International Journal of Molecular Sciences Review Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach Diana Cimiotti 1,* , Heidi Budde 2, Roua Hassoun 2 and Kornelia Jaquet 2,* 1 Department of Clinical Pharmacology, Ruhr-University Bochum, 44801 Bochum, Germany 2 Experimental and Molecular Cardiology, St. Josef Hospital and BG Bergmannsheil, Clinics of the Ruhr-University Bochum, 44791 Bochum, Germany; [email protected] (H.B.); [email protected] (R.H.) * Correspondence: [email protected] (D.C.); [email protected] (K.J.); Tel.: +49-234-32-27639 (D.C.) Abstract: The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non- sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM. Keywords: cardiomyopathy; restrictive cardiomyopathy; pediatric; sarcomere; contractile dysfunc- tion; calcium; aggregation; gene expression 1. The Sarcomere The sarcomere as the substructure of myofibrils is the contractile unit of striated muscles i.e. skeletal and cardiac muscle (Figure1). It forms a symmetric unit with the Citation: Cimiotti, D.; Budde, H.; M-disc in the center and is bordered by the Z-discs. M-disc and Z-disc provide the anchors Hassoun, R.; Jaquet, K. Genetic for thin, thick and elastic filaments. The elastic filament is composed of the giant protein Restrictive Cardiomyopathy: Causes and Consequences—An Integrative titin spanning half the sarcomere. The thin filament contains mainly filamentous actin and Approach. Int. J. Mol. Sci. 2021, 22, the regulatory proteins tropomyosin and troponin. The thick filament includes the motor 558. https://doi.org/10.3390/ijms protein myosin and the regulatory protein myosin binding protein C linking thick and thin 2+ 22020558 filament. Ca -dependent interaction of myosin with actin leads to the gliding of the thin and thick filaments past each other, the sarcomere is shortened, myocytes and finally the Received: 11 December 2020 whole muscle contract [1,2]. The sarcomere consists of a large number of highly organized Accepted: 6 January 2021 proteins besides the proteins of thin and thick filaments and is linked to the extracellular Published: 8 January 2021 space and nucleus via the cytoskeleton. In addition, a number of associated proteins connect the sarcomere to various signaling pathways. Such a complexity is indispensable Publisher’s Note: MDPI stays neu- to coordinate the contractile function of each cardiomyocyte and adapt the heart’s work tral with regard to jurisdictional clai- continuously to the momentary demands of the body. Thus, the smooth work routine ms in published maps and institutio- of all the sarcomeres within each cardiomyocyte of the heart muscle is pivotal for the nal affiliations. contractile function of the heart and is based on the highly balanced interplay of sarcom- eric proteins and of the sarcomeres themselves. Apparently, sarcomeric function is very sensitive to disturbances of any kind. Even one dysfunctional sarcomeric protein, altered Copyright: © 2021 by the authors. Li- protein-protein interactions, changes in sarcomeric structure and dynamics, alterations in censee MDPI, Basel, Switzerland. expression, proteolytic degradation etc., progress to contractile dysfunctions and finally to This article is an open access article cardiomyopathies and heart failure. Sometimes, compensation mechanisms to overcome distributed under the terms and con- the defects are provoked which, however, over time also may become pathological. ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 558. https://doi.org/10.3390/ijms22020558 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 558 2 of 26 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 26 FigureFigure 1. 1.Organization Organization ofof thethe contractilecontractile machinery.machinery. CardiomyocytesCardiomyocytes are thickly packed with con- tractile elements, the myofibrils, which are connected to each other and via the cytoskeleton to the tractile elements, the myofibrils, which are connected to each other and via the cytoskeleton to extracellular matrix and to the nucleus. Myofibrils are composed of sarcomeres, the smallest con- the extracellular matrix and to the nucleus. Myofibrils are composed of sarcomeres, the small- tractile units of the cardiac muscle cell. Proteins, whose genes are targets for mutations leading to estrestrictive contractile cardiomyopathy units of the cardiac are indicated. muscle cMyBP-C cell. Proteins, = myosin whose binding genes protein are targets C; cTnI, for cTnT, mutations cTnC leading= cardiac to troponin restrictive subunits cardiomyopathy I, T and C; are Sur2A indicated. = sulfonylurea cMyBP-C receptor = myosin isoform binding 2A; proteinBAG3 = C;Bcl2- cTnI, cTnT,associated cTnC athanogene = cardiac troponin 3. The figure subunits was created I, T and using C; Sur2A PowerPoint = sulfonylurea (Microsoft). receptor isoform 2A; BAG3 = Bcl2-associated athanogene 3. The figure was created using PowerPoint (Microsoft). 2. Cardiomyopathies 2. Cardiomyopathies Cardiomyopathies are defined as cardiac diseases, in which the heart muscle is af- Cardiomyopathies are defined as cardiac diseases, in which the heart muscle is affected fected showing functional and structural defects [3]. According to the classification of car- showing functional and structural defects [3]. According to the classification of cardiomy- diomyopathies as described by Elliott et al., 2008, they can be subdivided into RCM (re- opathies as described by Elliott et al., 2008, they can be subdivided into RCM (restrictive strictive cardiomyopathy), HCM (hypertrophic cardiomyopathy), DCM (dilated cardio- cardiomyopathy), HCM (hypertrophic cardiomyopathy), DCM (dilated cardiomyopathy), myopathy), ACM (arrhythmogenic cardiomyopathy) and unclassified cardiomyopathies ACM (arrhythmogenic cardiomyopathy) and unclassified cardiomyopathies as for example as for example non-compaction cardiomyopathy (LVNC) (Figure 2). The causes of these non-compaction cardiomyopathy (LVNC) (Figure2). The causes of these cardiomyopathies cardiomyopathies may be genetic/familial or non-genetic and idiopathic. may be genetic/familial or non-genetic and idiopathic. 2.1. Left Ventricular Non-Compaction Cardiomyopathy LVNC seems to be the common cardiomyopathy type in the class of unclassified car- diomyopathies at least in children [4,5]. The origin of the disease is thought to lie in an Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 26 impaired embryonic development, leading to a sponge-like ventricle and dilation due to abnormal trabeculations. In several cases mutations have been identified for example in the genes encoding a member of the dystrophin–related protein family, tafazzin, a mito- chondrial membrane protein involved in cardiolipin metabolism, in dystrobrevin, or in a gene encoding lamin, located in the nuclear envelope [6]. But also sarcomeric genes as MYH7, ACTC, TNNT2, TPM1, ZASP are affected [7]. TNNT2 seems to be involved in car- diogenesis in the regulation of atrial septal growth and formation of trabeculae [8]. How- ever, the mechanism of disease development still is obscure and it is not clear, if and how these mutations impair correct embryonic development of the heart. Clinically, LVNC is Int. J. Mol. Sci. 2021, 22, 558 associated with left ventricular dysfunction and severe arrhythmia, sudden cardiac death,3 of 26 or embolic stroke due to an enhanced risk of thrombus formation within the trabeculaes. Figure 2. Classification of cardiomyopathies. LVNC = left ventricular non-compaction cardiomyopa- Figurethy, 2. ACM Classification = arrhythmogenic of cardiomyopathies. cardiomyopathy, LVNC DCM = left = dilatedventricular cardiomyopathy, non-compaction HCM cardiomyo- = hypertrophic pathy, ACM = arrhythmogenic cardiomyopathy, DCM = dilated cardiomyopathy, HCM = hyper- cardiomyopathy, RCM = restrictive cardiomyopathy. The figure was created using PowerPoint trophic cardiomyopathy, RCM = restrictive cardiomyopathy. The figure was created using Power- (Microsoft). Point (Microsoft). 2.1. Left Ventricular Non-Compaction Cardiomyopathy 2.2. Arrhythmogenic Cardiomyopathy LVNC seems to be the common cardiomyopathy type in the class of unclassified cardiomyopathiesACM has an estimated at least frequency in children in the [4,5 gene]. Theral origin population of the of disease 1:100 to is thought1:5000. Since to lie in suddenan impaired cardiac death embryonic similar development, to hypertrophic leading cardiomyopathy to a sponge-like may ventricleoccur as the and first dilation man- due ifestationto abnormal of the disease, trabeculations. there might In several be an additional cases mutations number have of unreported been identified cases forof ACM example in thein general the genes population encoding [9]. a memberThe hallmark of the of dystrophin–relatedACM is the replacement protein of ventricular family, tafazzin, car- a diomyocytesmitochondrial by fibrotic membrane and fatty protein tissue, involved which progresses in cardiolipin with