Cardiomyopathies–From Basic Research To Clinical Management

Intercellular Connections in the Heart: The Intercalated Disc (Pathophysiology and Genetics of Cardiomyopathies) Part 3

Desmosomal cadherins Desmosomal cadherins are a superfamily of Ca2+-dependent adhesion molecules, which form dimers to make up the core of desmosomal junctions (Dusek et al., 2007). Desmogleins and desmocollins, the two main types of desmosomal cadherins, possess several isoforms (4 and 3 respectively in humans, Green and Simpson, 2007; Lorimer et al., 1994; Schmelz et […]

Familial Hypertrophic Cardiomyopathy-Related Troponin Mutations and Sudden Cardiac Death (Pathophysiology and Genetics of Cardiomyopathies) Part 1

Introduction Hypertrophic cardiomyopathy (HCM) is a common structural anomaly of the myocardium that is unexplained by an underlying condition such as hypertension. The main findings in HCM are varying degrees of ventricular and/or septal hypertrophy, myocyte disarray and increased myocardial fibrosis (Maron et al., 1995). There is significant variation in the clinical manifestation among patients, […]

Familial Hypertrophic Cardiomyopathy-Related Troponin Mutations and Sudden Cardiac Death (Pathophysiology and Genetics of Cardiomyopathies) Part 2

In vitro and in vivo approaches, animal models and in silico predictions Cardiac TnT mutations are predicted to affect the regulatory role of the Tn-Tm complex on sarcomere activation given that TnT functions to attach the Tn complex to Tm and actin (Tobacman, 1996). In vitro studies with different FHC mutations (including cTnT mutants) show […]

Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights (Pathophysiology and Genetics of Cardiomyopathies) Part 1

Introduction Cardiac troponin is the main regulatory protein of the thin filament and mediates the Ca2+-sensitivity of the actin-myosin interaction. Troponin forms a heterotrimeric complex composed of the tropomyosin binding subunit (cTnT), the inhibitory subunit (cTnI) and the Ca2+-binding subunit (cTnC). A complex interplay between the cardiac troponin subunits and other thin filament proteins, as […]

Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights (Pathophysiology and Genetics of Cardiomyopathies) Part 2

RCM inducing mutations There are only few RCM mutations detected in TNNT2 (Table 1). Most RCM mutations in genes encoding for cardiac troponin subunits are found in TNNI3 (see below). However,interestingly I79N, originally listed as HCM mutation, might also cause RCM or DCM even in members of the same family. This indicates that other factors […]

Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights (Pathophysiology and Genetics of Cardiomyopathies) Part 3

Clinical presentation Diagnosis of HCM In 1989 (Jarcho et al., 1989) and 1990 (Geisterfer-Lowrance et al., 1990), the first "disease genes" have been identified in family members with inherited hypertrophic cardiomyopathy (HCM). This identification of disease genes has raised many expectations, among others in the better understanding of the molecular mechanisms of disease development, in […]

Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights (Pathophysiology and Genetics of Cardiomyopathies) Part 4

What we can learn from patients with troponin mutations What can we learn from the patients with troponin mutations? One important message to the clinicians is that the risk of sudden cardiac death does not go along with the severity of left ventricular hypertrophy/wall thickness. Furthermore, sudden cardiac death may occur in all age groups […]

Cardiomyopathies Associated with Myofibrillar Myopathies (Pathophysiology and Genetics of Cardiomyopathies) Part 1

Introduction The aim of this topic is to describe cardiomyopathies associated with myofibrillar myopathies (MFM, OMIM 601419). Myofibrillar myopathies are a group of heterogeneous neuromuscular disorders usually characterized by a severe myopathy, and generally associated with cardiomyopathy in 15% to 30% of the affected individuals. These familial or sporadic muscle disorders are characterized morphologically by […]

Cardiomyopathies Associated with Myofibrillar Myopathies (Pathophysiology and Genetics of Cardiomyopathies) Part 2

The smallest contractile unit: The sarcomere The myocardium is composed of an assembly of a number of interconnecting, branching fibers, or short cells, separated at their end by the intercalated disk. The fibers contain numerous fibrils, composed of a regular repeating structure termed the "sarcomere" (Figure 2A) (Sonnenblick, 1968). The sarcomere is the basic and […]

Cardiomyopathies Associated with Myofibrillar Myopathies (Pathophysiology and Genetics of Cardiomyopathies) Part 3

The specific ubiquitin – Proteasome system in the sarcomere The ubiquitin-proteasome system (UPS) recognizes specific proteins and target them for degradation. Ubiquitin ligases recognize proteins to be degraded and interact with E1 (activating) and E2 (conjugating) enzymes to create poly-ubiquitin chains on the substrate. Poly-ubiquitin chains are then recognized by the 20S proteasome prior to […]

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