The "Final Common Pathway" Hypothesis and Inherited Cardiovascular Disease

Abstract

The genetic basis of a number of inherited cardiovascular diseases has been elucidated over the last few years, including the long QT syndromes, hypertrophic cardiomyopathy and dilated cardiomyopathy. While genetic heterogeneity has been demonstrated in most of these diseases, a pattern has emerged, specifically that genes encoding proteins with similar functions or involved in the same pathway are responsible for a particular disease or syndrome. Based on this observation we proposed the "final common pathway" hypothesis. In the case of the arrhythmogenic disorders, the long QT syndromes and Brugada syndrome, mutations have been described in a number of ion channel proteins, including cardiac potassium (KVLQT1, HERG and minK) and sodium (SCN5A) channels. Thus, using the "final common pathway" hypothesis we have proposed these diseases to be "ion channelopathies". Hypertrophic cardiomyopathy appears to be a disease of the sarcomere ("sarcomyopathy") since all the disease-causing mutations have been identified in the gene encoding many of the sarcomeric proteins, including beta-myosin heavy chain, alpha-tropomyosin, troponin I and troponin T, as well as in actin, close to the beta-myosin heavy chain binding site. The genes responsible for familial dilated cardiomyopathy have been less well characterized. For X-linked dilated cardiomyopathy, mutations in the dystrophin and G4.5 genes have been reported. In addition, mutations in actin (close to the dystrophin binding domain) and desmin, a component of the intermediate filaments, have been reported. However, the genes at a further 6 loci associated with autosomal dominant dilated cardiomyopathy (associated with conduction disease in 2 cases) remain unidentified. Due to the mutations in dystrophin, actin and desmin, we have proposed that dilated cardiomyopathy is a "cytoskeletalopathy", and we are currently investigating the involvement of these genes in patients.

α-E-Catenin Inactivation Disrupts the Cardiomyocyte Adherens Junction, Resulting in Cardiomyopathy and Susceptibility to Wall Rupture

“…Specifically, ␣-E-catenin is highly expressed in the adherens junction of the cardiac intercalated disc, and perturbations in its expression are associated with dilated cardiomyopathy, a disease associated with and shown to influence the cytoskeleton. 1,2,20,23,24 Because ␣-E-catenin is dynamically linked to the cytoskeleton in other cell types, we hypothesized that ␣-E-catenin would play an essential role in cardiac adherens junction ultrastructure and function in the myocardium in vivo. ␣-Catenin is required for early vertebrate embryonic development 8 and is ubiquitously expressed; thus, we utilized a conditional approach to explore its functional role in the myocardium.…”

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

“…However, the genes responsible for DCM are less well characterized than those for HCM. The mutation or deletion of some myofibrillar and extracellular matrix proteins, such as α-CA, β-MHC, cTnI, cTnT, TM, alpha-actinin, desmin, titin and dystrophin, were observed (Table 3) (215)(216)(217). Some studies in knock-out mice and humans have offered insight into the putative role of these proteins in maintaining sarcomere integrity (176,211).…”

“…The mutant proteins most likely act in a dominant negative way and lead to the appearance of desminpositive aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates, and these aggregates are characteristic of human desmin-related myopathy. The pathomechanism for this entity is not yet fully understood, but the defective desmin protein was seen to result in an impaired force transmission or in contraction-induced cellular damage (215). A genetic analysis of patients suffering from dominantly inherited or desmin-related myopathy revealed that the mutant desmin interferes with the normal assembly of intermediate filaments, resulting in fragility of the myofibrils and severe cardiac dysfunction (236).…”

Animal models of arrhythmogenic cardiomyopathy

“…The 'final common pathway' hypothesis by Towbin and Bowles was one of the first attempts to link structural protein mutations to the major presentations of heart failure: most notably dilated and hypertrophic cardiomyopathies (Bowles et al, 2000). According to this hypothesis, DCM arises primarily from alterations in cytoskeletal proteins, whereas ARVC/D is caused by structural weakening of the desmosome, which predisposes the RV to fibrosis and dilation (Stokes, 2007).…”