When ‘moderate’ is not benign: rethinking risk in multivalvular valve disease

This editorial refers to ‘Prognostic significance of concomitant valvular disease in moderate aortic regurgitation’, by G. Benzoni et al., https://doi.org/10.1093/ehjci/jeag045. Valvular heart disease (VHD) is increasingly recognized as a complex and heterogeneous entity rather than a collection of isolated valve lesions.1,2 Yet clinical decision-making still relies predominantly on the evaluation of a single dominant lesion. ‘Moderate’ abnormalities are therefore usually managed conservatively, although this simplified framework may fail to capture the cumulative haemodynamic burden in patients with more than one abnormal valve. In this issue, Benzoni et al.3 report the prognostic significance of concomitant moderate valvular disease in patients with moderate aortic regurgitation (AR).3 In a retrospective cohort of nearly 800 patients with at least moderate AR, they show that the combination of moderate AR with another moderate valve lesion was associated with significantly worse outcomes than isolated moderate AR, and with a prognosis comparable to that of isolated significant AR. These findings challenge the traditional assumption that moderate lesions are clinically low risk when considered individually, and they prompt a re-examination of how risk is assessed in patients with multivalvular disease. The lesion-centric paradigm has long influenced the management of VHD. Severe aortic stenosis (AS), severe mitral regurgitation (MR), or severe AR are each associated with well-established thresholds for intervention, supported by robust data and incorporated into contemporary guidelines.1,2 This approach is effective for isolated lesions, where natural history and treatment benefit are well-established. However, multivalvular disease is common, particularly in elderly patients with degenerative pathology. Epidemiological studies suggest that a substantial proportion of patients evaluated for VHD have involvement of more than one valve.4,5 Despite this prevalence, guidance for patients with multiple moderate lesions remains limited, and current recommendations offer little specific direction for this growing population. The study by Benzoni et al.3 illustrates the limitations of a purely lesion-centric framework in the management of VHD. Patients with moderate AR and another moderate valve lesion were older, more frequently symptomatic, and more burdened by comorbidities such as atrial fibrillation, chronic kidney disease, and coronary artery disease. Echocardiographically, they exhibited larger left atrial volumes and higher E/e′ ratios despite preserved left ventricular ejection fraction (LVEF), findings consistent with elevated filling pressures and diastolic dysfunction. This constellation of features resembles the clinical phenotype of heart failure with preserved LVEF (HFpEF) and suggests that multivalvular disease may represent an important structural substrate for this syndrome in elderly patients. From a pathophysiological standpoint, the adverse outcomes observed in these patients are not unexpected. Moderate AR alone imposes a chronic volume overload on the LV. When combined with another moderate lesion, whether MR, tricuspid regurgitation, or AS, the cumulative haemodynamic burden may exceed the heart’s compensatory capacity (Figure 1). These interactions are often non-linear with moderate lesions amplifying each other through increased preload, altered ventricular geometry and myocardial contractility, and impaired diastolic function, particularly in elderly patients. Moderate AR and cumulative haemodynamic burden. There are previous observations that support the concept that the aggregate haemodynamic burden of multiple moderate lesions may be more prognostically relevant than the severity of any single lesion.6–8 In the present study, patients with moderate AR and another moderate lesion had nearly a threefold higher risk of death or heart failure hospitalization compared with those with isolated moderate AR (HR 2.83). Notably, their prognosis was similar to that of patients with isolated significant AR (HR 2.65), suggesting that the combination of moderate lesions may be functionally and clinically equivalent to a single severe lesion. This finding reinforces the notion that risk assessment based solely on the most severe lesion may underestimate the clinical impact of multivalvular disease. Another key message is the distinct clinical phenotype associated with moderate multivalvular disease especially in this population. Compared with isolated moderate AR, these patients were older, more comorbid, and more symptomatic, with larger left atria and higher filling pressures despite preserved LVEF. Importantly, these differences were not reflected by conventional markers such as LVEF, underscoring the limitations of traditional severity metrics. These findings highlight the need for focus on chambers (ventricular and atrial), more sensitive markers of their dysfunction and load. Imaging techniques, including myocardial strain analysis and cardiac magnetic resonance, can detect subclinical myocardial dysfunction, fibrosis, and adverse chamber remodelling before overt systolic impairment becomes apparent.9,10 In patients with moderate multivalvular disease, these tools may refine risk stratification and better capture the cumulative burden of disease. The evolving approach of machine learning-based phenotyping VHD, which includes severity of the valve lesion, imaging, clinical and circulating biomarkers may be a better way to assess the risk in the setting of multiple VHD.11 The most provocative implication of this study concerns the timing and intensity of management. Current guidelines do not recommend surgical or transcatheter intervention for moderate valve lesions in the absence of severe disease or clearly attributable symptoms.1,2 As a result, patients with multiple moderate lesions are typically managed conservatively, often under the implicit assumption that their condition carries a relatively low risk, contrary to the findings in the current study. The word ‘moderate’ has connotations of being relatively ‘benign’ and often elicits a conservative management approach. However, there is data that the risk in VHD is a continuous risk with excess adverse clinical events occurring earlier that the current cut-offs of valve lesion parameters meets the criteria of a ‘severe’ valve lesion.12 However, much of the evidence like the one by Benzoni et al.3 is from retrospective and observational cohorts and not designed to define new intervention thresholds or to evaluate the benefits of surgery or transcatheter therapy in this population. Their data should not be interpreted as a mandate for immediate guideline changes. Rather, they provide a strong rationale for prospective studies evaluating whether earlier or combined valve interventions, especially in the era of expanding transcatheter options, might improve outcomes in carefully selected patients with moderate multivalvular disease. At present, intensified surveillance, with structured clinical and echocardiographic reassessment in heart Valve Clinics, is the most immediate and pragmatic consequence of these findings.13 Another aspect deserving attention is the potential role of medical therapy. The clinical profile described by Benzoni et al.,3 elderly, comorbid patients with HFpEF-like features, closely resembles the population in which sodium–glucose cotransporter-2 inhibitors have shown benefit across the spectrum of ejection fraction.14 Yet, patients with significant VHD have largely been excluded from major heart-failure trials. Whether SGLT2 inhibitors or other HFpEF therapies can improve outcomes in this population remains an important open question. Taken together, the work by Benzoni et al.3 supports a shift from a strictly valve lesion-centric to a more patient-centric approach in VHD, in which cumulative haemodynamic burden and the clinical phenotype inform decision-making. In this framework, moderate multivalvular disease should be regarded as a distinct, high-risk clinical entity rather than a collection of benign abnormalities.3 As population’s age and degenerative VHD becomes more prevalent, the number of patients harbouring multiple moderate lesions will inevitably rise. Recognizing this phenotype, refining risk stratification, and revisiting follow-up and intervention strategies will be key challenges for the next generation of valve guidelines. ‘Much to learn, you still have.’—Yoda Patrizio Lancellotti (Conceptualization, Writing—original draft [lead]; Writing—review & editing [lead]), Raluca Dulgheru MD, PhD (Conceptualization, Writing—original draft [supporting]; Writing—review & editing [supporting])), and Mani A. Vannan MD (Conceptualization, Writing—original draft [supporting]; Writing—review & editing [supporting])) This article is an editorial and does not contain original data. Data sharing is therefore not applicable.