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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.

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 (BMI30 kg/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%, p0.05). 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 p0.10). 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.

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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.

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.

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.

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.To assess the accuracy of a deep learning workflow in quantifying ventricular hypertrophy and predicting the cause of increased LV wall thickness.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.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.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.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.

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.

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. Conclusions: 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.

In vivo mechanisms of amyloid clearance and cardiac tissue damage in cardiac amyloidosis are not well understood.We aimed to define and quantify the amyloid plaque proteome in cardiac transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL) and identify associations with patient characteristics and outcomes.A proteomics approach was used to identify all proteins in cardiac amyloid plaques, and to compare both normal and diseased controls. All proteins identified within amyloid plaques were defined as the expanded proteome; only proteins that were enriched in comparison to normal and disease controls were defined as the amyloid-specific proteome.Proteomic data from 292 patients with ATTR and 139 patients with AL cardiac amyloidosis were included; 160 and 161 unique proteins were identified in the expanded proteomes, respectively. In the amyloid-specific proteomes, we identified 28 proteins in ATTR, 19 in AL amyloidosis, with 13 proteins overlapping between ATTR and AL. ATTR was characterized by a higher abundance of complement and contractile proteins and AL by a higher abundance of keratins. We found that the proteome of kappa AL had higher levels of clusterin, a protective chaperone, and lower levels of light chains than lambda despite higher levels of circulating light chains. Hierarchical clustering identified a group of patients with worse survival in ATTR, characterized by high levels of PIK3C3, a protein with a central role in autophagy.Cardiac AL and ATTR have both common and distinct pathogenetic mechanisms of tissue damage. Our findings suggest that autophagy represents a pathway that may be impaired in ATTR and should be further studied.

Social determinants of health in the African diaspora drive the lack of disease testing, increased prevalence of comorbid disease and reduced access to drugs, resulting in disproportionately higher COVID-19-related mortality among Black individuals than the rest of the population. We urge decisive attention to and action against ethnicity-based inequities that undermine cardiovascular health.

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.

Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual health care 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 this study were to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals.This retrospective study used National Vital Statistics Data from 1999 to 2016 provided by the Centers for Disease Control and International Classification of Diseases (10th edition) codes for heart failure and dementia as defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed to by both heart failure and dementia totaled 214,706 and constituted 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% confidence interval [CI] 38.47-38.87) versus 32.90 (95% CI 32.65-33.15; P.001). Whites were affected more than blacks, with age-adjusted mortality rates (per 1,000,000 person-years) of 38.00 (95% CI 37.83-38.16) versus 31.06 (95% CI 30.54-31.59; P.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.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 of age, whites, and women.

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.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Transthyretin cardiac amyloidosis is a morbid, life-threatening disease. Gradual amyloid fibril deposition can lead to arrhythmias, heart failure, and sudden death. Once thought to be rare, transthyretin cardiac amyloidosis is simply under-recognized and underdiagnosed. Moreover, a significant burden of transthyretin amyloidosis exists among certain racial and ethnic populations, such as African Americans, due to the relatively high prevalence of amyloidogenic transthyretin mutations in these groups. In recent years, bone scintigraphy imaging has enabled a non-invasive way to diagnose this disease in certain cases. Furthermore, effective therapies have emerged for transthyretin amyloidosis. These treatments appear to be most effective if started before significant amyloid deposition has occurred. Despite these advances, significant barriers remain for promoting the early and accurate diagnosis of transthyretin amyloidosis, particularly among African American and Hispanic populations. Therefore, raising disease awareness and promoting targeted screening are of upmost importance to improve outcomes for this disease.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a disease with high morbidity and mortality. This disease is significantly underdiagnosed and is more common than previously appreciated, particularly among older adults and people of African descent. This review discusses recent advances in the diagnosis and treatment for ATTR-CM. Historically, ATTR-CM was diagnosed via endomyocardial biopsy, a resource-intensive and invasive approach. However, in most cases, ATTR-CM can now be diagnosed non-invasively using bone tracer cardiac scintigraphy, which may facilitate earlier diagnosis. In recent clinical trials, a transthyretin stabilizer (tafamidis) and transthyretin gene silencers (patisiran and inotersen) have emerged as effective ATTR amyloidosis therapies and have been approved for use in the USA and many other countries. ATTR-CM is now recognized as an important cause of heart failure. Approaches to the diagnosis and treatment of ATTR-CM are rapidly evolving. Now, more than ever, there are opportunities to improve clinical care of patients with this challenging disease.

OBJECTIVES: This study aimed to characterize trends in technetium Tc 99m pyrophosphate ((99m)Tc-PYP) scanning for amyloid transthyretin cardiac amyloidosis (ATTR-CA) diagnosis, to determine whether patients underwent appropriate assessment with monoclonal protein and genetic testing, to evaluate use of single-photon emission computed tomography (SPECT) in addition to planar imaging, and to identify predictive factors for ATTR-CA. BACKGROUND: (99m)Tc-PYP scintigraphy has been repurposed for noninvasive diagnosis of ATTR-CA. Increasing use of (99m)Tc-PYP can facilitate identification of ATTR-CA, but appropriate use is critical for accurate diagnosis in an era of high-cost targeted therapeutics. METHODS: Patients undergoing (99m)Tc-PYP scanning 1 h after injection at a quaternary care center from 2010 to 2019 were analyzed; clinical information was abstracted; and SPECT results were analyzed. RESULTS: Over the decade, endomyocardial biopsy rates remained stable with scanning rates peaking at 132 in 2019 (p < 0.001). Among 753 patients (516 men, mean age 77 years), 307 (41%) had a visual score of 0, 177 (23%) of 1, and 269 (36%) of 2 or 3. Of 751 patients with analyzable heart to contralateral chest ratios, 249 (33%) had a ratio ≥1.5. Monoclonal protein testing status was assessed in 550 patients, of these, 174 (32%) did not undergo both serum immunofixation and serum free light chain analysis tests, and 331 (60%) did not undergo all 3 tests—serum immunofixation, serum free light chain analysis, and urine protein electrophoresis. Of 196 patients with confirmed ATTR-CA, 143 (73%) had genetic testing for transthyretin mutations. In 103 patients undergoing cardiac biopsy, grades 2 and 3 99mTc-PYP had sensitivity of 94% and specificity of 89% for ATTR-CA with 100% specificity for grade 3 scans. With respect to SPECT as a reference standard, planar imaging had false positive results in 16 of 25 (64%) grade 2 scans. CONCLUSIONS: Use of noninvasive testing with (99m)Tc-PYP scanning for evaluation of ATTR-CA is increasing, and the inclusion of monoclonal protein testing and SPECT imaging is crucial to rule out amyloid light chain amyloidosis and distinguish myocardial retention from blood pooling.

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.

Supplemental Digital Content is available in the text., Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. Methods: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin 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 antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. 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 antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

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.

Objectives 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). Background 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. Methods 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. Results 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). Conclusions 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)

Purpose Characteristics and outcomes of heart transplant (HT) recipients who contract coronavirus (SARS-CoV-2) have been poorly described. The current study was undertaken to better understand the risk obesity may pose in this patient population Methods A prospectively-maintained Trans-CoV-VAD Registry containing HT recipients at 11 participating institutions who presented with SARS-CoV-2 were reviewed. Presenting characteristics, hospitalization rates, ventilator & intensive care unit usage, and mortality were queried. Patients were grouped by body mass index (BMI) into obese (BMI≥30 k/m2) and non-obese cohorts (BMI0.10) Conclusion Acute presentations of SARS-CoV-2 amongst HT recipients carry significantly higher mortality over the general population. Obesity appears to impact presenting symptoms and secondary infections, but does not strongly impact ICU requirements or mortality

Purpose Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HTx). The purpose of this study was to determine the mortality risk and incidence of PGD pre- and post-implementation of the new UNOS heart allocation policy. Methods A total of 426 consecutive adult patients underwent HTx from 1/2010 to 5/2019. Recipients of combined organ transplants were excluded. Definition of severe PGD was based on the 2014 ISHLT consensus statement which includes dependence on mechanical circulatory support, excluding requirement for intra-aortic balloon pump (IABP). The primary outcome was the incidence of PGD and overall 1-year survival. Results The cohort studied was predominantly male (70.8%), with a mean age of 53.4±12.8 years; 31.6% were supported with a left ventricular assist device as a bridge to HTx, and 38.4% were blood type O. There were 17 (4.0%) cases of severe PGD, all of which required extracorporeal membrane oxygenation support. Baseline characteristics pre-HTx were similar in those with and without PGD (Figure 1). There was no difference in the incidence of severe PGD following the introduction of the new allocation policy in October 18, 2018 (5.9 vs. 4.5%, p=0.70), but there was a significant increase in the use of post-transplant IABP (23.5 vs. 9.1%, p=0.009). There was no correlation between RADIAL score and incidence of severe PGD (p=0.41). Severe PGD was associated with reduced 30-day survival (97.6% [95% CI: 95.5-98.8] vs. 68.7% [40.5-85.6], p Conclusion Incidence of severe PGD has not increased in the contemporary era with the new UNOS heart allocation policy. PGD is associated with poor 1-year survival and is not predicted by the RADIAL score, which underscores the need for a new risk prediction model.

Objectives The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience. Background 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. Methods 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. Results 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. Conclusions 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.

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.

Amyloid light chain (AL) amyloidosis results from tissue deposition of clonal light chains, most commonly produced by clonal plasma cells. AL amyloidosis is closely associated with multiple myeloma (MM), another disease which arises from clonal plasma cell proliferation. Here we aim to identify gene signatures to distinguish AL cardiomyopathy (AL-CM) risk in MM patients. We utilized publicly available data sets and applied Graph Cluster Perturbation approach to cluster the co-expression networks based on pathways in MM and AL-CM utilizing 225 samples from four datasets: GSE42955 study (12 dilated CM, 12 ischemic CM and 5 control LV human heart tissues), GSE95077 study (16 amiloride drug treated/untreated myeloma cell line samples), GSE24128 study (16 newly diagnosed AL with monoclonal plasma cell samples over- or under-expressing cyclin D1), and GSE6477 study (76 primary bone marrow samples from hyper-diploid myeloma patients and 80 non-hyperdiploid MM patients). From these data sets, the networks for extracellular matrix organization, immune system, innate immune system, metabolism, and neutrophil degranulation pathways for MM and amyloid CM were extracted. Summary: Ranking of the perturbed genes based on pathways similarity index in MM and AL resulted in a panel of genes: CD44, NRAS, GRAP2, CTLA4, GSN, CCND1, NFKB1, and IRF1 (p= Figure , the high hazard ratio of this gene cluster in MM with AL-CM (3.76; p=0.021) compared to MM without CM (0.96; p=0.032) suggests the potential of this gene panel to distinguish high or low risk groups in MM based on survival.

Background: Neonatal mammalian hearts have the unique characteristic to fully repair and regenerate following injury. This discovery has led to visionary endeavors to understand and subsequently reawaken regeneration processes in the human adult heart that are lost after birth, contributing to heart failure and death after ischemic insults. In utero exposure to tobacco smoke has detrimental effects on fetal development and growth. However, the consequences of prenatal exposure to cigarette smoke on murine neonate’s cardiac regeneration have never been explored. Methods: To study the impact of cigarette smoke during the entire pregnancy on cardiac regeneration in the offspring, plugged female wild type C57LB/6J mice were exposed either to cigarette smoke (n=6) or filtered air (control, n=6). Two days after birth, 5 pups from each litter were assigned to the two experimental groups: Myocardial infarction (MI) and sham. Detrimental effects of in utero exposure to tobacco smoke on the recovery of cardiac function following MI surgery were followed using two-dimensional speckle tracking echocardiography and strain imaging. To investigate the underlying mechanism, cardiac tissue of the infarct and remote zone was collected for non-coding RNA analysis. Results: In utero exposure to cigarette smoke significantly compromised cardiac regeneration in neonates. At both early and late time points in the phase of cardiac repair, hearts of neonates exposed to cigarette smoke during pregnancy showed a marked impairment of cardiac regenerative potential. In particular, ejection fraction, fractional area change and shortening, as well as left ventricular internal diameter during systole remained pathologically changed following MI insult in the smoked group until the very endpoint. Conclusions: Collectively, we here provide evidence that in utero exposure to cigarette smoke strongly compromises cardiac regeneration in the newborn offspring. This result reinforces smoking cessation during pregnancy. Additionally, understanding the changes in non-coding RNA expression in a setting of preserved versus disrupted repair of the heart might be an important first step towards the identification of key cellular processes in cardiac regeneration after injury.

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.

Purpose Infection with the Coronavirus (SARS-CoV-2) is particularly dangerous for patients with left ventricular assist devices (LVAD). Obesity is associated with worse outcomes among both LVAD and SARS-CoV-2 patients. This study evaluated the risk of obesity among LVAD patients who contracted SARS-CoV-2. Methods A prospectively maintained Trans-CoV-VAD Registry of LVAD patients from 11 institutions who presented with SARS-CoV-2 was analyzed. Two cohorts, 1) non-obese and 2) obese, were formed utilizing a body mass index (BMI) cutoff of 30 k/m2. Presenting characteristics, hospitalization rates, ventilator & intensive care unit usage, and mortality were compared. Chi-squared, Fisher's exact test, Mann-Whitney U-tests and multivariable logistic regression models were utilized. Results Across all centers, 46 LVAD patients contracted SARS-CoV-2 during the study period of whom 19 (41%) were obese. Time from LVAD implantation to infection was 2.4±2.5 years. Age and gender profiles were similar. Non-obese and obese patients had similar presenting symptoms, most commonly cough (52% vs 47%), fever (48% vs 37%), dyspnea (41% vs 47%) and fatigue (41% vs 37%). No difference in rates of hospital (70% vs 63%, p 0.8) and ICU admissions (26% vs 37%, p 0.3) was observed. Hospital (20.0±23.2 vs 17.1±14.2) and ICU length of stay were similar (16.2±26.1 vs. 13.9±13.1 days). Obese patients were more likely to require mechanical ventilation than non-obese patients (7% vs 26%, p0.10). Conclusion Among LVAD patients who contract SARS-CoV-2, obese patients appear to have higher risk of intubation, but did not experience increased ICU requirements or mortality.

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.

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.

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Deepak L. Bhatt), who responds to the information, sharing his reasoning with the reader (regular type). A discussion by the authors follows. P atient presentation: A 32-year-old male endurance athlete with no significant past history was admitted after experiencing multiple episodes of chest tightness while training for a triathlon. Occasionally, when running up hills, he noted substernal chest pressure that radiated to his left arm and was associated with severe shortness of breath. His past medical history includes seasonal allergic rhinitis and childhood asthma. He takes cetirizine/pseudoephedrine occasionally, but has not taken it recently, and denies taking any other medication or over-the-counter supplement. He admits to occasional binge drinking of 6 to 10 beers once or twice a month. He quit smoking 2 years ago but previously smoked a pack a week for 5 years. He also endorsed a remote history of cocaine use and recent marijuana and energy drink (1–2 small cans; 80 mg of caffeine per 8.4-oz can) use. His family history is only notable for a maternal grandmother who had a myocardial infarction in her 60s and a sister diagnosed with an atrial tachycardia. There is no history of premature coronary artery disease, heart failure, or sudden death. His biological parents and brother are alive and well. Dr Bhatt: At this point, the differential diagnosis for chest pain in a young, otherwise healthy patient is broad. Certainly, the exertional component of his symptoms is concerning and raises the possibility of premature coronary artery disease, although the family history obtained does not suggest a strong predisposition for atherosclerosis. Coronary artery vasospasm would be another possibility, and he has several potential triggers, including alcohol, pseudoephedrine, caffeine, and marijuana use. Vasospasm can occur with …

Importance 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. Objective 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. Design, Setting, and Participants 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. Exposures Region of residence. Main Outcomes and Measures Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence. Results 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. Conclusions and Relevance 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.

Stage A heart failure is characterized by the presence of heart failure risk factors without evidence of cardiac structural or functional abnormalities and without heart failure symptoms. Coronary heart disease, hypertension, obesity, diabetes, and smoking are among the most important heart failure risk factors for new-onset heart failure and are responsible for the greatest population attributable risk. An increasing number of additional risk factors contribute to heart failure progression, and the associated risks vary according to the clinical situation. Early identification and treatment of heart failure risk factors (when indicated) is necessary to prevent disease progression.

Amyloidosis is a multisystem disease involving tissue deposition of misfolded proteins resulting in organ dysfunction and is associated with significant morbidity and mortality. Recent amyloid ligh...

This cross-sectional study compares the frequency of rupture of the distal biceps tendon in patients with wild-type transthyretin amyloidosis cardiomyopathy vs those with other causes of heart failure.

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.

Purpose Cardiac amyloidosis causes significant morbidity and mortality, leading to restrictive cardiomyopathy, heart failure, and death. Many patients are diagnosed late when irreversible amyloid fibril deposition has occurred. Heart transplantation may be considered in such patients. Historically, heart transplant outcomes were worse in cardiac amyloid patients compared with other types of heart failure, in part due to the systemic nature of the disease. However, effective therapies, particularly for light chain (AL) amyloidosis, have emerged, and disease remission is now possible. We aimed to assess whether transplant outcomes for cardiac amyloidosis are better in the contemporary era. Methods We studied cardiac amyloid patients seen during 2004-2017 at the Stanford University and Kaiser Permanente Santa Clara medical centers who underwent heart transplantation. We examined pre-transplant characteristics and post-transplant outcomes in this group compared with the overall transplant population at our centers. Results During the study period, 31 patients (13 with AL amyloidosis and 18 with transthyretin (ATTR) amyloidosis) underwent heart transplantation. ATTR patients were older, more likely to be male, had worse baseline renal function, and had longer waitlist times compared with AL patients and the overall transplant population. Post-transplant, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in the overall survival between cardiac amyloid patients and the overall population (median follow up: 1462 days; Figure 1). Conclusion This single-center, retrospective study reports detailed, long-term heart transplantation outcomes in a large cohort of cardiac amyloid patients. 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.

Purpose Managing venous thromboembolism (VTE) and Atrial Fibrillation (AF) with warfarin can be difficult given the frequent need to hold anticoagulation for procedures performed; however there is limited evidence on the safety and efficacy of direct-acting oral anticoagulants (DOAC) in HTx recipients. Methods Single-center, retrospective study of all HTx recipients who received oral anticoagulation between January 2010 and August 2018. Patients were classified according to warfarin vs DOAC use and their baseline characteristics were compared using Student's t test or chi-square test where appropriate. We compared bleeding among groups, defined as any significant blood loss requiring discontinuation of anticoagulation within the first year of treatment using univariable logistic regression. We assessed survival after initiation of anticoagulation among groups using Kaplan-Meier curves and the log-rank test. Results Among 426 HTx recipients screened, 80 patients were intitiated on oral anticoagulation for VTE in 75 (94%) and AF in 5 (6%) cases. Overall, warfarin was used in 27 (34%) and DOAC in 62 (78%) cases of whom 36, 21 and 5 were on apixaban, dabigatran and rivaroxaban, respectively. The median (IQR) time to initiation of warfarin and DOAC were respectively 61 (26-267) and 33 (16-135) days following HTx. Baseline characteristics showed more women, lower GFR and higher dialysis use in the warfarin group. Warfarin was associated with a significant increase in bleeding (OR 4.55, 95% CI 1.2 to 16.2), as well as bleeding requiring blood products (OR 7.6, 95% CI 1.4 to 42.8). There was no difference in overall survival between groups (logrank P = NS). No bleeding complications occurred following endomyocardial biopsy. Conclusion This is the largest cohort of HTx recipients treated with oral anticoagulants. Patients selected for DOAC had better baseline renal function than those treated with warfarin, but there were no differences in subsequent survival or procedural complications.

We thank Dr McGorrian and colleagues for their insights on our challenging case recently presented in Circulation .1 Eosinophilic coronary periarteritis is an intriguing potential cause of our patient’s presentation. As the authors describe, the disease entity has been characterized in patients with coronary artery vasospasm and associated coronary dissection or sudden cardiac death. As in our case, some may have a preexisting history of atopy. The most distinguishing features of eosinophilic coronary periarteritis are appreciated by histology, which reveals eosinophilic infiltration isolated to the adventitia and vasa vasorum of the epicardial coronary arteries.2 Thus, this diagnosis is difficult to confirm outside of autopsy. Some features of our case make eosinophilic coronary periarteritis less likely to be the main contributor to his presentation. On coronary angiography, there was no evidence of aneurysmal changes, which …