Sex differences in volume overload in skinned fibers

In this study, we observed sex differences in the contractile performance of patients with severe MR. Skinned fibers from females achieved more force at higher supra-normal calcium concentrations (pCa of 4.0 and pCa of 4.5). In contrast, male fibers developed higher forces at lower calcium concentrations (pCa of 5.0–6.5), which included the “physiological concentration” at pCa of 5.0–6.0. The calcium sensitivity of the male and female fibers was similar. We propose that females save force capacities, which can be mobilized at higher force values, whereas males tap the full force capacity at physiological concentrations of pCa of 5.0 and 6.0. However, it is unclear how female fibers could develop increased contractibility at higher calcium concentrations. Thus, it is uncertain whether force fatigue. On the other hand, clinical signs, such as wedge pressure, mean PAP, TAPSE, and LVEF might give some evidence for a reduced biventricular function, which was observed in females, compared to males. Although there is controversy in the literature on the force values of healthy male and female skinned fibers (i.e., whether they are higher in females or males), all the previous studies were performed in rats or other animal models [1–3, 5–7, 9, 10].

In common with the findings of the present study, Schwertz observed increased forces in female skinned human rat atria at high extracellular calcium in the presence of tetanic contraction and greater force and a higher maximal rate of contraction in females compared to males [8]. Another study also reported that the calcium sensitivity of female rats seemed to be higher than that of male rats [6].

In the presence of volume overload, Dent found sex-specific differences: Females developed greater increase in cardiac mass, but the rates of pressure development (+dP/dt) and decay (?dP/dt) were depressed and left ventricular end-diastolic pressure increased in male rats at 16 weeks post-AV shunt. Decreased LV internal diameters, as well as depressed fractional shortening, occurred in males, whereas increases in posterior wall thickness were seen in female rats at 16 weeks post-AV shunt [11, 12]. Therefore, sex-specific remodeling processes seem to occur, at least in rodents. In the present study, the pressure values (wedge and PAP) of females increased more often than those of males, but they had decreased RAP values. Furthermore, the LVEF was slightly reduced in females compared to males. Thus, the observations are somewhat similar to those reported by Dent. Calcium sensitivity was different among genders, males needed less calcium to achieve half maximal activation. This means, they are more sensitive to calcium compared to females. Wattanapermpool and coworkers presented similar results, with a loss of estrogen by ovariectomy increasing the sensitivity of rats to calcium [13]. Their results are in accordance with the findings in the present study of reduced calcium sensitivity in fibers obtained from female patients.

According to the difference in cardiac properties, we observed gender-related differences in the clinical picture of mitral valve regurgitation scheduled for elective mitral valve surgery due to MR. We observed more mitral annulus dilatation in females but no significantly higher incidence of prolapse, flail leaflet, or chorda rupture in one of the groups. However, prolapse and LA dilatation were more common in the female group. These findings are accordance with those in the literature [14].

In the present study, although there were no differences in the preoperative clinical presentation in terms of pathological findings in the mitral valve, sex-specific cardiac remodeling can be assumed, as female patients present more frequently with left atrial dilatation, and male patients present more often with left ventricular dilatation. However, this was not significant, but might be an explanation for reduced force capacity at the level of the atria because right heart function parameters, such as TAPSE, were also slightly increased in females. In the literature, there are only a few studies on the sex-specific clinical presentation in humans with severe MR.

Several animal studies have provided evidence for differences in the remodeling process. Janicki et al. described a sex-specific remodeling process in a rodent model of induced volume overload [15]. In their study, female rodent hearts showed less chamber dilatation but more ventricular hypertrophy than male hearts, which showed significant dilatation and wall thinning [15]. Another rodent study demonstrated that the female heart was cardioprotected, developed concentric hypertrophy, and remained compensated [16]. The idea of sex-specific remodeling processes extends to the cellular level. Studies reported an increase in the cardiomyocyte cross-sectional area (parallel sarcomeres) and length (in-series sarcomeres) after volume overload in female rats but no such increases in male rats [17, 18]. This might explain the possibility of females to recruit further force when exposed to even higher calcium concentrations. Further studies should be conducted to determine whether such a compensatory mechanism exists and its clinical relevance.

In our opinion, these findings could have clinical relevance for on the timing of interventions in patients presenting with severe mitral valve regurgitation. To date, the guidelines on surgical treatment for asymptomatic severe MI have relied solely on the level of LV dilatation, end-systolic diameter, EF, and presence of atrial fibrillation and/or pulmonary hypertension [19]. If we assume the existence of a sex-specific remodeling process, it is possible that female patients are referred too late for mitral valve surgery because the first response to overload in females is ventricular hypertrophy and an increase in LV mass rather than ventricular dilatation. The aforementioned hypothesis is supported by data from the literature showing that the short- and long-term survival of females who undergo surgery for MR is worse than that of male patients [20].