Myocyte repolarization modulates myocardial function in aging dogs

Abstract

Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. aging; myocardium; contractile reserve NEW & NOTEWORTHYWe have investigated the effects of aging on the heart using a genetically uniform large animal model, maintained under highly regulated conditions. Our results indicate that the myocyte compartment undergoes physiological alterations with age that negatively interfere with ventricular function.STUDIES OF MYOCARDIAL AGING in humans are complex, as it is difficult to separate the effects of time from genetic, ethnic, lifestyle, and environmental factors, which may modify physiological cardiac aging. Additionally, the incidence of cardiovascular diseases increases with age (24) and intervening pathologies may change the natural temporal evolution of the organ. Therefore, the mechanisms involved in the age-related deterioration of ventricular performance and decreased functional reserve of the old heart (9, 12, 17, 18, 39) remain to be properly defined.The general belief has been that abnormalities in ventricular compliance with age occur as a result of collagen deposition and diffuse interstitial fibrosis, which, together with cardiomyocyte loss, lead to depressed systolic and diastolic function (17,18,26,39). Additionally, myocardial hypertrophy has been proposed as a critical variable of the senescent myopathy (5), in spite of the lack of organ hypertrophy in older humans (25). Current understanding of the pathophysiology of the aging myopathy and the mechanisms involved in the increased incidence of heart failure and ...

Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes

“…Patch-clamp studies. Isolated LV myocytes were placed in a bath on the stage of an IX53 inverted microscope (Olympus) for patchclamp measurements (17,26,(31)(32)(33). Experiments were conducted at 37°C.…”

“…For action potentials (AP) measurements, cells were stimulated at 4 Hz with current pulses 1-1.5-fold the AP threshold (17,(31)(32)(33). Myocytes were bathed with Tyrode solution containing (in mM) 140 NaCl, 5.4 KCl, 1 MgCl 2, 5 HEPES, 5.5 glucose, and 1 CaCl2 (pH 7.4, adjusted with NaOH).…”

“…Statistical analysis was performed using Sigma-Plot 11.0 software. Data were initially tested for normality (Shapiro-Wilk) and equal variance for assignment to parametric or nonparametric analysis (17,31,33). Parametric test included Student's t-test or ANOVA followed by Bonferroni test for non-paired comparison between two or among multiple groups, respectively.…”

Depleted Myocardial Coenzyme Q10 in Cavalier King Charles Spaniels with Congestive Heart Failure Due to Myxomatous Mitral Valve Disease

“…The presence of, for example, replacement fibrosis was not within the scope of this work but is of high relevance to interpret the finding of impaired CS activity. Replacement fibrosis occurs in the myocardium of aging dogs [ 51 ] and this would reduce measures of CS activity correlated to tissue weight in myocardial tissue samples [ 52 ]. Studies need to be done in the future to understand in detail the role of age-related changes in mitochondrial mass in canine myocardium as this may be a relevant therapeutic target.…”

Novel methods for high-resolution assessment of cardiac action potential repolarization

“…Methods presented here were applied to APs with a strictly decreasing repolarization phase, a typical feature of the electrical recovery of rodent cardiomyocytes. However, cells obtained from large mammals have APs with a prominent plateau phase [14][15][16] with repolarization not strictly decreasing. It is conceivable that segmentation of the AP repolarization represents a valid strategy for the application of our algorithms.…”