LOXL-2 as a marker of myocardial fibrosis, remodeling, and outcomes in severe rheumatic mitral regurgitation
M S Santoshi Kumari, D R Sandeep Seth, D R Traymbak Basak, D R Sudheer Kumar Arava, D R S Ramakrishnan, D R Satyavir Yadav, D R Sanjeev Kumar, D R Vineeta Ojha, D R Chittaranjan Behera, D R Pradeep Ramakrishnan, D R M. Kalaivani, D R Rajiv Narang, D R Shantanu Sen Gupta, D R Beena Pillai, D R Ruma R. S. K. MaulikAbstract
Background
Rheumatic heart disease (RHD) with severe mitral regurgitation is associated with increasing myocardial fibrosis caused by chronic rheumatic inflammation and persistent volume overload, which results in unfavorable ventricular remodeling and poor clinical outcomes despite prompt intervention. Myocardial fibrosis causes ventricular stiffness, reduced contractility, and a higher risk of heart failure and arrhythmias. Lysyl oxidase-like -2 (LOXL-2), a critical regulator of collagen cross-linking, causes extracellular matrix stability while increasing fibrotic tissue stiffness, aggravating cardiac dysfunction.
Aim
-The current study aims to investigate the clinical importance of LOXL-2 level in RHD with severe mitral regurgitation, as well as it’s the relationship with fibrosis and adverse events.
Methods
In prospective observational study, LOXL-2 levels were assessed in rheumatic heart disease with severe mitral regurgitation (n = 87) and age -gender matched controls (n = 87) at baseline. Patients were managed either surgically (mitral valve repair or replacement) or medically and followed up at 3–12 months. Myocardial fibrosis, was assessed as collagen volume fraction percentage using cardiac magnetic resonance imaging and myocardial biopsy. Association was observed between LOXL-2 and other parameters like echocardiography and adverse events. Adverse events which included emergency surgery, hospitalizations, increased diuretic requirements, all-cause mortality, and a ≥5% decline in left ventricular ejection fraction.
Results
LOXL-2 level at baseline was elevated in RHD with severe MR compared to controls (791.71(8.66-1036) vs. 656.37(559-745.43pg/dL; p=<0.001). There was significant decrease in the level of LOXL-2 after surgery (622.35,(542.50-733.59, p<0.001) and medical follow-up (746.83(616.42-798.44), p<0.019) compared with baseline (791.71, (668.66-1036). The level of LOXL-2 was elevated in patients who experienced events (798.35(684.36–1039.6) compared to patients with no events (685.37(597–886.2). Baseline LOXL-2 levels were elevated in patients who experienced adverse events, with the highest median levels observed in those who developed a post-surgical decline in ejection fraction compared with other event groups (Figure-1). LOXL-2 levels increased progressively with higher collagen volume fraction, indicating an association with increasing myocardial fibrosis(figure-2). LOXL-2 levels were higher in patients with extracellular volume >30%, reflecting greater myocardial remodeling(figure-3).
Conclusion
LOXL-2 levels are elevated in RHD with severe mitral regurgitation, and they are closely linked with myocardial fibrosis, unfavorable remodeling, and clinical outcomes. Surgical intervention reduces LOXL-2 levels more than medical therapy, indicating that it may serve as a biomarker for fibrotic load, therapeutic response, and prognosis in RHD.LOXL-2 and EventsFor image description, please refer to the figure legend and surrounding text.LOXL-2 and CVF(%) anf ECVFor image description, please refer to the figure legend and surrounding text.