Validation of the Minnesota Pectoralis Risk Score to predict mortality in the HeartMate 3 population.

BACKGROUND: The Minnesota Pectoralis Risk Score (MPRS) utilizes computed tomography-quantified thoracic muscle and clinical variables to predict survival after left ventricular assist device (LVAD) implantation. The model has not been prospectively tested in HeartMate 3 recipients. METHODS: A single-center HeartMate 3 cohort from July 2016 to July 2021 (n = 108) was utilized for this analysis. Cohort subjects with complete covariates for MPRS calculation (pectoralis muscle measures, Black race, creatinine, total bilirubin, body mass index, bridge to transplant status, and presence/absence of contrast) implanted after MPRS development were included. MPRS were calculated on each subject. Receiver operating characteristic curves were generated to test model discrimination at 30-day, 90-day, and 1-year mortality post-LVAD. Next, the performance of the 1-year post-LVAD outcome was compared to the HeartMate 3 survival risk score (HM3RS). RESULTS: The mean age was 58 (15 years), 80% (86/108) were male, and 26% (28/108) were destination therapy. The area under the curve (AUC) for the MPRS model to predict post-LVAD mortality was 0.73 at 30 days, 0.78 at 90 days, and 0.81 at 1 year. The AUC for the HM3RS for the 1-year outcome was 0.693. Each 1-unit point of the MPRS was associated with a significant increase in the hazard rate of death after LVAD (hazard ratio 2.1, 95% confidence interval 1.5-3.0, p < 0.0001). CONCLUSIONS: The MPRS had high performance in this prospective validation, particularly with respect to 90-day and 1-year post-LVAD mortality. Such a tool can provide additional information regarding risk stratification to aid informed decision-making.

Outcomes of Patients Referred for Cardiac Rehabilitation After Left Ventricular Assist Device Implantation.

A single-center continuous-flow left ventricular assist device (LVAD) cohort (n = 503) was reviewed for patients with information on cardiac rehabilitation (CR) participation (n = 273) over a 13-year period. The analysis was then limited LVAD recipients who fit into three main CR categories: those who graduated CR (n = 138), those who were able to but declined participation (n = 61), and those who were too sick to complete or start CR (n = 28). To assess the association between CR categories and mortality and hospitalizations on LVAD support, multivariate cox regression and negative binomial regression analyses were performed, respectively. Among those who started CR and had the opportunity to finish (enough follow-up time, insurance coverage), 79% graduated. Those who graduated CR had a 96% survival at 1 year (95% confidence interval [CI], 91-98). Compared with the graduated group, those in the too sick group had an increased hazards rate of mortality (hazard ratio, 2.85; 95% CI, 1.49-5.44; p < 0.01) and an increase in the incidence rate of hospitalizations (incidence rate ratio, 1.74; 95% CI, 1.14-2.66, p = 0.01). This study is the largest to date to report outcomes of LVAD recipients referred for CR. The lower readmission rates and high survival in the group that graduated CR provides further evidence for the safety of CR in LVAD recipients.

Disparities in Practice Patterns by Sex, Race, and Ethnicity in Patients Referred for Advanced Heart Failure Therapies.

Advanced heart failure (HF) therapies improve survival in patients with stage D HF. We sought to evaluate differences by race/ethnicity and sex in advanced HF therapy referrals and decision-making across a multicenter survey. We performed a retrospective analysis of patients referred for evaluation for advanced HF therapies at 9 centers (n = 515) across the United States. The median age was 58 years, and 73% were male. White patients comprised 55.7% of referrals, whereas non-White patients comprised 44.3%. Non-ischemic etiology was more common in non-White patients (66.6% vs 47.4% p = 0.0005), and ischemic etiology was more common in men (37.8% vs 20.4% p = 0.0005). The primary reason for referral differed by race/ethnicity but not sex, with ventricular arrhythmias (7.6% vs 3%, p = 0.024) and pulmonary hypertension (3.4% vs 0.4% p = 0.018) being more common in White patients, whereas worsening HF was less common (25.4% vs 35.9%; p = 0.009). White patients were offered left ventricular assist devices (LVADs) (60.3% vs 54.7 p = 0.039) and heart transplants (51.8% vs 33.1% p = 0.0007) more often than non-White patients. The preference not to pursue LVAD therapy was more common in non-White patients (17.6% vs 9.6%; p = 0.049). Men were more often declined for a heart transplant because of psychosocial contraindications (34% vs 15%, p = 0.005). In conclusion, in this multicenter analysis of referrals for advanced HF therapies, we observed significant differences by race, ethnicity, and sex in both referral characteristics and evaluation outcomes. Further investigation is warranted to better understand why rates of LVAD and transplantation may be lower in non-White patients who are referred for advanced therapies.

Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy.

More than 60% of hypertrophic cardiomyopathy (HCM)-causing mutations are found in the gene loci encoding cardiac myosin-associated proteins including myosin heavy chain (MHC) and myosin binding protein C (MyBP-C). Moreover, patients with more than one independent HCM mutation may be at increased risk for more severe disease expression and adverse outcomes. However detailed mechanistic understanding, especially at early stages of disease progression, is limited. To identify early-stage HCM triggers, we generated single (MYH7 c.2167C > T [R723C] with a known pathogenic significance in the MHC converter domain) and double (MYH7 c.2167C > T [R723C]; MYH6 c.2173C > T [R725C] with unknown significance) myosin gene mutations in human induced pluripotent stem cells (hiPSCs) using a base-editing strategy. Cardiomyocytes (CMs) derived from hiPSCs with either single or double mutation exhibited phenotypic characteristics consistent with later-stage HCM including hypertrophy, multinucleation, altered calcium handling, metabolism, and arrhythmia. We then probed mutant CMs at time points prior to the detection of known HCM characteristics. We found MYH7/MYH6 dual mutation dysregulated extracellular matrix (ECM) remodeling, altered integrin expression, and interrupted cell-ECM adhesion by limiting the formation of focal adhesions. These results point to a new phenotypic feature of early-stage HCM and reveal novel therapeutic avenues aimed to delay or prohibit disease onset.

A rare case report of severe cardiomyopathy associated with myotonic dystrophy type 2.

Background: Myotonic dystrophies (DM) are multi-systemic diseases characterized by muscle weakness and myotonia. Despite a growing appreciation for the cardiovascular manifestations in myotonic dystrophy type 1 (DM1), cardiac involvement in myotonic dystrophy type 2 (DM2) has been less well characterized. In patients with DM2, cardiomyopathy has rarely been described. Case summary: This case report describes a rare case of DM2 associated cardiomyopathy. A 56-year-old male with DM2 who presented with palpitations and fatigue. Cardiac magnetic resonance (CMR) imaging confirmed a severely enlarged left ventricular cavity with a left ventricular ejection fraction of 28% consistent with severely reduced global systolic function. The lateral wall epicardium exhibited late gadolinium enhancement in a pattern seen in myotonic dystrophy-related cardiomyopathy. Discussion: This case highlights the potential for significant cardiovascular involvement in DM2, as well as the importance of screening, including CMR imaging, and therapy in the myotonic dystrophy patient population.

Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation.

Human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are based on ground-breaking technology that has significantly impacted cardiovascular research. They provide a renewable source of human cardiomyocytes for a variety of applications including in vitro disease modeling and drug toxicity testing. Cardiac calcium regulation plays a critical role in the cardiomyocyte and is often dysregulated in cardiovascular disease. Due to the limited availability of human cardiac tissue, calcium handling and its regulation have most commonly been studied in the context of animal models. hiPSC-CMs can provide unique insights into human physiology and pathophysiology, although a remaining limitation is the relative immaturity of these cells compared to adult cardiomyocytes Therefore, this field is rapidly developing techniques to improve the maturity of hiPSC-CMs, further establishing their place in cardiovascular research. This review briefly covers the basics of cardiomyocyte calcium cycling and hiPSC technology, and will provide a detailed description of our current understanding of calcium in hiPSC-CMs.

Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.

BACKGROUND: Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure. OBJECTIVES: The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies. METHODS: To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and ß-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models. RESULTS: At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive ß-blocker therapy. CONCLUSIONS: The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of ß-blocker therapy in patients with dystrophinopathies.

Viral expression of a SERCA2a-activating PLB mutant improves calcium cycling and synchronicity in dilated cardiomyopathic hiPSC-CMs.

There is increasing momentum toward the development of gene therapy for heart failure (HF) that is defined by impaired calcium (Ca2+) transport and reduced contractility. We have used FRET (fluorescence resonance energy transfer) between fluorescently-tagged SERCA2a (the cardiac Ca2+ pump) and PLB (phospholamban, ventricular peptide inhibitor of SERCA) to test directly the effectiveness of loss-of-inhibition/gain-of-binding (LOI/GOB) PLB mutants (PLBM) that were engineered to compete with the binding of inhibitory wild-type PLB (PLBWT). Our therapeutic strategy is to relieve PLBWT inhibition of SERCA2a by using the reserve adrenergic capacity mediated by PLB to enhance cardiac contractility. Using a FRET assay, we determined that the combination of a LOI PLB mutation (L31A) and a GOB PLB mutation (I40A) results in a novel engineered LOI/GOB PLBM (L31A/I40A) that effectively competes with PLBWT binding to cardiac SERCA2a in HEK293-6E cells. We demonstrated that co-expression of PLBM enhances SERCA Ca-ATPase activity by increasing enzyme Ca2+ affinity (1/KCa) in PLBWT-inhibited HEK293 cell homogenates. For an initial assessment of PLBM physiological effectiveness, we used human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) from a healthy individual. In this system, we observed that adeno-associated virus 2 (rAAV2)-driven expression of PLBM enhances the amplitude of SR Ca2+ release and the rate of SR Ca2+ re-uptake. To assess therapeutic potential, we used a hiPSC-CM model of dilated cardiomyopathy (DCM) containing PLB mutation R14del, where we observed that rAAV2-driven expression of PLBM rescues arrhythmic Ca2+ transients and alleviates decreased Ca2+ transport. Thus, we propose that PLBM transgene expression is a promising gene therapy strategy that directly targets the underlying pathophysiology of abnormal Ca2+ transport and thus contractility in underlying systolic heart failure.

Prevalence of Myocardial Fibrosis by Left Ventricular Assist Device Apical Core Biopsy and Correlation with Other Markers of Myocardial Recovery.

Myocardial fibrosis identified by apical core pathology at the time of left ventricular assist device (LVAD) implantation may add information regarding myocardial recovery potential. In this analysis, we report the prevalence of myocardial fibrosis by cardiomyopathy type and its association with other known markers of left ventricular recovery. Left ventricular assist device core pathology was reviewed on 332 patients who underwent LVAD implantation at a single institution between 2005 and 2016. Baseline clinical and echocardiographic characteristics were compared among patients with and without myocardial fibrosis by cardiomyopathy type. Among the 332 LVAD core specimens, myocardial fibrosis was present in 79%. Myocardial fibrosis was more common in ischemic than in nonischemic patients (90% vs. 66%; p < 0.001). Patients with fibrosis were older than those without (58 ± 12 vs. 55 ± 19; p < 0.05). Among the nonischemic cardiomyopathy cases, those with fibrosis were more likely to have an implantable cardioverter defibrillator (ICD) 81% and to be diabetic 81%. Fibrosis was not associated with left ventricular end-diastolic diameter (LVEDD), creatinine, or N-terminal prohormone of brain natriuretic peptide (NT-pro BNP). Myocardial fibrosis by apical core biopsy correlated with several known markers of left ventricular recovery including cardiomyopathy type, age, and presence of an ICD. In nonischemic cardiomyopathy patients, the degree of myocardial fibrosis may add information regarding recovery potential.

Integrative effects of dystrophin loss on metabolic function of the mdx mouse.

Duchenne muscular dystrophy (DMD) is a disease marked by the development of skeletal muscle weakness and wasting. DMD results from mutations in the gene for the cytoskeletal protein dystrophin. The loss of dystrophin expression is not limited to muscle weakness but has multiple systemic consequences. Managing the nutritional requirements is an important aspect of the clinical care of DMD patients and is complicated by the poor understanding of the role of dystrophin, and dystrophic processes, in regulating metabolism. Here, we show that mdx mice, a genetic model of DMD, have significantly reduced fat mass relative to wild type C57BL/10. The alteration in body composition is independent of the presence of skeletal muscle disease, as it is still present in mice with transgenic expression of a fully-functional dystrophin in skeletal muscle. Furthermore, mdx mice do not increase their fat mass or body weight when housed under thermoneutral conditions, in marked contrast to C57BL/10 mice. We also demonstrated that mdx mice have significantly reduced fat metabolism and altered glucose uptake. These significant metabolic changes in dystrophic mice implicate dystrophin as an important regulator of metabolism. Understanding the metabolic functions of dystrophin is important for managing the nutritional needs of DMD patients.

Contemporary Controversies in Digoxin Use in Systolic Heart Failure.

Digoxin remains one of the oldest therapies for heart failure; however, its safety and efficacy have been controversial since its initial use. Questions that remain include the clinical efficacy of digoxin when added to contemporary medical therapy, when and if it should be added, and how to minimize adverse effects. In this review, we will summarize recent data on the use of digoxin in systolic heart failure and address some of the controversies regarding the role of digoxin in the modern era of heart failure treatment.

Dystrophin-Deficient Cardiomyopathy.

Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient.