The cell biology of disease: cellular mechanisms of cardiomyopathy

Abstract

The heart exhibits remarkable adaptive responses to a wide array of genetic and extrinsic factors to maintain contractile function. When compensatory responses are not sustainable, cardiac dysfunction occurs, leading to cardiomyopathy. The many forms of cardiomyopathy exhibit a set of overlapping phenotypes reflecting the limited range of compensatory responses that the heart can use. These include cardiac hypertrophy, induction of genes normally expressed during development, fibrotic deposits that replace necrotic and apoptotic cardiomyocytes, and metabolic disturbances. The compensatory responses are mediated by signaling pathways that initially serve to maintain normal contractility; however, persistent activation of these pathways leads to cardiac dysfunction. Current research focuses on ways to target these specific pathways therapeutically.

Figure 1.

Anatomy of the cardiac sarcomere. (A) Diagram of the basic organization of the sarcomere. The sarcomere forms the basic contractile unit in the cardiomyocytes of the heart. Thin filaments composed of actin are anchored at the Z line and form transient sliding interactions with thick filaments composed of myosin molecules. The M Line, I Band, and A Band are anatomical features defined by their components (actin, myosin, and cytoskeletal proteins) and appearance in polarized light. Titin connects the Z line with the M line and contributes to the elastic properties and force production of the sarcomere through its extensible region in the I Band. Coordinated shortening of the sarcomere creates contraction of the cardiomyocyte. (B) Representation of the major proteins of the cardiac sarcomere. Attachment to the ECM is mediated by costameres composed of the dystroglycan–glycoprotein complex and the integrin complex. Force transduction and intracellular signaling are coordinated through the costamere. The unique roles of each of these proteins are critical to appropriate function of the heart. T-cap, titin cap; MyBP-C, myosin-binding protein C; NOS, nitric oxide synthase.

Figure 2.

Gross pathology associated with cardiomyopathies. Illustrations depicting (A) a healthy heart with normal wall thicknesses and chamber volumes and (B) hypertrophic cardiomyopathy. Asymmetric hypertrophy of the interventricular septum as well as the left ventricular posterior wall and apex is present. (C) Dilated cardiomyopathy. Thinning of the ventricular walls enlarges the interior dimensions of the ventricular chamber. The left and right atria are also enlarged due to impaired ventricular relaxation. (D) Left ventricular noncompaction. Trabeculated ventricular walls create a spongy appearance, prominent in the left ventricular wall. Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

Figure 3.

Isolated cardiomyocytes exhibiting hypertrophy and heart failure. (A) Untreated adult ventricular cardiomyocyte demonstrating normal brick-like morphology. (B) An adult ventricular cardiomyocyte treated with endothelin-1 precursor protein exhibiting significant concentric hypertrophy. The cardiomyocyte is decreased in length and increased in width, consistent with the phenotype observed in human cardiomyocytes with concentric hypertrophy. A and B are reproduced from Gupta et al. (2005) with permission from Elsevier. (C) Cardiomyocyte isolated from a healthy human heart. (D) Cardiomyocyte isolated from the heart of a patient in heart failure. Increased length and decreased width are characteristic of eccentric hypertrophy. C and D are reproduced from Ohler et al. (2009) with permission from Brian O’Rourke.

Figure 4.

Signaling pathways associated with cardiac hypertrophy. Although many pathways are associated with cardiomyopathy, up-regulation of transcription and induction of apoptosis are major mediators of pathogenic responses in the heart. The GPCR-associated pathway (dark red) can be activated by ET-1 and AngII, which are released in response to reduced contractility, and mediates contractile adaptation through increased calcium release from the sarcoplasmic reticulum. Increased intracellular calcium activates calmodulin and induces activation of the transcription factor MEF2. Incorporation into the sarcomere of mutant proteins that exhibit reduced ATP efficiency inhibits the sequestration of calcium from the cytosol and further enhances increases in intracellular calcium concentration. GPCR signaling is also associated with activation of the Akt signaling pathway (light green) that induces fetal gene expression and the cardiac hypertrophic response through inhibition of GSK3β. Apoptotic pathways (light blue) are induced by cytochrome c (CytC) release from mitochondria and activation of death receptors (like FasR) by cytokines such as TNF. Calcium overload and myocyte loss significantly contribute to reduced contractility in many forms of cardiomyopathy. ET-1, endothelin-1; HDAC, histone deacetylase; NFAT, nuclear factor of activated T cells; MEF-2, myocyte enhancer factor 2; SERCA, sarco/endoplasmic reticulum calcium-ATPase; cFLIP, cellular FLICE-inhibitory protein; AngII, angiotensin II; FasR, Fas receptor.