The mitral annulus is a fibrous structure that surrounds the mitral valve leaflets and is prone to calcification. Despite its common occurrence, association with cardiovascular morbidity and mortality and relationship with dysfunction of the mitral valve, the pathobiology of mitral annular calcification is incompletely understood. Mitral annular calcification is no longer regarded as a local, chronic and degenerative process resulting in precipitation of calcium and phosphate, but as an active and regulated molecular process that is related to lipid metabolism, hemodynamic stress, chronic kidney disease, bone and mineral metabolism and inflammation. This review summarizes the current evidence examining the pathophysiologic determinants of mitral annular calcification.

Background: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression. Methods: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent ¹⁸ F-sodium fluoride (calcification activity) and ¹⁸ F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years. Results: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased ¹⁸ F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81–3.27] versus 1.30 [1.22–1.49]; P <0.001) and ¹⁸ F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37–1.58] versus 1.17 [1.12–1.24]; P <0.001) compared with patients without MAC. MAC activity ( ¹⁸ F-fluoride uptake) was closely associated with the local calcium score and ¹⁸ F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression. Conclusions: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.

In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. To evaluate the safety and efficacy of ninerafaxstat in nHCM. Patients with HCM and left ventricular (LV) outflow gradient <30 mmHg, ejection fraction ≥50% and peak VO₂ <80% predicted, were randomized to ninerafaxstat 200 mg BID or placebo (1:1) for 12 weeks. Primary endpoint was safety and tolerability with efficacy outcomes also assessed as secondary endpoints. A total of 67 patients with nHCM were enrolled at 12 centers (57 yrs ± 11.8; 55% women). Serious adverse events occurred in 11.8% (4/34) in the ninerafaxstat group and 6.1% of patients (2/33) in placebo. From baseline to 12 weeks, ninerafaxstat was associated with significantly better ventilatory efficiency (V_E/VCO₂ slope) compared to placebo with a least square (LS) mean difference between the groups of -2.1 (95% CI, -3.4, -0.6; p=0.006), with no significant difference in pVO₂ (p=0.9). KCCQ-CCS was directionally though not significantly improved with ninerafaxstat vs. placebo (LS mean, 3.2 [95% CI, -2.9, 9.2; p=0.2]), though was statistically significant when analyzed post-hoc in the 35 patients with baseline KCCQ-CSS ≤80 (LS mean, 9.4 [95% CI, 0.2, 18.5; p=0.04]). In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a Phase 3 study.