Transmural heterogeneity of cellular level power output is reduced in human heart failure

Abstract

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function. Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06 μW mg−1) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33 kN m−2) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain- 1. Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.

Numerical Evaluation of Myofiber Orientation and Transmural Contractile Strength on Left Ventricular Function

“…To put a different way, the more strongly a particular myocardial layer can contract, the less the reorientation of its myofibers can impact LV pump function. This may have important implications in the development of heart disease, especially those associated with myofiber reorientation as well as transmural changes in myocardium contractile function [10].…”

“…Recently, both computational and ex vivo studies have demonstrated transmural differences in myocyte contractile function at the cellular level [9,10]. In these studies, the peak isometric tension generated by myocytes depended on their transmural location in the LV wall.…”

“…These studies, however, reported different patterns of transmural variations, suggesting that the transmural distribution of myocyte contractile strength may vary from species to species, and even from individual to individual. Moreover, the transmural distribution of myocyte contractile function also could be changed during the development of heart disease, as demonstrated in ex vivo studies [10]. Although the transmural variations in myocyte contractility have been implicated in cellular level measurements [9][10][11], their effects on the global function of the LV still remain unclear and the potential interplay between myofiber orientation and transmural myocardial contractility has been neglected in previous studies.…”

“…Some parameters (i.e., c and B) were adjusted to obtain the end-diastolic volume (EDV) and end-systolic volume (ESV) prescribed in previous work [3,20]. In order to introduce transmural changes in active contraction, two distributions of T max parameters were selected according to previously reported results from either normal or failing hearts [9,10]. The values of T max for epi-, mid-, and endocardium were, in case (i) 150, 110, and 70 kPa, respectively, and in case (ii) 70, 110, and 150 kPa, respectively.…”

Myocardial hypertrophy reduces transmural variation in mitochondrial function

“…A recent study by Haynes et al (2014) showed that isometric force is higher in the mid-myocardium than in the sub-epicardium and sub-endocardium of non-failing humans hearts. Most of this transmural variation was lost in diseased human organs.…”