Idiopathic Restrictive Cardiomyopathy - Perspectives from Genetics Studies. Is It Time to Redefine These Disorders?

Abstract

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in 33-66% of cases. Among these, the mutations most commonly involve TNNI3 and MYH7. There is a disproportionately high incidence of TNNI3 mutations in patients with restrictive physiology. De novo mutations are also frequently seen in this group of patients. IRC and hypertrophic cardiomyopathy (HCM) with restrictive phenotype reflect the same or very similar disorders with different names due to arbitrary cut offs in the left ventricular wall thickness rather than two separate distinct diseases. HCM with restrictive physiology should be considered part of a continuous spectrum with IRC. This is because patients with HCM with restrictive phenotype bear far greater clinical and genetic resemblance to IRC than to rest of the HCM cohort.

Coronary arterial vasculature in the pathophysiology of hypertrophic cardiomyopathy

“…In sarcomeric RCM, adaptation of perfusion with metabolism and the compaction process itself overestimated the capability of the blood supply to match myocardial energy demand and can be related to a temporal effect of mutations on energetics—more acute or sudden. This is demonstrated by the preferential involvement of genes differentially expressed (cTnI expressed after birth and β-MHC slowly replacing α- MHC) or alternatively spliced (cTnT adult vs fetal variants) during development [10, 126]. The temporal effect of a mutation can be further potentiated by the increased rates of turn-over of troponin subunits [88].…”

Restrictive Cardiomyopathy and Hypertrophic Cardiomyopathy Overlap: The Importance of the Phenotype

“…As demonstrated by the article by Bahl and colleagues in the current issue of Cardiogenetics, 3 no single classification scheme for cardiomyopathies is perfect. However, the approach of the ESC position statement, based on the recognition of the clinical phenotype, is relevant to everyday clinical practice.…”

“…The most common causes of RCM are summarized in Table 1. As discussed by Bahl et al, 3 between 30 and 60% of cases of RCM are caused by mutations in cardiac sarcomere protein genes. 4,5 Other relatively common causes include amyloidosis, and, in the tropics, endomyocardial fibrosis.…”

“…2 Restrictive ventricular pathophysiology also occurs in other subtypes of cardiomyopathy such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and in the current issue of Cardiogenetics, Bahl and colleagues propose that these conditions should be considered part of the same disease spec-trum. 3 Whilst the authors highlight the clinical and genetic overlap between HCM with restrictive physiology and idiopathic RCM, and correctly point out that the treatment and prognosis in many cases is similar, the suggestion that patients with left ventricular hypertrophy and restrictive physiology should be reclassified as RCM is, in our view, potentially misleading and likely to result in confusion in the clinical setting.…”

Mutations in Hotspot Region of MYH7 Gene Exon 23 Associated with Restrictive Cardiomyopathy

“…In the last decade, restrictive cardiomyopathy was also found to be associated with mutations in sarcomeric genes, suggesting common etiologies among different cardiomyopathies. 12 To date all sarcomeric proteins encoding genes are associated with the etiology of RCM with 33-66% incident rate 13,14 with TNNI3 being the first sarcomere gene implicated. However, there are many reports of MYH7 gene to be associated with RCM.…”