Relationship between circulating matrix metalloproteinase-9 levels and the hemodynamic response during exercise stress echocardiography in patients with heart failure with preserved ejection fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is a prevalent clinical syndrome with a complex and incompletely understood pathophysiology. Although left ventricular (LV) filling pressures may be normal at rest, exercise stress echocardiography (ESE) can unmask abnormal loading conditions. Role of matrix metalloproteinase-9 (MMP-9) has been implicated in the development of cardiac fibrosis and pulmonary vascular remodelling, which is closely linked to the pathophysiology of HFpEF. Additionally, the disrupted balance between the inactive, 92 kDa isoform and the activated, 86 kDa isoform may contribute to pathological extracellular matrix degradation. Purpose The study aimed to evaluate the relationship between ESE-derived mitral E/e′ ratio and the elevation of pulmonary systolic pressure in relation to circulating MMP-9 levels in a cohort of patients with HFpEF. Methods Thirty-eight patients with HFpEF were prospectively enrolled in this single-center study. All participants underwent semi-supine bicycle ESE following a standardized protocol. Echocardiographic measurements were obtained at rest, at a 50-watt workload, and peak stress, with a focus on LV diastolic function and right ventricular hemodynamics. Blood samples were collected immediately before the stress test for the measurement of NT-proBNP and novel biomarkers. In this pilot analysis, serum MMP-9 levels were assessed using gelatin zymography in a subset of 13 patients (mean age: 71.25 ± 4.59 years; 92.31% female). Results The analyzed subgroup had a mean HFA-PEFF score of 5.45 ± 1.29, and an HFpEF score of 5.69 ± 1.60. Mean NT-proBNP level was 279.30 ± 106.19 pg/mL. Mean serum levels of MMP-9 were 212.17 ± 79.04 AU for the 92 kDa isoform and 1642.20 ± 256.09 AU for the 86 kDa isoform. The mitral E/e′ ratio significantly increased at peak stress compared to rest (rest: 12.10 ± 3.51; stress: 14.71 ± 3.88; p = 0.014), such as TRV (rest: 2.21 ± 0.51 m/s vs. stress: 3.36 ± 0.43 m/s; p < 0.001). Peak-stress TRV significantly correlated with the 86 kDa isoform of MMP-9 (r = 0.58; p = 0.038) (Figure 1). Patients with TRV ≥ 3.5 m/s had higher mean levels of 86 kDa MMP-9 compared to those with TRV < 3.5 m/s (1834.43 ± 276.82 AU vs. 1522.05 ± 160.44 AU; p = 0.012). No significant correlations were found between MMP-9 levels and echocardiographic indices of diastolic dysfunction or elevated LV filling pressures. Conclusion In this HFpEF cohort, elevated levels of the activated MMP-9 isoform may reflect reduced pulmonary vascular compliance, rather than impaired LV function.Figure 1