The current study shows three important findings. First, RV and LV strains were impaired in patients with HCM despite normal LVEF. There was a small reduction in RVEF, albeit within accepted normal limits. Second, whilst LVEF remained stable, both RVEF and RV strain, as well as LV strain parameters progressively declined in HCM over time. Third, RVEF was an independent predictors of adverse cardiovascular outcomes even after adjusted for conventional LV parameters such as LV wall thickness and LGE.
RV function is impaired despite preserved LV function in hypertrophic cardiomyopathy
Whilst both morphological and functional changes of the LV have been well characterised in HCM, less is known about the RV function owing to difficulties encountered during assessment of the RV, arising from its complex geometry [
20]. Two-dimensional echocardiography is the most widely used imaging modality for RV assessment, but remains limited due to dependence of image quality on operator experience and subject characteristics (body habitus and comorbidities). The lack of clear endocardial definition on echocardiography can also contribute to inaccuracies of RV chamber size estimation, wall thickness and function [
20]. In the current study, we used CMR to assess the RV wall thickness, volumes and function in HCM. In contrast to echocardiography, CMR has been shown to be more accurate for the measurement of RV function, providing 3-dimensional coverage of the heart [
13] and alleviating the need for geometric assumptions about shape. In line with this, we and others [
21] found both measurements of RVEF and strain on CMR to be highly reproducible with good inter and intraobserver variability.
In the present study, we showed that despite normal LVEF, RV function, in particular RV strains in HCM patients were significantly reduced, with a small reduction in RVEF although this was still within the normal range, for an age- and sex-matched controls. We also showed that LV strain parameters were reduced in line with a previous study [
22]. Our findings are in agreement with a smaller echocardiography study of 43 HCM which also reported subtle impairment in RV function [
23], though the evidence in support of RV dysfunction has been conflicting in previous studies [
9,
24]. Here, we also found no evidence that reduced RV function was secondary to increased pulmonary artery pressure, indicating that RV dysfunction is an intrinsic feature of HCM [
25] and contesting the commonly accepted notion that RV failure may be an adaptive response to increased pulmonary pressures and LV dysfunction in HCM.
Although the mechanisms underlying RV dysfunction in HCM are unclear, previous studies have reported histological evidence of hypertrophy, myocyte disarray and fibrosis involving the RV of HCM patients [
26]. Indeed, RV hypertrophy and fibrosis (in the form of LGE on CMR) have also been reported in other non-invasive imaging studies [
6,
8,
9] suggesting that the cardiomyopathic process in HCM is likely to be more diffuse. Given that myocardial fibrosis and disarray may contribute to contractile abnormalities of the LV [
27‐
29], it seems plausible that RV dysfunction in our patients may be the result of intrinsic myocardial disease [
26,
30] caused by the sarcomeric mutant protein which would be found in all cardiomyocytes (involving both left and right ventricles).
Myocardial strain is a sensitive tool for the assessment of subclinical cardiac dysfunction on both echocardiogram and CMR [
31]. Although RV strain is not as widely used as LV strain, we and others [
21] have found RV strain to be highly reproducible using CMR tissue tracking. As with RVEF (although small reduction), RV longitudinal strain was impaired in HCM patients, a finding consistent with previous echocardiographic studies [
32‐
34]. Additionally, we show that on CMR, RV circumferential and radial strain were also reduced in HCM patients. Interestingly, RV longitudinal strain was worse in those with more severe LV hypertrophy, implying that RV function is linked to the phenotypic severity of HCM [
32]. Taken together, these data suggest that the comprehensive evaluation of RV function on CMR may be useful in detecting the extent of disease involvement in HCM despite normal LVEF.
RV function in HCM declines over time
This study also examined the natural history of RV dysfunction on interval CMR scans in a subset of patients. We found a significant decrease in RVEF and longitudinal strain, but not circumferential or radial strain. Interestingly, the reduction in RVEF was not accompanied by a parallel reduction in LVEF, though LV global longitudinal strain did decrease over time. This would suggest that RVEF may be more sensitive than LVEF to disease progression [
35]. We have shown that in HCM, myocardial fibrosis and LV hypertrophy can progress on serial CMR [
36] and affects subtle markers of contractility such as global longitudinal strain. Based on these findings, we postulate that the reduction in RV function may also be due to an accumulating burden of pathology. Given that the RV is relatively thin-walled, changes in myocardial architecture (such as hypertrophy, disarray or fibrosis) could potentially alter myocardial contractility to a greater extent than that seen in the muscular LV. Whilst the qualitative and quantitative assessment of myocardial fibrosis/LGE in the RV could in theory help resolve this, detection of fibrosis in the RV is challenging and frequently confounded by partial volume effects of blood pool due to the thin-walled, trabeculated myocardium of the RV. The low frequency of focal RV LGE (3%) in our study and others [
9] could additionally be reflective of these technical limitations as such, further development in acquisition strategies (high resolution imaging) may be required to improve the accuracy of fibrosis assessment in the RV. The impact of worsening LV stiffness and diastolic dysfunction also deserves further consideration [
37] as increasing pulmonary vascular resistance is likely to increase the RV afterload and consequently function. In the present study serial imaging was only limited to CMR and not echocardiography and hence we remain limited in our ability to clarify delineate the specific cause of progressive RV dysfunction.
RV function predicts adverse cardiovascular outcomes
In this study, clinical follow up of 290 HCM patients was undertaken over a median interval of 4.4 years. Previous studies have found RV hypertrophy to be prognostically important. Here, although maximum RV wall thickness was a determinant of HF outcomes on univariate analysis, there was no association seen with ventricular arrythmias. Additionally, in our study the relationship between RV wall thickness and HF progression was lost after adjusting for RV function and other univariate predictors. The presence of LGE in the RV also did not associate with clinical outcomes and is likely to reflect the reduced power of this study owing to the low frequency of RV LGE. On the other hand, reduced RVEF was predictive of NSVT and composite cardiovascular events (NSVT, HF outcomes and cardiovascular death), while RV global longitudinal strain was predictive of NSVT even after adjusting for confounding variables (although its diagnostic performance in predicting such events remain limited). These findings are consistent with a recent study by Shah et al. [
7] which showed an increased risk of cardiovascular mortality in HCM patients with moderate RV systolic dysfunction (RVEF < 45%) and evidence of LV impairment. Our study extends these findings as we show that even in cases with mild RV dysfunction (RVEF < 55%) and preserved LVEF, RV function independently predicted poor clinical outcomes.
Another interesting observation was the association of RVEF with NSVT and composite cardiovascular events in those under the age of 55. Ho et al. [
38] have similarly noted that younger patients with HCM tended to have higher risk of HF and life-threatening arrhythmias compared to age matched healthy population. As CMR is increasingly performed for clarification of anatomy and risk stratification with LGE imaging [
3], extending the assessment to involve RV function and strain may help refine risk prediction particularly in younger HCM patients and serve as a guide for closer surveillance.
Study limitations
The limitations of this study follow from its observational, single-centre study design. The population studied were at low risk for SCD and some of the endpoints (NSVT and AF) chosen, although clinically relevant, were soft. Furthermore, details about the number of ventricular triplets of NSVT, which on its own is a soft end point were not available. The echocardiographic analysis of the RV was performed as per clinical need, therefore targeted RV acquisition may have been suboptimal, particularly early on in the enrolment period before the publication of American Society of Echocardiography (ASE) guidelines for evaluation of the right heart in 2010 [
39]. The lack of serial echocardiography in the longitudinal assessment limits our ability to draw definitive conclusions on cause for progressive RV dysfunction. Similarly, diastolic functional parameters, in line with contemporary guidelines, were available only for those patients who underwent CMR scans after 2010 [
40]. Follow up CMR was undertaken in only 63 patients as a part of a natural history sub-study (funding limited) specifically designed to examine differences in left and right ventricular parameters over time. As such, this may not have been sufficiently powered and may be unrepresentative of the baseline cohort to examine the prognostic value of progressive RV dysfunction. RV afterload was not formally investigated with right heart catheterisation, but echocardiography provided an estimation of pulmonary arterial pressure. The prevalence of visible LGE in the RV was low, in line with a previous study [
9], and may be underestimated due to partial volume effects of blood. Finally, our results may be sustained by an exceptional reproducibility in RVEF measurement, better than previously reported in 2004 [
41].