**1. From genetic abnormality to cardiomyopathy phenotype**

It's widely accepted that inherited cardiomyopathies are a group of heterogeneous diseases of heart muscle resulting from genetic alterations in cardiac myocytes, the chief contractile cell type in the heart [1]. The genes encoding proteins that build muscle cytoskeleton and contractile apparatus are responsible for a cardiomyopathy phenotype with distinctive morpho-/histological cardiac remodeling [2]. Further, disruption of particular genetic and protein networks and pathways may intersect with other intracellular and intercellular pathways and disturbances in molecular signaling. Apoptosis, necrosis, autophagy, and metabolic and arrhythmogenic fluxes—which may present as the sole features or as overlapping signs of decompensated cardiac homeostasis—result in definitive forms of cardiac remodeling including fibrosis, cardiomyocyte hypertrophy, and atrophy. Typically, molecular signaling activates associated compensatory responses and cooperates with other modifiers such as genetic modifiers and environment, stress, or toxicity related that, in turn, may or may not influence the final cardiomyopathy phenotype. Alterations in cellular morphology and size, gene expression patterns, and metabolic shifts in cardiomyocytes initially compensate and maintain cardiac function in the subtle, preclinical stages of cardiomyopathy. Thus, inherited forms of cardiomyopathy, irrespective of the specific genetic or morpho-/clinical condition, may or may not present signs of a failing heart. Five types of inherited cardiomyopathies are distinguished based on clinical features: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic ventricular cardiomyopathies (ACM), and left ventricular noncompaction cardiomyopathy (LVNC) [3] as demonstrated in **Table 1**. DCM is characterized by left ventricular (LV) dilation and systolic dysfunction; HCM is characterized by LV hypertrophy with diastolic dysfunction; and RCM is accompanied by increased stiffness of the myocardium and dilated atria due to


#### **Table 1.**

*Clinical types of inherited cardiomyopathy and specific hallmarks of different types of cardiomyopathy.*

diastolic dysfunction without significant hypertrophy [4]. Frequent and often lifethreatening arrhythmias and associated sudden cardiac death and progressive heart failure are the main hallmarks of ACMs [5], while myocardial hypertrabeculation, intertrabecular recesses, and thin compact LV wall are the characteristics of LVNC [6]. Sustained maladaptive remodeling due to pathologic genetic insult results in the development of decompensated cardiomyopathy when the failing heart is unable to keep up with the hemodynamic demands at all levels, from the molecule to the whole organism. When compensatory mechanisms fail, additional neuroendocrine signaling and other pathways are activated on an organ and whole organism level, leading to CHF. Cellular and molecular level alterations of end-stage cardiomyopathy and CHF respond to irreversible cardiac remodeling with significant changes in membrane ion currents and intracellular Ca2+ metabolism, fibrosis, hypertrophic or atrophic remodeling, and cell death. Cardiac function is significantly depressed with depleted contractile force development and slowed relaxation [7].
