In the present study, we sought to investigate whether RVLSS, a novel noninvasive metric of regional and global RV contractile function derived by STE, measured during supine bicycle exercise, provides an improved detection method over conventional 2DE measures alone to identify RV contractile dysfunction in at-risk SSc patients. SSc patients in our study were primarily referred for SBE based on the indication of unexplained dyspnea. At rest, mean RVSP was normal with normal conventional 2DE derived measures of RV contractility (TAPSE, FAC). With exertion, there were increases in these conventional measures suggesting normal RV contractile response to exercise provocation. However, the innovative application of STE-based metrics revealed both resting and exercise abnormalities in RV contractile function. At rest, global RVLSS was diminished with evidence of regional heterogeneity in which there was normal contractility of the basal RV free wall segment with relative hypokinesis of midventricular and apical segments. With exercise, there were significant increases in global RVLSS, largely due to regional increases in midventricular and apical contractility, suggestive of myocardial reserve in these segments. Interestingly, despite normal resting basal contractility, there was no further augmentation of basal segment contractility with exercise. These findings suggest that at rest, the basal segment is already contracting maximally and is unable to augment further with exercise provocation. Overall, these findings demonstrate that SSc patients have a differential RV regional contractile response to exercise, suggesting limitations in RV reserve that are missed by conventional 2DE.
We also examined the effects of loading conditions on RV contractility and found differential contractile response based on resting loading conditions. In patients with low load, defined as resting RVSP < 35 mmHg, global RVLSS increased with exertion due to augmented contractility across all three RV free wall segments, including the initially hypokinetic midventricular and apical segments. In patients with high load, defined as RVSP ≥ 35 mmHg, global RVLSS did not augment significantly from baseline and there were no regional increases in RVLSS of the basal, midventricular, or apical segments. These findings suggest that the RV in high loading conditions may already contracting at its maximal capacity at rest and is unable to augment further with exercise.
Additionally, we also found significant increases in RV end-diastolic areas with exercise in the high load group. These findings are consistent with several prior studies from our group using invasive pressure-volume assessments showing that SSc-PAH patients have depressed RV contractility compared with patients with idiopathic PAH (IPAH) at similar levels of afterload, and maintain stroke volume and augment cardiac output by dilatation of the RV chamber. We also found that there were minimal differences in peak RVSP between the low and high resting load groups suggesting that contractile differences are not entirely due to a primary load phenomenon at the time of exercise. Rather, these data suggest that intrinsic contractile abnormalities may be present in SSc that affect the adaptive response to increases in afterload. These changes may be attributable due to differential myofilament contractility and calcium sensitivity as well as changes to the pulmonary vascular bed inherent to the disease process. To our knowledge, our study is the first to demonstrate the utility of novel noninvasive STE-based metrics that establish the failure of the scleroderma RV to augment contractility with high loading conditions, resulting in RV chamber dilatation. STE in conjunction with exercise provocation may provide crucial clinical information by identifying SSc patients with limitations in RV reserve and emerging pulmonary vascular disease.
There were several limitations to our study. First, this was a single-center prospective study with a relatively small sample size as exercise studies were performed based on clinical indications. There was a lack of correlation with simultaneous invasive hemodynamics and absence of a control group. There are currently no accepted reference values for the normal RV strain response to exercise and this is an important priority for future studies. Recently, there has been a notable change in the invasive hemodynamic definition of PAH, with mean PAP ≥ 21 to < 25 mmHg representing an intermediate form of disease that is high risk for emerging PAH. However, there has not been a corresponding change to the definition of pulmonary hypertension by echocardiography. While understanding that this is a continuum of disease, we chose to dichotomize our SSc patients based on the current ASE recommendations for the noninvasive cut-off of RVSP ≥ 35 mmHg for the purposes of this study. Further longitudinal studies are needed to determine if exertional changes in contractility by exercise echocardiography identify SSc patients at risk for resting PAH, and whether strain metrics can serve as a target for disease-modifying therapies. Lastly, given the well-described vendor-specific variability in strain measures, there may be inherent differences that limit the generalizability of our findings.
In this prospective study of at-risk SSc patients, we demonstrated STE-based abnormalities in RV contractile response to exercise that was not detectable by conventional measures alone and may identify SSc patients with limitations in RV reserve and poor clinical outcomes from emerging. We further demonstrated the effect of resting loading conditions on RV contractile response to exercise in which the RV chamber differentially dilates with no further augmentation in contractility in those with elevated RVSP at rest. These findings suggest a maladaptive contractile response of the RV when resting loading conditions are elevated. The significance of our study lies in the use of exercise provocation in conjunction with STE measures, an important noninvasive tool, in assessing the degree of RV contractile reserve in SSc patients at risk for PAH. Our findings of impairments in RV reserve may have clinical implications for the use of exercise provocation in screening for emerging pulmonary vascular disease in at-risk SSc patients.