Gene Replacement Therapy in Cardiac Diseases: challenges in trial design and management of adverse events.

Gene replacement therapy has emerged as a promising strategy to address the underlying molecular defects in inherited and acquired cardiomyopathies, shifting treatment from symptom palliation to potentially disease-modifying interventions. Most clinical programs employ AAV vectors to deliver functional DNAs, demonstrating safety, durable myocardial transduction, and early improvements in biomarkers or imaging endpoints. However, the rarity and heterogeneity of target populations constrain trial size and duration, making traditional morbidity and mortality outcomes infeasible.

Multi-Organ Transplantation in Adult Congenital Heart Disease: Navigating the Unique Challenges of a Distinct Patient Population.

The prevalence of adult congenital heart disease (ACHD) is increasing, with heart failure being the leading cause of death. For many ACHD patients, heart transplantation is the only treatment option for advanced heart failure, though significant extracardiac involvement may require multi-organ transplantation. Despite the rising number of ACHD transplants, multi-organ transplants in this population remain challenging, and a substantial gap remains between those in need and those who receive a transplant.

Concomitant Surgical Procedures and Aspirin Avoidance With Left Ventricular Assist Device Therapy.

Background: ARIES-HM3 (Antiplatelet Removal and Hemocompatibility Events With the HeartMate 3 Pump) demonstrated that aspirin avoidance with a fully magnetically levitated HeartMate 3 (HM3) left ventricular assist device (LVAD) reduces bleeding complications and does not increase thromboembolism. Whether a concomitant surgical procedure modifies the observed safety and benefits remains uncertain.

Objectives: This prespecified analysis of ARIES-HM3 studied clinical outcomes when concomitant surgical procedures are performed during LVAD implantation with excluding aspirin but maintaining a vitamin K antagonist.

Overlapping functions between and in cardiac autophagy.

LAMP2 is a ubiquitously expressed protein critical for autophagy. Alternative splicing gives rise to three isoforms. However, the roles of major LAMP2 isoforms in the heart are not known.

Cardiomyopathy genetic testing: insights into demographics, counseling, and cascade screening.

Background: Genetic testing (GT) is clinically indicated for patients with suspected inherited cardiomyopathy (CM) but is underutilized.

Methods: This single-center study included patients with CM who underwent outpatient GT from 2018 to 2023. Data were collected from the medical record.

Outpatient worsening heart failure: innovative decongestion strategies and health equity implications.

Worsening heart failure (WHF) is a major clinical and economic challenge, contributing to high rates of hospitalization and significant healthcare costs. While WHF has traditionally been managed through hospitalization, recent approaches are shifting toward outpatient care to maximize patient time spent at home and optimize allocation of hospital resources. Emerging treatments like subcutaneous furosemide and intranasal bumetanide offer promising alternatives for safe, well-tolerated, and effective diuresis outside the hospital.

An International Longitudinal Natural History Study of Patients With Danon Disease: Unique Cardiac Trajectories Identified Based on Sex and Heart Failure Outcomes.

Background: Danon disease is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 gene. Though the severe morbidity of disease in men is well established, longitudinal studies describing the trajectory of cardiovascular disease in both sexes are lacking.

Methods And Results: Data were from the International Danon Disease Registry and includes retrospective data on 116 patients who provided informed consent between 2005 and 2022.

Advances in the study and treatment of genetic cardiomyopathies.

Cardiomyopathies are primary disorders of the heart muscle. Three key phenotypes have been defined, based on morphology and arrhythmia burden: hypertrophic cardiomyopathy (HCM), with thickened heart muscle and diastolic dysfunction; dilated cardiomyopathy (DCM), with left ventricular enlargement and systolic dysfunction; and arrhythmogenic cardiomyopathy (ACM), with right, left, or biventricular involvement and arrhythmias out of proportion to systolic dysfunction. Genetic discoveries of the molecular basis of disease are paving the way for greater precision in diagnosis and management and revealing mechanisms that account for distinguishing clinical features.

Burden of atherogenic lipids and association with cardiac allograft vasculopathy in heart transplant recipients.

Background: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.

Objective: We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients.

Genetic Testing Practices and Pathological Assessments in Patients With End-stage Heart Failure Undergoing Heart Transplantation and Left Ventricular Assist Device Use.

Background: Genetic cardiomyopathies (CMs) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. However, genetic testing practices are understudied in patients with ESHF.

Catheter ablation vs advanced therapy for patients with severe heart failure and ventricular electrical storm.

Background: Current data on outcomes of an initial strategy of catheter ablation vs advanced therapy in patients with severe heart failure (HF) and electric storm (ES) are limited.

Objective: The purpose of this study was to evaluate the outcomes of ventricular tachycardia (VT) ablation vs left ventricular assist device (LVAD) or heart transplantation (HT) in patients with severe HF and ventricular ES.

Methods: Patients with severe HF and ES who underwent VT ablation, LVAD, or HT between 2012 and 2022 at our medical center were reviewed.

Precision Genetic Therapies: Balancing Risk and Benefit in Patients with Heart Failure.

Purpose Of Review: Precision genetic medicine is evolving at a rapid pace and bears significant implications for clinical cardiology. Herein, we discuss the latest advancements and emerging strategies in gene therapy for cardiomyopathy and heart failure.

Recent Findings: Elucidating the genetic architecture of heart failure has paved the way for precision therapies in cardiovascular medicine.

Performance of risk models to predict mortality risk for patients with heart failure: evaluation in an integrated health system.

Background: Referral of patients with heart failure (HF) who are at high mortality risk for specialist evaluation is recommended. Yet, most tools for identifying such patients are difficult to implement in electronic health record (EHR) systems.

Objective: To assess the performance and ease of implementation of Machine learning Assessment of RisK and EaRly mortality in Heart Failure (MARKER-HF), a machine-learning model that uses structured data that is readily available in the EHR, and compare it with two commonly used risk scores: the Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic (MAGGIC) Heart Failure Risk Score.

Cardiac allograft vasculopathy in heart transplant recipients from hepatitis C viremic donors.

Background: Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-).

Incidence of Acute Rejection Compared With Endomyocardial Biopsy Complications for Heart Transplant Patients in the Contemporary Era.

Background: The reference standard of detecting acute rejection (AR) in adult heart transplant (HTx) patients is an endomyocardial biopsy (EMB). The majority of EMBs are performed in asymptomatic patients. However, the incidence of treated AR compared with EMB complications has not been compared in the contemporary era (2010-current).

International Consensus on Differential Diagnosis and Management of Patients With Danon Disease: JACC State-of-the-Art Review.

Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure.

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised.

Comparison of two donor-derived cell-free DNA tests and a blood gene-expression profile test in heart transplantation.

Background: Donor-derived cell-free DNA (dd-cfDNA) testing is an emerging screening modality for noninvasive detection of acute rejection (AR). This study compared the testing accuracy for AR of two commercially available dd-cfDNA and gene-expression profiling (GEP) testing in heart transplant (HTx) recipients.

Methods: This is a retrospective, observational study of HTx only patients who underwent standard and expanded single nucleotide polymorphism (SNP) dd-cfDNA between October 2020 to January 2022.

PROMIS: Physical, Mental and Social Health Outcomes Improve From Before to Early After LVAD Implant: Findings From the Mechanical Circulatory Support: Measures of Adjustment and Quality of Life (MCS A-QOL) Study.

Study participants (n = 272) completed 12 Patient-Reported Outcomes Measurement Information System (PROMIS) physical, mental and social health measures (questionnaires) prior to implantation of a left ventricular assist device (LVAD) and again at 3 and 6 months postimplant. All but 1 PROMIS measure demonstrated significant improvement from pre-implant to 3 months; there was little change between 3 and 6 months. Because PROMIS measures were developed in the general population, patients with an LVAD, their caregivers and their clinicians can interpret the meaning of PROMIS scores in relation to the general population, helping them to monitor a return to normalcy in everyday life.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

Background: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).

Objectives: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.

Methods: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies.

The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction.

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised.

Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation.