Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats

Abstract

The purpose of this study was to identify and explain changes in ventricular and cellular function that contribute to aging-associated cardiovascular disease in aging F344 rats. Three groups of female F344 rats, aged 6, 18, and 22 mo, were studied. Echocardiographic measurements in isoflurane-anesthetized animals showed an increase in peak left ventricular torsion between the 6- and the 18-mo-old groups that was partially reversed in the 22-mo-old animals (P < 0.05). Epicardial, midmyocardial, and endocardial myocytes were subsequently isolated from the left ventricles of each group of rats. Unloaded sarcomere shortening and Ca(2+) transients were then measured in these cells (n = >75 cells for each of the nine age-region groups). The decay time of the Ca(2+) transient and the time required for 50% length relaxation both increased with age but not uniformly across the three regions (P < 0.02). Further analysis revealed a significant shift in the transmural distribution of these properties between 18 and 22 mo of age, with the largest changes occurring in epicardial myocytes. Computational modeling suggested that these changes were due in part to slower Ca(2+) dissociation from troponin in aging epicardial myocytes. Subsequent biochemical assays revealed a >50% reduction in troponin I phosphoprotein content in 22-mo-old epicardium relative to the other regions. These data suggest that between 18 and 22 mo of age (before the onset of heart failure), F344 rats display epicardial-specific myofilament-level modifications that 1) break from the progression observed between 6 and 18 mo and 2) coincide with aberrant patterns of cardiac torsion.

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

“…According to a recent animal study, transmural variation in Ca 2+ sensitivity may also modulate ventricular torsion [18]. In the present experiments (Figure 3) non-failing samples exhibited a statistically significant increase in Ca 2+ sensitivity (p=0.010, ΔpCa 50 =0.075) going from the sub-epicardial to the sub-endocardial preparations.…”

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

“…The βAR signaling pathway is important in cardiac development, aging, and failure (25,(42)(43)(44)(45). Here, we demonstrate enhanced ionotropic responses to activation of the βAR pathway in Pkd2 +/− mice, with no effect on basal cardiac function.…”

“…Calcium transients were recorded for ten beats and averaged (25). Under normal Tyrode conditions, Pkd2 +/− cells had 39% higher magnitude of calcium release (Ca 2+ R mag , P < 0.001; Fig.…”

“…The time course of sarcomere shortening was collected simultaneously with calcium transients in electrically paced myocytes (25) (Fig. 3 A and B).…”

Acute Optogenetic Modulation of Cardiac Twitch Dynamics Explored Through Modeling

“…Simultaneous measurement of intracellular Ca 2þ concentration and contractile force over time therefore yields paired input/output data [12,13] that can be used for quantitative analyses. For instance, models of cardiac myofilament (MF) activation can be optimized to reproduce contraction force in response to a measured Ca 2þ input, giving insights into the behavior of muscle proteins [14][15][16].…”