Increased mitral valve fibroblast activation following myocardial infarction

Background It has been proposed that pro-fibrotic processes within the mitral valve following acute myocardial infarction (MI) lead to leaflet tethering and therefore represents an important mechanism driving the development of functional mitral regurgitation (FMR). Activated fibroblasts are key effector cells driving fibrogenesis. We used 68Ga-FAPI positron emission tomography (PET) to investigate whether fibroblast activation occurs within the mitral valve following MI. Methods We investigated fibroblast activation in the mitral valves of patients with and without MI without baseline MR. Thirty-six patients with acute (<4 weeks) and 19 patients with chronic (>2 years) MI, and 17 healthy controls matched for age and sex were recruited and underwent 68Ga-FAPI-46 PET-cardiovascular magnetic resonance. Analysis of mitral valvular 68Ga-FAPI-46 PET uptake was performed by 2 operators. Mitral valve fibroblast activation between all groups was compared by one-way ANOVA, and between 2 groups by t-test or Mann Whitney U test. Multivariate regression analysis determined relationships between mitral valvular fibroblast activation and clinical and imaging parameters. Interobserver reproducibility was analysed by intraclass correlation coefficient (ICC). Results Analysis of valvular 68Ga-FAPI-46 PET uptake demonstrated good interobserver reproducibility (ICC 0.93, 95% CI 0.86–0.96). Across the patient cohorts minimal MR was observed (MR volume 1.2ml±2.2ml, MR fraction 1.2±2.2%). Patients with acute MI (85% male, age 61±7 years) were imaged 11±6 days following MI and demonstrated higher mitral valve 68Ga-FAPI-46 PET uptake compared to healthy controls (Figure 1; MV SUV max: 2.6±0.7 vs 2.0±0.3; p=0.01). Mitral valve 68Ga-FAPI-46 PET uptake was also higher in patients with chronic MI compared to healthy controls. Blood pool activity across groups was similar. Higher mitral valve 68Ga-FAPI-46 PET uptake was associated with inferior infarcts compared to other territories (p=0.03) and higher LV end systolic volume (p=0.03), but not with either intensity or extent of fibroblast activation in the infarct. Discussion Fibroblast activation in the mitral valve is elevated in both acute and chronic MI, with the highest fibroblast activation observed in inferior infarcts. This data supports initial studies suggesting MI leads to pro-fibrotic processes in the mitral valve that result in FMR. Larger longitudinal studies are required to investigate mitral valve fibroblast activation over time and whether this translates to leaflet shortening and FMR. Conclusion Assessment of mitral fibroblast activation is a novel technique with excellent interobserver reproducibility. Mitral valvular fibroblast activation is elevated in acute and chronic MI when compared to healthy controls, particularly in inferior infarcts. Longitudinal studies are required to examine the potential relationship between MV fibroblast activation and development of FMR post MI.