Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach

Figure 1. Organization of the contractile machinery. Cardiomyocytes are thickly packed with contractile elements, the myofibrils, which are connected to each other and via the cytoskeleton to the extracellular matrix and to the nucleus. Myofibrils are composed of sarcomeres, the smallest contractile units of the cardiac muscle cell. Proteins, whose genes are targets for mutations leading to restrictive cardiomyopathy are indicated. cMyBP-C = myosin binding protein C; cTnI, cTnT, cTnC = cardiac troponin subunits I, T and C; Sur2A = sulfonylurea receptor isoform 2A; BAG3 = Bcl2-associated athanogene 3. The figure was created using PowerPoint (Microsoft).

Figure 2. Classification of cardiomyopathies. LVNC = left ventricular non-compaction cardiomyopathy, ACM = arrhythmogenic cardiomyopathy, DCM = dilated cardiomyopathy, HCM = hypertrophic cardiomyopathy, RCM = restrictive cardiomyopathy. The figure was created using PowerPoint (Microsoft).

Figure 3. Role of Calcium in contractility. Voltage gated Ca2+-channels, located within T-tubuli, open upon depolarization of the sarcolemma. The resulting Ca2+-influx activates the nearby ryanodine receptors (RyR) of the sarcoplasmatic reticulum (SR), releasing Ca2+ from the SR. Ca2+ now binds to the Ca2+-sensor of the sarcomere, cardiac troponin C (cTnC), which forms together with cTnI and cTnT the troponin complex (see insert). Ca2+-saturation of cTnC triggers conformational changes within the troponin complex, releasing cTnI from actin. This enables tropomyosin to roll over on the actin filament to demask the myosin binding sites, and force production occurs. At the same time, Ca2+ is pumped back into the SR by a phospholamban (PLB) regulated SR Ca2+-ATPase, into the extracellular space by Na+/Ca2+ exchanger (NCX) and into the mitochondria. As the cytoplasmic Ca2+-concentration reduces, Ca2+ is released from cTnC, cTnI rebinds to actin and tropomyosin is forced back masking the myosin binding sites. The muscle relaxes. The figure was created using PowerPoint (Microsoft).

Figure 4. cTnI organization. Exons, RCM mutations and binding sites are indicated. A-TM: a second actin-tropomyosin binding site, PP (PKA): Serines 22, 23 phosphorylated by the proteinkinase A (PKA). The RCM mutations mainly affect exon 7 and 8, encoding for the inhibitory region, TnC binding domains and the A-TM site. The figure was created using PowerPoint (Microsoft).

Figure 5. Disruption of thin filaments induced by RCM cTnI-variants. (A,B) Electron microscopic images obtained with reconstituted cardiac thin filaments. (C,D) schematic presentation. (A,C) wild-type cTnI; (B,D) the RCM cTnI-variant p.R170W leads to shortened, wavy and partially aggregated thin filaments. The figure was created using PowerPoint (Microsoft).

Figure 6. Factors leading to the development of the genetic RCM. While non-sarcomeric mutations lead to aggregations and promote cytoskeletal and sarcomeric disarray, sarcomeric mutations may affect the cardiac function in different ways, depending on their expression levels, stability, tendency to aggregate and to induce contractile dysfunction. Both finally lead to diastolic dysfunction and increased stiffness. The figure was created using PowerPoint (Microsoft).