Unravelling the complexity of heart failure with preserved ejection fraction and secondary mitral regurgitation

This article refers to ‘Cardiac function, haemodynamics, and valve competence with exercise in patients with heart failure with preserved ejection fraction and mild to moderate secondary mitral regurgitation’ by T. Harada et al., published in Eur J Heart Fail 2024;26:1616–1627. Recently, Harada and colleagues offered pivotal insights into the relationship between heart failure with preserved ejection fraction (HFpEF) and secondary mitral regurgitation (SMR).1 This prospective single-centre observational study enrolled 182 patients undergoing invasive haemodynamic exercise testing with simultaneous echocardiography and sheds light on the nuanced mechanisms contributing to exercise intolerance in HFpEF. In general, the syndrome of HFpEF is characterized by a ‘dual heterogeneity’ with multiple echocardiographic phenotypes on the one hand and diverse cardiac pathologies and diseases on the other, making diagnostics, treatment and scientific research highly challenging. Heart failure with preserved ejection fraction is a multifaceted condition characterized by exercise intolerance, elevated morbidity, and mortality.2, 3 Since being prognostically relevant, heart failure symptoms have to be taken seriously in HFpEF patients and hospitalizations need to be avoided.4 Despite advances in pharmacotherapy, such as sodium–glucose cotransporter 2 inhibitors, there remains a critical need for targeted therapies addressing specific phenotypes of HFpEF.5, 6 Harada and colleagues present evidence that exercise intolerance in HFpEF patients with SMR is predominantly characterized by left atrial (LA) and early left ventricular (LV) myocardial dysfunction as well as pulmonary vascular disease rather than valvular dysfunction itself. This contrasts sharply with results from prior studies as well as with heart failure with reduced ejection fraction (HFrEF), where LV dysfunction and exercise-induced LV end-diastolic volume increase is the primary contributor to SMR and can be effectively treated by mitral transcatheter edge-to-edge repair (M-TEER).7 Notably, the study reports that worsening of SMR during exercise is rare in HFpEF and no patient developed severe mitral regurgitation (MR), challenging the assumption that MR exacerbates symptoms during exercise in this specific cohort.8 The study additionally reveals that SMR in HFpEF is associated with more pronounced right ventricular dysfunction and pulmonary vascular disease at rest and during exercise. Besides, LA dysfunction, which has demonstrated to negatively impact exercise capacity,9 was significantly more present in HFpEF-MR patients. Overall, the authors suggest that the presence of SMR in HFpEF may serve as a marker for a more relevant myocardial and pulmonary pathology, rather than being a direct contributor to exercise intolerance. Given the huge complexity of the topic and the overall need for an enhanced pathophysiologic understanding enabling new treatment options, we would like to concentrate on three major aspects around the syndrome of HFpEF which we believe are important in the context of this study: (i) HFpEF phenotypes and mechanistic insights; (ii) exercise-induced MR and MR quantification in HFpEF; and (iii) SMR in the presence of normal LV ejection fraction. In fact, the HFpEF-MR cohort in the present study corresponds rather to a mixed LA/RV phenotype, whereas the control cohort without MR seems to have a rather ‘normal cardiac phenotype’. This difference in phenotypes and probably underlying cardiac pathology is certainly supported by the differences in baseline and haemodynamic characteristics such as female sex, atrial fibrillation, cardiac implantable electronic devices, LV size, RV and LA function as well as pulmonary pressures. Therefore, it might not be applicable to compare HFpEF-MR patients to HFpEF patients without MR as they might have totally diverging cardiac pathologies rather than different stages of disease. Overall, scientific research on exercise-induced ‘dynamic’ MR in HFpEF is scarce. Current European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend exercise echocardiography in patients with MR to unmask symptoms in asymptomatic patients, to identify the origin of dyspnoea, and to gain additional prognostic information.12, 13 Despite these recommendations, no specific exercise modalities are currently preferred, though bicycle exercise may not always be feasible for older patients with comorbid conditions. In the study by Harada et al.,1 MR severity did not worsen with cycle ergometry exercise but remained insignificant in most patients. However, a recent study from Spieker et al.8 observed that handgrip exercise in HFpEF patients led to a reclassification of MR severity in 35.0% of the patients, with 17.5% developing severe MR during exercise. Bertrand et al.14 have previously summarized the effect of different exercise modalities on the cardiovascular system: while dynamic exercises (running, cycling) reduce systemic vascular resistance and increase venous return and cardiac output, static exercises (handgripping) increase systemic vascular resistance, imposing pressure load on the left ventricle. This significant haemodynamic difference between the exercise modalities might explain the diverging results in the literature and may underscore the utility of handgrip exercise in unmasking dynamic MR. Another important aspect worth mentioning is the lack of quantitative measurements of MR severity in this study, which is of particular importance when interpreting the data. Current European guidelines recommend qualitative, semi-quantitative and quantitative assessments of MR for a precise characterization.12 Nevertheless, the authors conclude that MR might not contribute significantly to the patients' exercise-induced symptoms. These results have to be interpreted with caution respecting the low number of HFpEF-MR patients and the lack of detailed MR parameters. We believe that especially in these HFpEF-MR patients with smaller ventricles with diastolic dysfunction and enlarged plus dysfunctional left atria with pressure elevation, real MR severity can be easily misjudged. In these cases, even small regurgitant volumes can correspond to a significant regurgitant fraction which impairs cardiac output sufficiently to cause severe dyspnoea. This is of particular importance as treatment options for symptomatic HFpEF patients remain highly limited and M-TEER has demonstrated high efficacy and safety in some of these selected patients.15 Secondary MR in HFpEF, often falsely generalized as atrial functional MR (aFMR) can coexist in HFpEF patients. Real aFMR, however, represents a unique subset of mitral valve disease characterized by MR secondary to LA dilatation and dysfunction, rather than LV abnormalities. Unlike typical ventricular functional MR (vFMR), which is predominantly driven by LV remodelling and reduced LV function, aFMR arises from diverse pathophysiological mechanisms that affect the left atrium (among others: annular dilatation and LA dysfunction, atriogenic tethering and hamstringing). These underlying mechanisms include atrial fibrillation, elevated LA pressure, and atrial myopathy. The complexity of aFMR aetiology necessitates a comprehensive echocardiographic diagnostic approach including several characteristics to accurately identify and manage this condition, as it presents distinct therapeutic challenges compared to other forms of MR. The proportion of real aFMR patients in the present study remains unclear and mixed phenotypes as well as borderline vFMR patients may have been included. Overall, detailed studies like the one from Harada et al.1 help us to further understand these complex HFpEF cases. We should strive for an individual causal research of our patient symptoms. Mixed phenotypes and cardiac pathologies potentially mask patients who would benefit from existing low-risk interventional therapies such as M-TEER. Who are these HFpEF patients which develop functional MR? Can an early treatment of atrial fibrillation reduce MR development and symptoms? Overall, the study emphasizes the need for a comprehensive HFpEF patient characterization, including advanced imaging modalities, to detect subtle myocardial abnormalities not visible with standard techniques. Although the widespread application of these advanced modalities is limited, their superior diagnostic value, as demonstrated in this study, calls for broader implementation. By enhancing our diagnostic precision, we can better tailor treatments to the diverse phenotypes of HFpEF and SMR, ultimately improving patient outcomes. The authors detailed work help us to understand that HFpEF-MR is more than meets the eye. This research reinforces the necessity of a nuanced and detailed patient evaluation to unravel the complexities of HFpEF and optimize management strategies for affected patients with and without MR. Conflict of interest: none declared.