Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction

Abstract

Contractile dysfunction is common to many forms of cardiovascular disease. Approaches directed at enhancing cardiac contractility at the level of the myofilaments during heart failure (HF) may provide a means to improve overall cardiovascular function. We are interested in gender-based differences in cardiac function and the effect of sarcomere activation agents that increase contractility. Thus, we studied the effect of gender and time on integrated arterial-ventricular function (A-V relationship) following myocardial infarction (MI). In addition, transgenic mice that overexpress the slow skeletal troponin I isoform were used to determine the impact of increased myofilament Ca(2+) sensitivity following MI. Based on pressure-volume (P-V) loop measurements, we used derived parameters of cardiovascular function to reveal the effects of sex, time, and increased myofilament Ca(2+) sensitivity among groups of post-MI mice. Analysis of the A-V relationship revealed that the initial increase was similar between the sexes, but the vascular unloading of the heart served to delay the decompensated stage in females. Conversely, the vascular response at 6 and 10 wk post-MI in males contributed to the continuous decline in cardiovascular function. Increasing the myofilament Ca(2+) sensitivity appeared to provide sufficient contractile support to improve contractile function in both male and female transgenic mice. However, the improved contractile function was more beneficial in males as the concurrent vascular response contributed to a delayed decompensated stage in female transgenic mice post-MI. This study represents a quantitative approach to integrating the vascular-ventricular relationship to provide meaningful and diagnostic value following MI. Consequently, the data provide a basis for understanding how the A-V relationship is coupled between males and females and the enhanced ability of the cardiovascular system to tolerate pathophysiological stresses associated with HF in females.

Fig. 1.

A: representative image of 1-mm sections cut from control (CTL) and infarcted hearts at 2 (2w MI) and 10 wk (10w MI) incubated with 1% triphenyltetrazolium chloride (scale bar: 3 mm). B: heart weight-to-body weight ratio in female and male mice at different times postmyocardial infarction (post-MI). C: heart weight-to-body weight (Hw/Bw) ratio in female and male nontransgenic (NTG) and slow skeletal troponin I (ssTnI) transgenic (TG) mice, 2 and 10 wk post-MI. *P < 0.05 compared with control and ^bP < 0.05 ssTnl TG-related effect.

Fig. 2.

Sex-related differences in cardiovascular function in young adult mice following MI [A: cardiac index (CI); B: preload recruitable stroke work; C: systolic arterial-ventricular (A-V) coupling; D: cardiac contractile efficiency (CCE)]. The cardiovascular changes in post-MI mice were compared with their respective controls and expressed as %. *P < 0.05 and ^#P < 0.01. ^aP < 0.05 denotes sex-related effect. Dashed line represents mean response in 2-wk post-MI females.

Fig. 3.

Sex-related deterioration in cardiovascular function in 2- and 10-wk post-MI mice represented by a plot of the A-V relationship vs. CCE. Data are % of control.

Fig. 4.

Effect of increased myofilament calcium sensitivity on cardiovascular function in mature ssTnI TG and NTG mice post-MI (A: CI; B: preload recruitable stroke work; C: systolic A-V relationship; D: CCE). Cardiovascular changes in post-MI mice were compared with their respective controls and expressed as %. *P < 0.05 and #P < 0.01. ^aP < 0.05 denotes sex-related effect, and ^bP < 0.05 denotes ssTnI-related effect. Dashed line represents mean response in NTG females 2 wk post-MI.

Fig. 5.

Improvements in cardiovascular function in 2- and 10-wk post-MI ssTnI TG mice compared with NTG mice represented by plotting the A-V relationship vs. CCE (A: female TG and NTG mice; B: male TG and NTG mice). Data are % of control.