (8): 40
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
- 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 2019: 1–2
Management of Cardiac Amyloidosis: Do's and Don'ts.
The Canadian journal of cardiology
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
Mortality from Heart Failure and Dementia in the United States: CDC WONDER 1999-2016.
Journal of cardiac failure
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
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.
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 2018
Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors
Encyclopedia of Cardiovascular Research and Medicine
View details for DOI https://doi.org/10.1016/B978-0-12-809657-4.64288-6
Novel pharmacotherapies for cardiac amyloidosis.
Pharmacology & therapeutics
2017; 180: 129-138
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 2017; 318 (10): 962-963
Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation.
2016; 28 (10): 1580-1592
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
2016; 68 (12): 1323-1341
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 2016; 9 (9)
- Grim Messenger: Virchow's Node Presenting with Virchow's Triad AMERICAN JOURNAL OF MEDICINE 2016; 129 (9): 948-951
- Response by Alexander et al to Letters Regarding Article, "A Shocking Development in a Young Male Athlete With Chest Pain" CIRCULATION 2016; 134 (4): E22-E23
Utility of multimodality imaging in myopericarditis with aortitis.
Journal of nuclear cardiology
View details for PubMedID 27174190
- A Shocking Development in a Young Male Athlete With Chest Pain CIRCULATION 2016; 133 (8): 756-763
- Myocarditis and Pericarditis Infectious Diseases Emergencies Oxford University Press. 2016: 103–106
Mechanical circulatory support for advanced heart failure.
Current treatment options in cardiovascular medicine
2010; 12 (6): 549-565
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
2010; 84 (7): 3147-3161
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