The Impact of Left Ventricular Stiffness on Hemodynamic Responses to Mitral Regurgitation at Rest and During Exercise

The coexistence of mitral regurgitation (MR) and heart failure with preserved ejection fraction (HFpEF) poses a significant diagnostic challenge, as both increase left heart filling pressure and drive symptoms of congestion. Exercise testing has emerged as a valuable diagnostic tool in valvular heart disease, yet the comparative impact of myocardial abnormalities on exercise hemodynamics in MR patients remains unclear. Using computational modeling, we investigated how increased left ventricular (LV) stiffness – a characteristic feature of HFpEF – influences hemodynamic responses to MR both at rest and during exercise. Using the CircAdapt cardiovascular model, we simulated three myocardial phenotypes with comparable resting mean left atrial pressure (mLAP): isolated LV stiffening, isolated severe MR, and mild-to-moderate MR combined with increased LV stiffness. We analyzed conventional echocardiographic indices at rest and assessed cardiac exercise performance (CEP), defined as the maximum cardiac output achievable before reaching an exercise-limiting mLAP threshold of 35 mmHg, in addition to regurgitation fraction. Despite distinct underlying pathophysiology, all virtual patients demonstrated similar resting echocardiographic indices, including E/A ratio and maximum left atrial volume, while E-wave deceleration time showed variability across phenotypes. However, exercise simulation revealed marked differences in cardiac performance. Isolated LV stiffening resulted in the poorest exercise tolerance (CEP: 8.6 L/min) compared to isolated MR (CEP: 14.0 L/min) and combined mild-to-moderate MR with LV stiffening (CEP: 11.9 L/min). Our simulations imply that as exercise intensity increases, regurgitant fraction decreases, which reduces the hemodynamic impact of MR. This suggests that LV stiffening, rather than MR severity alone, appears to be the predominant limiting factor during exercise. Our computational study suggests that flow- and volumetric-derived resting echocardiographic indices may not differentiate between isolated MR and combined MR with LV stiffening, despite significant differences in exercise capacity. These findings emphasize the importance of exercise testing in evaluating cardiac function and highlight the need for comprehensive myocardial assessment in patients with MR and suspected HFpEF.