Right Ventricular Dysfunction in Degenerative Mitral Regurgitation: A Canary in the Coalmine?

Warnings are never in vain, if heeded in time.

Leonardo da Vinci

Although left‐sided chamber size and function feature prominently in current clinical guidelines on the surveillance and management for primary mitral regurgitation (MR), right‐sided chambers are overlooked. ¹ , ² Left ventricular parameters of dilatation and systolic dysfunction have traditionally been considered triggers for operative referral in asymptomatic patients, because these are markers of poorer prognosis. ³ , ⁴

Right ventricular dysfunction (RVD) is associated with worse outcomes in an array of cardiac conditions including cardiomyopathy and cardiac surgeries. ⁵ , ⁶ This maxim extends to MR, where it has been shown to portend increased cardiovascular mortality in primary MR in both operative and nonoperative management ⁷ , ⁸ as well as secondary MR, where it predicts adverse outcomes following mitral transcatheter edge‐to‐edge repair. ⁹ , ¹⁰ The pathophysiology of RVD in the setting of significant MR is often attributed to elevated right ventricular (RV) loading conditions secondary to the transmission of elevated left‐sided filling pressures and pulmonary artery pressures to the right chambers. Prior studies have attempted to cast light on the potential prognostic relevance of RVD in primary MR but have been limited by small sample populations. ⁷ , ¹¹ The precise prevalence of RVD in severe degenerative MR (DMR) has varied depending on the studied population. In a retrospective cohort of 208 patients with primary MR referred for surgery, severe RVD (defined as RV ejection fraction ≤35%) was present in 30% of patients and was associated with a 2.3 fold (P=0.042) risk for cardiovascular mortality. ⁷

In this issue of the Journal of the American Heart Association (JAHA), Bohbot et al ¹² endeavor to further elucidate the prognostic value of RVD on long‐term survival in severe DMR under surgical and medical management using a large registry. In total, 2917 patients from 5 centers in North America, Europe, and the Middle East in the MIDA‐Q (Mitral Regurgitation International Database–Quantitative) registry with severe DMR were included in their analysis. RVD was identified in 14.6% of patients. Those with RVD had greater left atrial and ventricular enlargement, worse left ventricular systolic function, higher quantitative parameters of MR, and higher systolic pulmonary artery pressure (sPAP) compared with patients with normal RV function. Presence of RVD was associated with reduced 8‐year survival from 55% compared with 77% (P<0.001), and this difference in long‐term survival was present in multiple subgroup analyses. Importantly, this association, although attenuated, persisted even after adjustment for key covariates implicated in postoperative outcomes in DMR, including age, symptoms, atrial fibrillation, left ventricular dysfunction and dilatation, left atrial volume, systolic pulmonary artery pressure, and effective regurgitant orifice area.

The authors should be commended for their efforts to extend our mechanistic understanding of the interplay between DMR and RVD by evaluating the role of pulmonary hypertension. Bohbot et al report that an elevated sPAP ≥50 mm Hg in addition to left ventricular ejection fraction ≤60% were the strongest factors associated RVD. However, a subanalysis found that RVD remained independently significantly associated with worse survival even among those with sPAP <50 mm Hg. Given the association between RVD and mortality persisted despite adjustment for pulmonary hypertension and that RVD portends reduced survival even among those without pulmonary hypertension, the impact of RVD on mortality in severe DMR must be multifactorial and not entirely mediated by pulmonary hypertension.

RV function is determined not only by RV load, but also myocardial function and ventricular interaction. ⁷ To this end, Le Tourneau et al previously demonstrated that the relationship between sPAP and RVD in patients with DMR is weak and not the primary determinant of RVD. Interventricular septal contraction contributes up to 35% of RV systolic function in the setting of increased pulmonary afterload. ¹³ Furthermore, adaptive left ventricular remodeling in response to DMR includes increased chamber sphericity and eccentric hypertrophy, invoking constraints on the right ventricle within the confines of the pericardium. Finally, RV myocardial impairment has been invoked as an additional consequence of DMR. ¹⁴ These results remind us that DMR is ultimately a biventricular disease and suggest that the right ventricle is perhaps the other chirping canary in the ventricular coal mine. In patients with DMR referred for surgery, combined biventricular impairment (defined by left ventricular ejection fraction <60% and RV ejection fraction ≤35%), not isolated left ventricular or RV dysfunction, emerged as the most potent predictor of cardiovascular and overall mortality with a 4‐fold increase in cardiovascular mortality after adjustment for multiple known prognostic factors. ⁷

Bohbot et al also reported the prognostic importance of RVD with surgical versus medical management. RVD was associated with a 1.6‐fold increased mortality under medical management. Of the 73% of patients who underwent mitral valve surgery, 1‐month postoperative mortality was 2.6% compared with 11.4% in patients with RVD and remained 3.8‐fold higher (P<0.001) among those with RVD after adjustment for age, sPAP, EuroSCORE II, and time from baseline echocardiography. Despite these comparatively worse outcomes, the absolute benefit of surgery, and particularly early surgical approaches, was apparent. Of those with RVD, 39.4% underwent early surgery within 3 months, which conferred an 8‐year survival advantage of 73% compared with 43% for those without initial operative management. Although the observational nature of these findings may preclude declarations of causality, it is clear that early detection of RVD and timely intervention portend improved survival in patients with significant DMR.

Whether medically or surgically managed, the right ventricle serves as a sentinel species in the myocardial ecosystem that portends worse clinical outcomes. Accordingly, comprehensive assessment for RVD should be included in routine assessment of DMR. The authors highlight their use of real‐world echocardiographic measurements that are readily available in routine clinical practice. However, with the nascence of speckle‐tracking echocardiography, cardiac magnetic resonance, and 3‐dimensional echocardiography, the once neglected right ventricle has undergone a renaissance beyond the easily obtained but limited tricuspid annular plane systolic excursion, tissue Doppler S′, and fractional area change, which provide rudimentary assessment of RV function. These traditional parameters fail to fully appreciate the load sensitivity and complex geometry of the right ventricle and are dependent on the angle of insonation. RV mechanics may be better assessed with more refined parameters such as RV free wall and 4‐chamber RV longitudinal strain (RVLS) or right ventricle–pulmonary artery coupling surrogates. RVLS in particular has been shown to be a more sensitive predictor of subclinical RV systolic dysfunction as well as clinical outcomes. ¹⁵ The omission of RV strain in the present study leaves an important gap in our understanding of the relationship between DMR and RVD. This is consistent with recent reports that RVLS, despite its many advantages, remains unfortunately significantly underused, although access to speckle‐tracking echocardiography is essentially universal (98%). ¹⁶ Furthermore, although the authors suggest that their use of observational data from routine practice for clinical use is not compatible with reproducibility assessment, these 2 are not mutually exclusive. This presents another opportunity for RVLS to enhance the analysis, because both automated and semiautomated RVLS provides rapid and reproducible RV function assessment. ¹⁷ Whether earlier detection of RVD using RVLS could optimize timing for intervention and improve outcomes in patients with significant DMR and RVD is uncertain but merits evaluation. A limitation to contend with is the possibility of unevaluable ventricular segments, which presents an opportunity to leverage advanced imaging modalities such as cardiac magnetic resonance for ventricular function assessment. However, practicality dictates we balance the advantages of the ubiquitous nature of echocardiography with the advantages of advanced imaging techniques.

The low proportion of women (28%) included in the study despite the increased prevalence of chronic primary MR among women ¹⁸ likely reflects the known tendency for women to present at a later stage of DMR with larger indexed chamber dimensions at time of surgical referral, ¹⁹ despite operative mitral valve (MV) repair being associated with improved long‐term survival irrespective of sex. ²⁰ These data are consistent with prior surgical referral bias with <40% of surgical cohorts being women. ²¹ However, Bohbot et al reported no significant sex difference between those with versus without RVD, and among those with RVD, with an early surgical versus nonoperative approach. More refined assessment of subclinical ventricular dysfunction through longitudinal strain assessment or cardiac magnetic resonance assessment of myocardial fibrosis could help close this gender gap in DMR surgical referral and outcomes.

In conclusion, the authors should be commended for their work, which strengthens the findings of prior studies with its large number of patients with extended follow‐up. These results should launch further studies to evaluate the relationship of RVD to outcomes in other forms of primary MR or complex multivalvular patients, the prognostic value of subclinical ventricular dysfunction measured by RV strain, and the prognostic value of RVD in the setting of newer therapeutic strategies for MR including transcatheter mitral valve repair.

Disclosures

Dr Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz‐AI, and Edgewise. No industry support was used to conduct this study. Dr Keen has no disclosures to report.