Inherited cardiomyopathy and arrhythmia syndromes are associated with significant morbidity and mortality, particularly in young people. Medical management of these conditions has primarily been limited to agents previously developed for more common forms of heart disease and not tailored to their distinct pathophysiology. As our understanding of their underlying genetics and disease mechanisms has improved, an era of targeted therapies for these rare conditions has begun to emerge. In recent years, several novel agents have been developed and tested in preclinical models and, in some cases, have advanced to both the clinical trial and clinical approval stages with exciting results. These new treatments are derived from multiple classes of therapeutics, including small molecules, antisense oligonucleotides, small interfering RNAs, adeno-associated virus-mediated gene therapies, and in vivo gene editing. Collectively, they carry the promise of revolutionizing management of affected patients and their families.

Dilated cardiomyopathy (DCM) is a nonischemic heart muscle disease characterized by impaired contractility, cardiac dilation, and heart failure, with both genetic and nongenetic causes. Emerging evidence highlights epigenetic mechanisms, including deoxyribonucleic acid methylation, histone modifications, chromatin remodeling, and noncoding RNAs, as critical regulators of gene expression in DCM pathogenesis. This article explores familial DCM linked to pathogenic variants in genes like lamin A/C and titin, as well as nongenetic forms such as diabetic and autoimmune DCM. By summarizing recent discoveries, it highlights the epigenetic factors in bridging genetic and environmental influences, offering potential biomarkers and therapeutic targets for improved DCM management.

Heart failure (HF) is an intricate syndrome damaging the heart's systolic and/or diastolic function. HF is burdening our health care systems globally, with a prevalence expected to rise in the future. Developing research is uncovering the mechanisms behind HF at the cellular and molecular level. These studies have implicated epigenetics as a key player in the pathogenesis of HF. Targeting these epigenetic mechanisms provides a promising new approach to treating HF. This article summarizes the recent epigenetic-based medications under clinical development and the promise of this novel drug class in the treatment of HF.

Hereditary cardiomyopathies are caused primarily by mutations in genes encoding the protein constituents of cardiac myocytes. The mutation imparts biochemical, mechanical, and metabolic stresses, which not only induce the cardiomyopathy phenotype but also damage the nuclear and mitochondrial DNA, through oxidation, alkylation, cross-linking, and others. The DNA lesions, if unrepaired, cause replication and transcription stress, and activate the DNA damage response (DDR) pathways, which are composed of the repair, cell cycle checkpoint, and cytosolic DNA-sensing protein pathways. The DDR pathways provoke cell cycle arrest, instigate an interferon response, activate the nuclear factor Kappa B pathway. The induced gene expression causes inflammation, cell death, senescence, fibrosis, and organ dysfunction.

Heart failure (HF) remains a major global health concern with high morbidity and mortality, particularly in cases with preserved ejection fraction, where treatment options are limited. Epigenetic mechanisms, including DNA methylation, histone modification, and noncoding RNAs, are increasingly recognized for their role in HF development and progression. These processes integrate genetic and environmental signals, offering novel targets for therapy. Emerging pharmacologic agents, alongside repurposed drugs with epigenetic effects, show promising results. Additionally, lifestyle factors such as diet and exercise influence the epigenome, opening new avenues for personalized, nonpharmacological interventions aimed at modifying disease trajectory and improving clinical outcomes.

Acute aortic dissection is a life-threatening event that requires immediate medical attention and surgical intervention. Aortic dissections affect 4 to 5 per 10,000 individuals in the USA. These emergency events can have as high as a 50% mortality risk. Twenty percent of patients who develop a thoracic aortic dissection have an underlying genetic cause for their increased risk for aortic aneurysm and dissection, which can be identified using genetic testing. Genes associated with abdominal aortic aneurysm and dissection have been identified but have not been reported for clinical use or management at this time.

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19-guided approach to P2Y inhibitor selection, genotyping has not yet been widely adopted in clinical practice.

Bidirectional ventricular tachycardia is a unique arrhythmia that can herald lethal arrhythmia syndromes. Using cases based on real patient stories, this article examines 3 different presentations to help clinicians learn the differential diagnosis associated with this condition. Each associated genetic disorder will be briefly discussed, and valuable tips for distinguishing them from each other will be provided.

Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction. Variants in numerous genes have been associated with this phenotype. Here, the authors review the literature on recent cohort studies of patients with variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43, and selected channelopathy genes also associated with structural disease. Unlike traditional sudden cardiac death risk assessment in nonischemic cardiomyopathy, left ventricular systolic function is an insensitive predictor of risk in patients with these genetic diagnoses.

Acute coronary syndrome (ACS) is a complex cardiovascular condition driven by chronic inflammation, immune system imbalances, and epigenetic alterations. Recent research highlights the crucial role of epigenetic modifications in disease progression. Furthermore, differentially methylated regions influence expression in genes associated with immune signaling and cellular functions in ACS patients. ACS is a multifactorial disease driven by complex interactions between genetic, epigenetic, and environmental factors. By leveraging multiomics approaches, clinicians and researchers can uncover novel pathophysiological mechanisms and refine therapeutic strategies for improved cardiovascular outcomes in ACS patients. Integrating multiomics technologies with machine learning-driven analysis is revolutionizing our understanding of ACS.

Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by increased myocardial thickness without cardiac, systemic, or metabolic causes to explain the observed left ventricular (LV) hypertrophy. Importantly, LV systolic dysfunction influences symptoms, heart failure, and the risk of SCD in HCM. LV global longitudinal strain (LV-GLS) is a sensitive marker for detecting subclinical LV dysfunction and improving risk stratification. Integrating LV-GLS with other imaging biomarkers, such as late gadolinium enhancement and left atrial reservoir strain, may improve risk prediction. Future research should focus on refining LV-GLS cutoffs and exploring its utility for personalized risk assessment in HCM.

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease defined by unexplained thickening and hypertrophy of ventricular myocardium. However, several other conditions-"phenocopies" or mimics-can present with a similar hypertrophic phenotype. This article details the major HCM phenocopies, including infiltrative and storage diseases (amyloidosis, Fabry, Pompe, and Danon), systemic granulomatous disease (sarcoidosis), mitochondrial disorders, physiologic hypertrophy (athlete's heart), and hypertensive heart disease and aortic stenosis. We describe their distinguishing clinical features, multimodality imaging findings, pathophysiology, and key diagnostic clues highlighting red-flag signs and recent advances in diagnostics.

Fixed wall thickness cutoffs have historically defined hypertrophic cardiomyopathy (HCM), yet this rigid approach overlooks patients with early, segmental, or morphologically subtle disease. Subthreshold phenotypes-particularly in women, individuals with short stature, and those with apical or focal variants-may not meet conventional criteria despite exhibiting pathologic features. This article examines the limitations of absolute diagnostic thresholds and advocates for a precision medicine framework. Integrating cardiac magnetic resonance imaging with individualized metrics and architectural markers enhances diagnostic accuracy, identifies nonclassical presentations, and facilitates earlier disease recognition, ultimately improving care across the heterogeneous spectrum of HCM.

Hypertrophic cardiomyopathy (HCM) is characterized by pathologic hypertrophy in the absence of a potentially causative disease process and carries increased risk of heart failure, atrial fibrillation, and sudden cardiac death. Synergistic use of multi-modal imaging is pivotal and necessary in the diagnosis and management of patients with, or at risk for, HCM. Echocardiography, cardiac MR, and cardiac computed tomography each have important roles and limitations in assessing the morphologic changes responsible for symptoms and morbidity in HCM. In this article, we will explore these modalities and their roles in evaluating HCM.

This review highlights recent advances in hypertrophic cardiomyopathy (HCM) treatment, focusing on how to effectively implement both traditional and novel pharmacologic strategies in clinical practice. Traditional medications like beta-blockers and calcium channel blockers continue to play a critical role. However, new treatments, such as cardiac myosin inhibitors, provide an innovative approach for relieving symptoms, especially in obstructive HCM cases. Emerging therapies, including sodium-glucose cotransporter 2 inhibitors, sacubitril/valsartan, and ninerafaxstat, show promising benefits. Proper management of related conditions such as atrial fibrillation and heart failure is also essential. A comprehensive approach that considers individual patient characteristics and the specific subtype of HCM is essential for achieving optimal outcomes.

This article outlines the evolving evidence and guidelines surrounding exercise in hypertrophic cardiomyopathy (HCM), challenging the traditional paradigm of universal restriction. It highlights that most patients with HCM can safely engage in physical activity (PA) and improve cardiovascular outcomes. Recent evidence demonstrates that vigorous PA improves functional capacity and does not increase adverse events in most low-risk HCM patients. Contemporary guidelines advocate for individualized exercise recommendations based on comprehensive risk stratification and shared decision-making. A clinical framework is proposed to support tailored exercise prescriptions and shared decision-making.

Hypertrophic cardiomyopathy (HCM) is one of the important causes of sudden cardiac death (SCD) in younger people and athletes. It is important to identify the risk factors for SCD in individuals with HCM. This article, based on recent systematic literature studies, will focus on the risk factors for progression in patients with HCM. The article discusses the established risk factors, such as a family history, unexplained syncope, and some new risk factors. The findings of this article demonstrate that there is a need for further research on individual risk factors and risk stratification in HCM patients remains a clinical challenge.

Cardiac genetic counseling is the process of helping individuals adapt to a personal diagnosis or family history of an inherited heart condition. The process is shown to benefit patients and includes specialized skills, such as counseling children and interpreting complex genetic results. Emerging areas include: evolving service delivery models for caring for patients and communicating risk to relatives, new areas of need including postmortem molecular autopsy, and new populations of individuals found to carry a likely pathogenic/pathogenic cardiac variant identified through genomic screening. This article provides an overview of the cardiac genetic counseling process and evolving areas in the field.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. Since the modern description of HCM more than seven decades ago, great focus has been placed on preventing its most catastrophic complication: sudden cardiac death (SCD). Implantable cardioverter-defibrillators (ICD) have been recognized to provide effective prophylactic therapy. Over the years, two leading societies, the European Society of Cardiology (ESC) and the American Heart Association/American College of Cardiology (AHA/ACC), have proposed risk stratification models to assess SCD in adults. European guidelines rely on a risk calculator, the HCM Risk-SCD, while American guidelines propose a stand-alone risk factor approach. Recently, risk prediction models were also developed in the pediatric population. This article reviews the latest recommendations on the risk stratification of SCD in HCM and summarises current indications for ICD use.