Insights into the origins of functional mitral regurgitation and development of a corrective epicardial device
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Functional mitral regurgitation (FMR) is a frequent complication of left ventricular remodeling and carries a significant adverse prognosis. While significant progress has recently been made in the understanding of the pathophysiology and treatment of this disease, failure to obtain acceptable outcomes is driving researchers and clinicians to investigate alternative approaches to the consensual treatments. A thorough understanding of the normal anatomy and physiology of the mitral valve is warranted to underline the pathophysiological mechanisms of left ventricular remodeling leading to functional mitral regurgitation. The accumulated experience with traditional techniques and the experimentation of emerging surgical procedures allowed us to identify strengths and points to be improved for each therapeutical approach. Based on this review, we defined the specifications of a new device designed to correct FMR. In the first study we tried to develop an acute model of myocardial ischemia to induce mitral valve regurgitation in sheep. In six sheep, acute myocardial infarction was induced by ligation of the second and third obtuse marginal branches of the left circumflex coronary artery, defining an ischemic (IZ) and non ischemic (NZ) zone. Aortic and left ventricular pressures, left ventricular volumes, ECG, and segmental length of the IZ and NZ were recorded. Aortic blood flow was measured with an aortic flow probe in three sheep. Maximum elastance, dP/dt, tau, left ventricular and myocardial stiffness, total mechanical energy (PVA), external work (Ew), contractile efficiency and the global and regional preload recruitable stroke work (PRSW and rPRSWX) were calculated. Myocardial perfusion was calculated with injection of microspheres. Mitral regurgitant volume was calculated as the difference between the aortic and the left ventricular stroke volume. The data was compared between baseline, after five to ten minutes and one hour of ischemia. Myocardial blood flow decreased from 1.53 ± 0.81 mL/g/min to 0.37 ± 0.37 mL/g/min (p=0.022) in the IZ. Mitral regurgitation was not observed at any time point. Ischemia reduced PRSW from 60.7 ± 9.1 mmHg at baseline to 42.3 ± 4.3 mmHg and t+60 min (p=0.002), and rPRSWIZ from 96.2 ± 33.9 mmHg.L.m-1 at baseline to 59.2 ± 28.6 mmHg.L.m-1 at t+5-10 min (p=0.026) and 63.7 ± 25.7 mmHg.L.m-1 at t+60 min (p=0.032). PVA decreased from 6260 ± 1387 mmHg.L at baseline to 4149 ± 1299 mmHg.L at t+5-10 min (p=0.019) and 4368 ± 1632 mmHg.L at t+60 min (p<0.001). Ew decreased from 3877 ± 1287 mmHg.L at baseline to 2334 ± 872 mmHg.L at t+5-10 min (p=0.037) and 2507 ± 883 mmHg.L (p=0.013) at t+60 min. Myocardial stiffness of the IZ decreased from 2.63 ± 1.23 mm-1 at baseline to 0.94 ± 0.57 mm-1 at t+5-10 min (p=0.014) before an increase to 3.56 ± 0.57 mm-1 at t + 60 min (p=0.033). In conclusion, acute occlusion of OM2 and OM3 did not induce acute functional mitral valve regurgitation. It did however, induce early systolic and diastolic regional dysfunction. The non-ischemic myocardium did not compensate for the left ventricular remodeling. In the second study, we used acute aortic banding to induce mitral valve regurgitation. This was done to assess the effects of an epicardial device designed to reposition the papillary muscles on FMR, considering that left ventricular remodeling with tethering of the papillary muscle is the most important factor leading to FMR. In seven sheep, aortic, left ventricular and atrial pressures, left ventricular volumes, aortic blood flow, mitral annulus diameter and ECG were recorded. Acute FMR was induced by aortic banding. Left ventricular end diastolic and end systolic volume, stroke volume, the constant of passive left ventricular stiffness and Tau were measured. Mitral regurgitant flow was calculated from the difference between aortic stroke volume and left ventricular stroke volume. Application of an epicardial device reduced FMR from 14.4 ± 5.4 to 7.7 ± 5.2 mL (p=0.001) without decreasing mitral annulus diameter in diastole (p=0.075) and systole (p=0.080). Left ventricular end diastolic volume decreased from 241.5 ± 52.5 to 227.6 ± 46.5 mL (p=0.044). Passive left ventricular stiffness increased from 0.92 ± 0.5 to 1.18 ± 0.59 mL-1 (p=0.044). Other parameters of diastolic dysfunction were not affected by the device. In conclusion, acute FMR was decreased by the application of an epicardial device. Diastolic function was not adversely affected by the device. Most likely, correction of FMR by the epicardial device was achieved by repositioning of the papillary muscles. The epicardial device was not in contact with blood and did not require cardiopulmonary bypass.