Enkhsaikhan Purevjav

By Enkhsaikhan Purevjav

Cardiomyopathies are a heterogeneous group of disorders of heart muscle that ultimately result in congestive heart failure (CHF). Rapid progress in genetics as well as in molecular and cellular biology over the past three decades has greatly improved the understanding of pathogenic signaling pathways in inherited cardiomyopathies. This chapter will focus on animal models of different clinical forms of human cardiomyopathies with their summaries of triggered key molecules, and signaling pathways will be described.

Part of the book: Animal Models in Medicine and Biology

By Enkhsaikhan Purevjav and Jeffrey A. Towbin

The sarcomeres represent the essential contractile units of the cardiac myocyte and are bordered by two Z-lines (disks) that are made by various proteins. The cardiac Z-disk is recognized as one of the nodal points in cardiomyocyte structural organization, mechano-sensation and signal transduction. Rapid progress in molecular and cellular biology has significantly improved the knowledge about pathogenic mechanisms and signaling pathways involved in the development of inherited cardiomyopathies. Genetic insult resulting in expression of mutated proteins that maintain the structure of the heart can perturb cardiac function. The primary mutation in the cardiac contractile apparatus or other subcellular complexes can lead to cardiac pathology on a tissue level, resulting in organ and organism level pathophysiology. The “final common pathway” hypothesis interpreting the genetic basis and molecular mechanisms involved in the development of cardiomyopathies suggests that mutations in cardiac genes encoding proteins with similar structure, function, or location and operating in the same pathway, are responsible for a particular phenotype of cardiomyopathy with unique morpho-histological remodeling of the heart. This chapter will describe genetic abnormalities of cardiac Z-disk and related “final common pathways” that are triggered by a Z-disk genetic insult leading to heart muscle diseases. In addition, animal models carrying mutations in Z-disk proteins will be described.

Part of the book: Cardiomyopathy

By Enkhsaikhan Purevjav, Michelle Chintanaphol, Buyan-Ochir Orgil, Nelly R. Alberson and Jeffrey A. Towbin

Cardiomyopathy or disease of the heart muscle involves abnormal enlargement and a thickened, stiff, or spongy-like appearance of the myocardium. As a result, the function of the myocardium is weakened and does not sufficiently pump blood throughout the body nor maintain a normal pumping rhythm, leading to heart failure. The main types of cardiomyopathies include dilated hypertrophic, restrictive, arrhythmogenic, and noncompaction cardiomyopathy. Abnormal trabeculations of the myocardium in the left ventricle are classified as left ventricular noncompaction cardiomyopathy (LVNC). Myocardial noncompaction most frequently is observed at the apex of the left ventricle and can be associated with chamber dilation or muscle hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Animal models are incredibly important for uncovering the etiology and pathogenesis involved in this disease. This chapter will describe the clinical and pathological features of LVNC in humans and present the animal models that have been used for the study of the genetic basis and pathogenesis of this disease.

Part of the book: Preclinical Animal Modeling in Medicine

By Buyan-Ochir Orgil, Neely R. Alberson, Jeffrey A. Towbin and Enkhsaikhan Purevjav

Most prominent functional abnormalities seen in the failing human heart are impaired contraction and slowed rates of relaxation of cardiac cells in the face of increased neurohormonal activation, sustained inflammation, mechanical and volume overload, and progressive maladaptive remodeling of the myocardium. Mechanical circulatory support devices (MCS) improve cardiac function and outcomes of patients with end-stage heart failure, allowing to bridge to heart transplantation and permitting the removal of MCS device as a bridge to recovery, in some patients with the sufficient recovery of heart function. Numerous reports have demonstrated favorable myocardial recovery and reverse remodeling after prolonged ventricular unloading by MCS. Ventricular unloading by MCS leads to a decreased concentration of peripheral natriuretic peptides in plasma, reduction in cardiac cytokines, kinases, collagens, and proteins involved in hypertrophy, fibrosis, programmed cell death, and necrosis in the heart. This chapter will summarize and review the effects and underlying mechanisms of myocardial remodeling during prolonged MCS in patients with end-stage heart failure. The mechanisms of myocardial recovery are multifactorial and remain to be further explored on cellular, organ, and systems levels.

Part of the book: Ventricular Assist Devices