Regionally heterogeneous tissue mechanics in cardiac amyloidosis.

OBJECTIVE: The goal of this study was to examine in vitro tissue stiffness and contractile performance in myocardial amyloidosis. BACKGROUND: Primary systemic amyloidosis involves the deposition of amyloid protein in mesodermal tissues including the heart. Functional assessment of cardiac amyloidosis is usually performed using echocardiography. However, this technique does not involve assessment of preload-dependent contractile reserve (the Frank-Starling mechanism). METHODS: At the time of heart transplantation, isolated myocardial trabeculae were dissected from the right ventricle of a patient with primary systemic amyloidosis. In vitro length-tension experiments were performed and trabeculae were subsequently fixed, sectioned and stained with crystal violet to determine amyloid deposition. RESULTS: Among the nine trabeculae capable of generating force transients, various combinations of myocardial stiffness and contractile performance were observed including normal stiffness and contractility, severely increased stiffness with impaired contractility and hybrid patterns. Histological analysis demonstrated varying degrees of amyloid deposition among sampled trabeculae. CONCLUSIONS: Our findings extend previous reports of functional heterogeneity among patients by demonstrating functional heterogeneity within a single patient's heart. Our findings also highlight the functional interdependence of passive stiffness and systolic performance in the diseased myocardium and demonstrate the value of dynamic assessments of myocardial performance.

Sex-based differences in myocardial contractile reserve.

Recent studies have identified sex differences in heart function that may affect the risk of developing heart failure. We hypothesized that there are fundamental differences in calcium (Ca) regulation in cardiac myocytes of males and premenopausal females. Isometric force transients (n = 45) were measured at various stimulation frequencies to define the force frequency responses (FFR) (0.5, 1.0, 1.5, and 2.0 Hz) during either changes in bath Ca ([Ca]o) (1.0, 1.75, 3.5, and 7.0 mM) or length-tension (20, 40, 60, 80, and 100% L(max)) in right ventricle trabeculae from normal male (MT) and premenopausal female (FT) cats. Force-Ca measurements were also obtained in chemically skinned trabeculae. Under basal conditions (0.5 Hz, 1.75 mM Ca, 80% L(max)) both MT and FT achieved similar developed forces (DF) (MT 11 +/- 1, FT = 10 +/- 1 mN/mm2). At low rates and lengths, there is no sex difference. At higher preloads and rates, there is a separation in DF in MT and FT. At basal [Ca]o both MT and FT exhibited positive FFR (2.0 Hz, 1.75 mM Ca: MT 38 +/- 3, FT 21 +/- 4 mN/mm2); however, at higher [Ca]o, MT achieved greater DF (2.0 Hz, 7.0 mM Ca: MT 40 +/- 3 and FT = 24 +/- 4 mN/mm2). We detected no sex difference in myofilament Ca sensitivity at a sarcomere length of 2.1 mum. However, rapid cooling contractures indicated greater sarcoplasmic reticulum (SR) Ca load in MT at higher frequencies. Despite virtually identical contractile performance under basal conditions, significant sex differences emerge under conditions of increased physiological stress. Given the lack of sex differences in myofilament Ca sensitivity, these studies suggest fundamental sex differences in cellular Ca regulation to achieve contractile reserve, with myocardium from males exhibiting higher SR Ca load.

Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium.

BACKGROUND: - The normal increase in isometric developed force (DF) with faster pacing rates, known as the positive force-frequency response/relationship (FFR), is altered in failing myocardium, as shown by its negative response to increased pacing. The objective of this study was to determine if increasing Ca2+ influx with L-type Ca2+ channel (L-CaCh) agonists: BayK 8644 (BayK) and FPL 64176 (FPL) or increased extracellular Ca2+ could increase contractility and normalize the FFR in failing myocardium. METHODS: - Isometric DF was measured in right ventricular trabeculae from failing (n = 28) and non-failing (n = 12) human hearts at various stimulation frequencies (0.5-2.5 Hz) before and after bath application of BayK (250 nM), FPL (100 nM), or high Ca2+ (7.0 mM). Post-rest (PR) experiments were also conducted on several trabeculae. RESULTS: - In trabeculae from failing hearts, the DF decreased with an increase in pacing. Addition of L-CaCh agonists increased DF to similar levels in trabeculae from both failing and non-failing hearts at slow pacing rates, but did not alter the negative FFR in the failing group. During increased rest intervals, the amount of PR potentiation was diminished in trabeculae from failing hearts as compared to the non-failing preparations. CONCLUSION: - This study demonstrates that the abnormal FFR observed in trabeculae from failing hearts is a reliable physiologic signature of the cardiomyopathic state even when DF, at slow stimulation frequencies, is relatively high. These studies further demonstrate that the impaired FFR is not due to an inability to further increase contractility. Rather, our findings suggest that the abnormal FFR and blunted PR potentiation alike are a reflection of an altered functional balance between Ca2+ re-uptake and Ca2+ extrusion.