Impairment of Diastolic Function by Lack of Frequency-Dependent Myofilament Desensitizationin Rabbit Right Ventricular Hypertrophy

Abstract

Background-Ventricular hypertrophy is a physiological response to pressure overload that, if left untreated, can ultimately result in ventricular dysfunction, including diastolic dysfunction. The aim of this study was to test the hypothesis that frequency-dependent myofilament desensitization, a physiological response of healthy myocardium, is altered in hypertrophied myocardium. Methods and Results-New Zealand white rabbits underwent a pulmonary artery banding procedure to induce pressure overload. After 10 weeks, the animals were euthanized, hearts removed, and suitable trabeculae harvested from the free wall of the right ventricle. Twitch contractions, calibrated bis-fura-2 calcium transients, and myofilament calcium sensitivity (potassium contractures) were measured at frequencies of 1, 2, 3, and 4 Hz. The force frequency response, relaxation frequency response, and calcium frequency relationships were significantly blunted, and diastolic tension significantly increased with frequency in the pulmonary artery banding rabbits compared with sham-operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11Ϯ0.03 versus 6.11Ϯ0.06), but the frequency-dependent desensitization that takes place in the sham group (⌬pCa 0.14Ϯ0.06, PϽ0.05) was not observed in the pulmonary artery banding animals (⌬pCa 0.02Ϯ0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of troponin-I is lost in pulmonary artery banding rabbits. Conclusions-The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy. (Circ Heart Fail. 2009;2:472-481.)Key Words: hypertrophy Ⅲ calcium sensitivity Ⅲ heart rate Ⅲ EC-coupling Ⅲ myofilaments V entricular hypertrophy can occur as a result of sustained pressure overload on the ventricles arising from hypertension, valvular stenosis, or ventricular dysfunction. The hypertrophic response is thought to be compensatory at first, but in later stages can result in ventricular dysfunction and eventually pump failure. 1 The normal myocardial responses to increases in heart rate can begin to change during the transition from compensatory hypertrophy to decompensation. The force frequency relationship (FFR), normally positive in healthy myocardium, is usually severely blunted or even negative in cases of decompensated hypertrophy and becomes worse as the heart approaches failure. 2,3 Clinical Perspective on p 481Although it is incompletely understood how the FFR changes with disease, it is clear that alterations in calcium handling play a major role. [3][4][5] The role (if any) the myofilaments play in the contractile dysfunction of decompensating ventricular hypertrophy remains unresolved, in particular as it relates to changes in heart rate. Myofilament calcium sensitivity has been reported to be unaltered in LV myocytes from rapid paced d...

Long Term Ablation of Protein Kinase A (PKA)-mediated Cardiac Troponin I Phosphorylation Leads to Excitation-Contraction Uncoupling and Diastolic Dysfunction in a Knock-in Mouse Model of Hypertrophic Cardiomyopathy

“…In normal conditions, frequency-dependent elevations in diastolic [Ca 2ϩ ] i occur as a result of bursts of calcium dissociating from cardiac myofilaments in response to cellular and molecular mechanisms that hasten cross-bridge detachment (66). Upon ␤-AR stimulation or increasing the pacing frequency of cardiac myocytes, the phosphorylation of cTnI and cardiac MyBP-C accelerates relaxation (24,62,69). Changes in the relaxation rate associated with stepwise increases in frequency must be accompanied by proportional decreases in the myofilament Ca 2ϩ sensitivity in order to prevent diastolic dysfunction (62,69).…”

“…Upon ␤-AR stimulation or increasing the pacing frequency of cardiac myocytes, the phosphorylation of cTnI and cardiac MyBP-C accelerates relaxation (24,62,69). Changes in the relaxation rate associated with stepwise increases in frequency must be accompanied by proportional decreases in the myofilament Ca 2ϩ sensitivity in order to prevent diastolic dysfunction (62,69). It follows that frequency-dependent accelerated relaxation is associated with proportional increases in cTnI phosphorylation (61,62).…”

Effects of increased preload on the force-frequency response and contractile kinetics in early stages of cardiac muscle hypertrophy

“…In this study, we set out to quantify functional changes that would occur as the muscle shifts from a healthy toward a hypertrophic state. An assessment of forcefrequency changes in already hypertrophied muscle (such as pulmonary artery banded rabbits in which the force-frequency relationship is already blunted) (14,44) would allow us to potentially follow the transition to end-stage failure, but this was deemed well beyond the scope of the current study.…”

“…A negative FFR is thought to reflect a decrease in sarcoplasmic reticulum calcium load (19,37). In addition to altered calcium handling, the FFR also appears to be regulated at the myofilament level: upon an increase in stimulation frequency, myofilament calcium sensitivity has been shown to be reduced in the rabbit (43), and this myofilament contribution can become dysfunctional under pathological conditions (44).…”

“…The effects of frequency-dependent changes in contractile and kinetic function of each individual muscle were tested in the culture set-up at either 0, 12, or 24 h. Briefly, muscles were cultured at 1 Hz, and the force was recorded before the FFR assessment (42)(43)(44). Force and kinetics were assessed during steady-state contractions at 1, 2, 3, and 4 Hz.…”