Heart transplantation strategies in arrhythmogenic right ventricular cardiomyopathy: a tertiary ARVC centre experience.

AIMS: End-stage heart failure necessitating evaluation for heart transplantation is increasingly recognized in arrhythmogenic right ventricular cardiomyopathy (ARVC). These patients present unique challenges in pre-transplant and peri-transplant management given their predominantly right ventricular (RV) failure and propensity for ventricular arrhythmias. We sought to utilize a tertiary ARVC referral and heart transplant centre experience to describe management of a series of patients with ARVC undergoing heart transplantation at our centre. METHODS AND RESULTS: We queried the Johns Hopkins ARVC Registry for all patients who underwent heart transplantation and further studied the subset undergoing transplantation at the Johns Hopkins Hospital. Patient demographics, clinical characteristics, and pre-transplant clinical course were obtained from the registry and electronic medical records. Of the 532 patients in the ARVC Registry, 63 (12%) underwent heart transplantation. Nine (six male) of these patients both had known ARVC prior to transplant and were transplanted at Johns Hopkins Hospital between 2006 and 2020 at a mean age of 42 ± 14 years old. Pathogenic ARVC genetic variants were identified in six (67%) patients, all of whom had variants in the plakophilin-2 (PKP2) gene. RV failure was universal with median right atrial to pulmonary capillary wedge pressure (RA/PCWP) ratio of 1.4 [interquartile range (IQR) 1.2-1.5] and median right ventricular stroke work index (RVSWI) of 0 g·m/m2 /beat (IQR 0-0.3). Six had a history of catheter ablation for ventricular arrhythmia with five of the six having at least three ablations. Transplant evaluation was initiated an average of 344 ± 407 days after first developing heart failure symptoms. The most common bridge to transplant support included inotropes (n = 3) and extracorporeal membrane oxygenation (ECMO) (n = 2). Contraindication to inotropes or mechanical support was common due to ventricular arrhythmia and RV predominant cardiomyopathy. CONCLUSIONS: Heart transplantation is a curative treatment for ARVC, but due to frequent ventricular arrhythmias and RV predominant pathology, patients require unique considerations in regard to timing of evaluation, haemodynamic support options, and wait listing qualification.

Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy.

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. Here, we report increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. By contrast, mice with genetic mitochondrial CaMKII inhibition are protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII overexpression (mtCaMKII) have severe dilated cardiomyopathy and decreased ATP that causes elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We map a metabolic pathway that rescues disease phenotypes in mtCaMKII mice, providing insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase or mitochondrial-targeted CaMKII inhibition.

An Update on the Utility of Coronary Artery Calcium Scoring for Coronary Heart Disease and Cardiovascular Disease Risk Prediction.

Estimating cardiovascular disease (CVD) risk is necessary for determining the potential net benefit of primary prevention pharmacotherapy. Risk estimation relying exclusively on traditional CVD risk factors may misclassify risk, resulting in both undertreatment and overtreatment. Coronary artery calcium (CAC) scoring personalizes risk prediction through direct visualization of calcified coronary atherosclerotic plaques and provides improved accuracy for coronary heart disease (CHD) or CVD risk estimation. In this review, we discuss the most recent studies on CAC, which unlike historical studies, focus sharply on clinical application. We describe the MESA CHD risk calculator, a recently developed CAC-based 10-year CHD risk estimator, which can help guide preventive therapy allocation by better identifying both high- and low-risk individuals. In closing, we discuss calcium density, regional distribution of CAC, and extra-coronary calcification, which represent the future of CAC and CVD risk assessment research and may lead to further improvements in risk prediction.

Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors.

Increasing the size and strength of muscles represents a promising therapeutic strategy for musculoskeletal disorders, and interest has focused on myostatin, a negative regulator of muscle growth. Various myostatin inhibitor approaches have been identified and tested in models of muscle disease with varying efficacies, depending on the age at which myostatin inhibition occurs. Here, we describe a one-time gene administration of myostatin-inhibitor-proteins to enhance muscle mass and strength in normal and dystrophic mouse models for >2 years, even when delivered in aged animals. These results demonstrate a promising therapeutic strategy that warrants consideration for clinical trials in human muscle diseases.

Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, follistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.

Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the neuromuscular system resulting in paralysis and ultimately death. Currently, no effective therapy is prescribed for patients; however, several therapeutic strategies are showing promise. Either exercise or treatment with adeno-associated virus/insulin-like growth factor-1 alone has therapeutic benefits in an amyotrophic lateral sclerosis transgenic mouse model. We show here that activity duration affects the therapeutic benefit associated with exercise, with 6- and 12-hour exposure to a running wheel providing significant motor function benefits and increased survival. Remarkably, a combination of insulin-like growth factor-1 gene delivery and exercise has profound effects on survival and function, indicative of synergistic effects with exercise and insulin-like growth factor-1. Our results indicate that a drug treatment in combination with appropriate exercise may provide the most promising therapy for amyotrophic lateral sclerosis to date.