Sarcoplasmic Ca²⁺ concentrations directly and critically control the contraction and relaxation of the sarcomere. In the initial compensated period of the genetically determined cardiomyopathy, contractility and heart rate are facilitated through altered Ca²⁺ transients, and this process is controlled by activation of ion channels, G protein-coupled receptors (GPCRs), stretch-activated channels, and many other biologic and chemical receptors. However, if Ca²⁺ overload stress is sustained, this activates calmodulin–calcineurin, a serine/threonine phosphatase through dephosphorylation of nuclear factor of activated T cells (NFAT). Activated calmodulin–calcineurin then translocates into the nucleus, changing gene expression and triggering abnormal contractility and pathological hypertrophy [3].

Mechanosensitive mechanisms are intracellular signaling events that alter and regulate gene expression in response to mechanical stretch. Altered stretch recruits the integrin-induced phosphorylation of focal adhesion kinase (FAK), activating downstream Rous sarcoma (SRC) signaling. The integrin–talin complex, components of the costamere, connects the sarcomere to the sarcolemma and extracellular matrix (ECM) through the Z-disk, which consists of numerous mechanosensitive proteins including α-actinin 2, nebulette, myopalladin, cardiac ankyrin repeat protein (CARP), and filamin C. Mutations in all these Z-disk proteins induce pathological signaling pathways in response to sustained stretch and initiate the development of cardiomyopathies [4].

In the healthy heart, phosphocreatine is the main reserve source of ATP during acute stress. In the initial compensatory stages of cardiomyopathy, the heart favors burning free fatty acids, which yield about three times more ATP than glucose, but require more oxygen to metabolize [5]. As contractility or relaxation is altered, the demand for ATP increases, yet the levels of phosphocreatine are progressively reduced. In the decompensated stage of cardiomyopathy, energy substrate utilization shifts from fatty acid oxidation to glucose, a less efficient resource for producing energy [6].

In adult cardiomyocytes, contractility is inversely proportional to levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MyHC), and α-skeletal actin (α-SMA), genes that are normally expressed during embryogenesis [7]. Circulating ANP and BNP in plasma induce diuresis and vasodilation, while β-MyHC exhibits lower ATPase activity and enhanced ATP use. To compensate for increased myocardial wall stress, expression of these genes is induced through immediate early genes (IEGs) encoding transcription factors such as SRC, cellular FBJ osteosarcoma oncogene (c-FOS), transcriptional factor AP-1 (c-JUN), early growth response-1 (EGR-1), myelocytomatosis c (c-MYC), rat sarcoma (RAS) oncogenes, and mitogen-activated protein kinases (MAPK). Persistent expression of these fetal genes may contribute to contractile dysfunction and prolonged relaxation of cardiomyocytes independent of Ca²⁺ handling [8].

Besides cardiomyocytes, composing approximately 56 % of the adult murine heart, fibroblasts (27 %), endothelial cells (7 %), and smooth muscle cells (10 %) reside in the ECM containing numerous transient immune cells [9]. The interaction between all these cell types via ongoing reciprocal secretion of autocrine and paracrine factors is essential in preserving normal cardiac function. This process is regulated by signaling molecules such as integrins, endothelin1 (ET1), bone morphogenetic proteins (BMPs), platelet endothelial cell adhesion molecule 1 (PECAM1), vascular endothelial (VE)-cadherin, vascular endothelial growth factor (VEGF), and transforming growth factor beta 3 (TGFβ3). Genetic mutations may trigger pathological signaling between these messengers.

Cardiomyocyte hypertrophy (increase in size) and atrophy (decrease in size) are the most common alterations that occur when cardiac cells respond to genetic abnormalities. Two types of hypertrophy exist at the cellular level: concentric and eccentric. Concentric hypertrophy is an increase in myocyte width-to-length ratios that occur as a result of addition of sarcomeres in parallel as physiological adaptive responses to keep pace with hemodynamic demand. Persistent stress may transform physiological hypertrophy into a pathological state when reduced volumes of ventricular chambers affect cardiac output, ultimately resulting in the development of CHF [10]. In contrast, eccentric hypertrophy is an increase in myocyte length-to-width ratios associated with increased end-to-end addition of sarcomeres, primarily associated with decreased force production and often associated with DCM and CHF. In inherited cardiomyopathies, triggering of intracellular and extracellular hypertrophic signal-transduction pathways is dependent on the location of the genetic mutation. Major signal transduction cascades such as G protein-coupled receptors (GPCRs), protein kinase B (PKB), or AKT, MAPK, and tumor necrosis factor alpha (TNF-α) have been shown to play a significant role in the development and progression of cardiac hypertrophy.

GPCRs are integral membrane proteins consisting of seven membrane-spanning domains that are competent to respond to paracrine and autocrine factors including adrenergic factors, angiotensin II (AngII), and ET1 [11]. The sarcomere, when composed of mutant proteins, exhibits blunted myofilament Ca²⁺ sensitivity, reduces ATP efficiency, and inhibits the sequestration of Ca²⁺ from the cytosol. Further, mutation-induced contractile dysfunction causes activation of GPCR signaling by ET1 and AngII and increases release of Ca²⁺ from the sarcoplasmic reticulum (SR), activating calmodulin and myocyte enhancer factor 2 (MEF2). GPCR signaling is also associated with activation of the AKT signaling pathway.

Many adaptive processes in the heart such as protein synthesis, apoptosis, gene expression, and metabolism are regulated by phosphoinositide 3-kinase (PI3K). Activation of PI3K on the cardiomyocyte sarcolemma initiates activation of PKB/AKT [12]. When PKB/AKT-mediated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) inactivates it, hypertrophic transcriptional effectors including erythroid transcription factor (GATA4), β-catenin, c-MYC, and NFAT are activated within the heart. Compensated hypertrophy and increased contractile efficiency are induced by AKT1 and AKT2 [13]; however, chronic activation of the PI3K/AKT pathway via mammalian target of rapamycin (mTOR) may lead to pathological cardiac hypertrophy [14].

The MAPK family consists of four subfamilies of kinases: extracellular signal-related kinases (ERK1/2), c-Jun N-terminal kinases (JNK1-3), p38 kinases, and ERK5 that convert extracellular stimuli into a wide range of cellular responses [3]. In cardiomyocytes, MAPK signaling is initiated by GPCRs, insulin-like growth factor-1 (IGF-1) and fibroblast growth factor receptor (FGFR), TGFβ, and by cytokines, stretch, AngII, or ET1. When activated via the three-module cascade of phosphorylating kinases, MAPKs then translocate into the nucleus and activate transcription factors, resulting in reprogramming of cardiac gene expression.

Activated ERK1/2 stimulates the transcription of genes such as BNP and ETS domain-containing protein 1 (Elk1) [15]. JNKs and p38 are activated mainly by inflammatory cytokines, ischemia, oxidative stress, heat shock, endotoxins, as well as secondarily by growth factors and GPCR [16]. JNKs activation increase expression of ANP, alpha smooth muscle actin (α-SMA), TGFβ1, Elk1, p53, and collagen type I in cardiac hypertrophy and inhibit NFAT4, NFATc1, and signal transducer and activator of transcription-3 (STAT3). The p38 module promotes expression of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and TNF-α through the integrin-FAK-SRC-RAS pathway [17].

TNF-α is a cytokine that initiates an inflammatory response via coupling with TNF receptor and activating nuclear factor kappa-light-chain-enhancer of activated B (NF-κB), protein kinase C (PKC), stress-activated protein kinases (SAPKs), and JNKs in response to stress. Once activated, TNF-α triggers expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade the ECM components. Levels of TNF-α and MMPs have been found to be concordantly increased in DCM and the failing human heart [13]. The NF-kB cascade is initiated upon activation of NF-κB-inducing kinase (NIK) and IKK complex, triggering subsequent inhibitor of κB alpha (IkB-α) degradation. Activated NF-κB translocates to the nucleus causing cardiac hypertrophy.

Cardiac atrophy is a pathogenic event associated with mechanical unloading of the myocardium and is typically a result of maladaptive processes of apoptosis, necrosis, or excessive autophagy.

Evidence of interstitial and/or perivascular fibrosis is one of the major hallmarks of cardiomyopathies and is known to disrupt excitation–contraction coupling between cardiomyocytes, increases myocardial stiffness, and decreases contractility. Fibrosis is primarily produced by resident fibroblasts in the heart; however, there is evidence for collagen production by cardiomyocytes [25]. There are two forms of fibrosis that exist: reactive and replacement. Several pro-fibrotic factors such as AngII, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and the renin–angiotensin–aldosterone system (RAAS) along with prominent downstream mediators including TGFβ1 cause fibrotic responses in the heart.

Electrophysiological remodeling in cardiomyopathy occurs at the cellular and tissue levels, and it is not fully understood how exactly these changes contribute to electrical instability and increased risk of arrhythmias. Ca²⁺ transients, ion channels located within the sarcolemma and intercalated disks, sarcomere sensitivity and cell–cell coupling through gap junctions and desmosomes are all crucial components in regulating cardiac electrical remodeling.

A pathologic causative genetic insult followed by sustained maladaptive remodeling results in the development of decompensated cardiomyopathy when the failing heart is unable to keep up with hemodynamic demands at all levels, from the molecule to the whole organism. Molecular cell 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. Cell–cell coupling abnormalities include reorganization of gap junctions and desmosomal proteins. Cardiac function is significantly depressed with depleted force development and slowed relaxation [31].