Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems

Abstract

The classic clinical definition of hypertrophic cardiomyopathy (HCM) as originally described by Teare is deceptively simple, "left ventricular hypertrophy in the absence of any identifiable cause". Longitudinal studies, however, including a seminal study performed by Frank and Braunwald in 1968, clearly described the disorder much as we know it today, a complex, progressive and highly variable cardiomyopathy affecting ~1/500 individuals worldwide. Subsequent genetic linkage studies in the early 1990's identified mutations in virtually all of the protein components of the cardiac sarcomere as the primary molecular cause of HCM. In addition, a substantial proportion of inherited dilated cardiomyopathy (DCM) has also been linked to sarcomeric protein mutations. Despite our deep understanding of the overall function of the sarcomere as the primary driver of cardiac contractility, the ability to use genotype in patient management remains elusive. A persistent challenge in the field from both the biophysical and clinical standpoints is how to rigorously link high-resolution protein dynamics and mechanics to the long-term cardiovascular remodeling process that characterizes these complex disorders. In this review, we will explore the depth of the problem from both the standpoint of a multi-subunit, highly conserved and dynamic "machine" to the resultant clinical and structural human phenotype with an emphasis on new, integrative approaches that can be widely applied to identify both novel disease mechanisms and new therapeutic targets for these primary biophysical disorders of the cardiac sarcomere. Keywordsthin filament; hypertrophic cardiomyopathy; dilated cardiomyopathy; troponin; tropomyosin Current Challenges in our Understanding of Sarcomeric CardiomyopathiesMutations in the genes that encode the protein components of the cardiac thin filament were first linked to clinical cardiomyopathies in 1994 [85]. Mutations in the regulatory thin filament comprise ~ 7-10% of hypertrophic cardiomyopathy (HCM) cases and represent a distinct and complex subset of the disorder with marked mutation-specific phenotypes [11,84]. Despite 25 years of basic research, many questions remain regarding the clinical

Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect Length-Dependent Calcium Sensitivity of Force Generation

“…Several hypotheses have been formulated to explain the diverging heart phenotypes in HCM versus DCM manifesting from specific mutations within the same protein like cTnT: (1) mutations directly affecting calcium sensitivity (Robinson et al, 2002(Robinson et al, , 2007, (2) mutations affecting EC coupling or Ca 2+ homeostasis (Tardiff et al, 2015;Crocini et al, 2016), and (3) mutations interfering with the effect of posttranslational modifications on calcium sensitivity (Sfichi-Duke et al, 2010;Memo et al, 2013;Messer et al, 2016). The systemic development of each of the two diseases in the human is even more complex and highly variable (Maron et al, 2012;Deranek et al, 2019). Studies of human samples revealed that hcTnI is hypo-phosphorylated in myocardial samples from HCM and DCM patients compared to control samples from donor hearts (Hamdani et al, 2008;Sequeira et al, 2013Sequeira et al, , 2015.…”

“…Although, our study is in agreement with previous functional studies of the K210 mutation and the prevalent disposition of HCM mutations increasing and DCM mutations decreasing calcium sensitivity, the definite reasons why the K210 mutation results in DCM and the R130C mutation in HCM remain elusive. While typical features of HCM are increased wall thickness, cardiomyocyte disarray, fibrosis and impaired diastolic filling, DCM is characterized by enlarged ventricles, reduced ventricular wall thickness to volume ratio and impaired systolic contraction, i.e., reduced ejection fraction (Garfinkel et al, 2018;Deranek et al, 2019). An interesting hypothesis is that the primary, acute effects of mutations on LDA, in the long term, might contribute to the directionality of the diverging histological and morphological phenotypes of HCM and DCM.…”

The Effect of Tropomyosin Mutations on Actin-Tropomyosin Binding: In Search of Lost Time

“…In principle, an enhanced bias of tropomyosin for the thin filament blocking state should lead to decreased cardiac thin-filament activation, in this case potentially predisposing heart muscle to dilated cardiomyopathy (DCM) (46). For example, the interaction energetics of DCM-linked E40K tropomyosin for F-actin is considerably stronger than that for wild-type tropomyosin (Table 1; also see ( 51)), whereas the Ca 2þ sensitivity of reconstituted filaments containing E40K is lower (32,(52)(53)(54)(55)(56)(57). As expected, the E40K-F-actin complex shows stable interactions during MD and no evidence of localized detachment from F-actin.…”

Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response

“…Initial diastolic dysfunction in HCM patients is triggered by altered myofilament properties induced by protein mutations. However, the overall HCM phenotype depends not only on the mutation per se but also on additional contributing factors during progression of the disease (Arad et al, 2002;Deranek et al, 2019). These factors include both the response of myofilament force and kinetics to Ca 2+ as well as membrane-controlled Ca 2+ fluxes to and from the myofilaments.…”