Retrofitting the Heart: Explaining the Enigmatic Septal Thickening in Hypertrophic Cardiomyopathy

Author:

Federspiel Jan M.12ORCID,Reil Jan-Christian3ORCID,Xu Anton1,Scholtz Smita3,Batzner Angelika14ORCID,Maack Christoph1ORCID,Sequeira Vasco1ORCID

Affiliation:

1. Comprehensive Heart Failure Center, Department of Translational Science University Clinic Würzburg, Germany (J.M.F., A.X., A.B., C.M., V.S.).

2. Saarland University, Faculty of Medicine, Institute for Legal Medicine, Homburg (Saar), Germany (J.M.F.).

3. Klinik für allgemeine und interventionelle Kardiologie, Herz- und Diabetes-Zentrum Nordrhein-Westphalen, Germany (J.-C.R., S.S.).

4. Department of Internal Medicine I, University Hospital Würzburg, Germany (A.B.).

Abstract

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum’s predisposition toward hypertrophy.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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