Desmin Correlated with Cx43 May Facilitate Intercellular Electrical Coupling during Chronic Heart Failure

Desmin is one of five major intermediate filament proteins in cardiomyocytes. Desmin contributes to the maintenance of healthy muscle. The desmin content in cardiomyocytes directly affects the long-term prognosis of patients with heart failure, and lack of desmin leads to myocyte contractile dysfunction. However, the mechanism is elusive. In this study, we measured desmin expression using western blotting and qPCR in the failed hearts of human patients and rats. Our results showed that desmin content was reduced at the protein level in failed hearts and isolated cardiomyocytes. The association of desmin and the gap junction proteins connexin 43 (Cx43) and zonula occludens-1 (ZO-1) was also investigated. Immunoprecipitation assay showed that desmin was associated with Cx43 in cardiomyocytes. To compare the electrical integration of skeletal myoblasts in cocultures with cardiac myocytes, familial amyloid polyneuropathy (FAP) activation rate was found in 33% desmin overexpressing skeletal myoblasts. Desmin not only affected Cx43 and ZO-1 expression but also facilitated the complex of Cx43 and ZO-1 in skeletal myoblasts, which enhanced cell-to-cell electrical coupling of skeletal myoblasts with cardiac myocytes. Desmin has potential as a novel therapeutic target for heart failure. Preservation of desmin may attenuate heart failure.

Are pharmacological treatments for familial amyloid polyneuropathy effective and safe? A Cochrane Review summary with commentary

BACKGROUND: Familial amyloid polyneuropathies (FAPs) are a group of rare autosomal dominant transmitted disorders that can progressive lead to disability from neuropathy, autonomic failure and other system involvement. OBJECTIVE: The aim of this commentary is to discuss Cochrane evidence on the efficacy and safety of disease-modifying drugs (DMDs) for the treatment of FAPs from a rehabilitation perspective. METHODS: To summarize and discuss from a rehabilitation perspective the published Cochrane Review “Pharmacological treatment for familial amyloid polyneuropathy” by Magrinelli et al. RESULTS: This Cochrane review included 4 randomized controlled trials (RCTs) involving 655 adults with FAP. These four trials compared four different DMDs with placebo. The Cochrane Systematic Review reported that current evidence is limited. CONCLUSIONS: FAPs are a group of chronic disabling conditions in which a multidisciplinary approach, including an adequate rehabilitation programme along with a long-term effective pharmacological therapy, should always be envisaged.

Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.