Ischemic mitral regurgitation (MR) remains a common and morbid complication of coronary artery disease. Ischemic MR is defined as MR occurring after myocardial infarction with one or more segmental wall motion abnormalities, significant coronary disease in one of the territories supplying the wall motion abnormalities, and structurally normal mitral valve leaflets and chordae tendinae.¹ Moderate-to-severe MR is reported in 10-20% of patients with ischemic heart disease.^2,3 The presence of even mild MR in patients with ischemic heart disease is a powerful independent predictor of adverse events, increasing the degree of heart failure and essentially doubling mortality.^4,5 The mechanism of ischemic MR is complex and must be understood as an ultimate manifestation of a decompensating ventricle, not an intrinsic disease of the valve. Ischemic MR is a consequence of adverse left ventricular (LV) remodeling with distortion of the ventricle and mitral annulus, along with apical and lateral migration of the papillary muscles. This remodeling creates a tethering force that distorts the papillary muscles and surrounding myocardium and, therefore, pulls the valve leaflets away from the annulus during systole, preventing valve coaptation and leading to regurgitation.⁶

Cardiologists and cardiac surgeons treating patients with ischemic MR must navigate several important clinical decision points. First, when the regurgitation is moderate, the question has been whether coronary revascularization alone will suffice or whether additional valvular intervention is required. Second, when the regurgitation is severe, practice guidelines recommend mitral valve surgery in the presence of limiting symptoms but do not specify valve repair versus replacement due to inconclusive evidence. The Cardiothoracic Surgical Trials Network (CTSN) has conducted two multicenter randomized trials to address these important questions and guide future decision making.

In the Surgical Treatment of Moderate Ischemic MR trial,⁷ 301 patients with moderate ischemic MR were randomized to coronary artery bypass graft (CABG) alone or CABG plus mitral valve repair with a primary endpoint of LV end-systolic volume index (ESVI), a measurement of LV remodeling and a known predictor of poor prognosis.^8,9 Secondary endpoints included major adverse cardiac and cerebrovascular events, mortality, degree of residual MR, functional status, and quality of life. At 1 year, both groups achieved reductions in the primary endpoint of LVESVI with a median reduction of 6 mL/m² (z score 0.50; P = 0.61). One-year mortality was similar with 6.7% in the combined CABG plus mitral repair group and 7.3% in the CABG-alone group (hazard ratio for mitral repair 0.90; 95% CI 0.38-2.12; P = 0.81). Patients undergoing combined CABG and mitral repair had lower rates of residual moderate or severe MR (11% vs. 31%; P < 0.001) but had longer operative and bypass time (P < 0.001), longer hospital stay (P = 0.002), and a higher frequency of neurologic events (P = 0.03). There were no other differences in secondary endpoints, including stroke rate. Taken together these results show that both approaches were safe, but there was no discernable clinical advantage in adding mitral valve repair to CABG in the setting of moderate MR at 1 year. Additional follow-up at two years is planned to assess the durability of these comparisons.

In the Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation trial,¹⁰ 251 patients with severe ischemic MR were randomized to mitral valve repair or chordal-sparing mitral valve replacement with a primary endpoint of LV ESVI and secondary endpoints of major adverse cardiac and cerebrovascular events, mortality, degree of residual MR, functional status, and quality of life. At one year, the mean reduction from baseline LV ESVI was 6.6 mL/m² in the repair and 6.8 mL/m² in the replacement group. There was no difference in cumulative mortality between repair and replacement (14.3% vs. 17.6%; hazard ratio for repair 0.79; 95% CI 0.42-1.47) and no significant between-group difference in any other secondary endpoint. Notably, the rate of recurrent moderate or severe MR at 1 year was 32.6% in the repair group and only 2.3% in the replacement group (P < 0.001). Of those undergoing repair, the LV ESVI was 64.1 ± 23.9 mL/m² in those with recurrent MR versus 47.3 ± 23.0 ml/m² in those without recurrent MR (P < 0.001). The observed high rate of recurrent MR following repair at just 1 year challenges the common clinician bias toward valve repair over replacement even for ischemic disease. At the same time, champions of valve repair can point toward the dramatically improved LV ESVI seen in those who received a durable repair. Indeed, these data suggest that if one can predict a durable repair based on certain preoperative factors, there is likely a subset of patients who would benefit from repair over replacement.

In order to further investigate the question of whether recurrence of MR after mitral valve repair can be predicted by certain preoperative characteristics, the CTSN investigators have performed a recent subgroup analysis of the 116 patients who were randomized to and received mitral valve repair in the severe MR trial;¹¹ this time with a 2-year follow-up. At 2 years, 35% of patients were alive without moderate or severe MR, 46% of patients were alive with recurrent moderate or severe MR, and 20% of patients had died. Logistic regression was used to determine baseline echocardiographic and clinical characteristics that predict failure of repair or death, and a predictive model based on 10 factors (age; gender; race; body mass index; New York Heart Association class; effective regurgitant orifice; basal aneurysm/dyskinesia; and history of CABG, percutaneous coronary intervention, or ventricular arrhythmias) was developed with a favorable area under the receiver operating characteristic curve of 0.82. Those patients who suffered from recurrent moderate/severe MR or died were older, had a lower frequency of NYHA class III or IV, and had a higher rate of basal aneurysm/dyskinesis. Of the ten variables, the standout predictor of recurrent moderate or severe MR was basal aneurysm/dyskinesia; reflecting a severe form of preoperative LV ischemic remodeling with the abnormalities of papillary muscle displacement, leaflet tethering, and annular dilation. Refinement and validation of the model will be necessary before the ultimate goal of creating a "risk score" that could be used to predict recurrence of MR after mitral valve repair, and therefore inform treatment decisions is reached. Nevertheless, these promising results demonstrate that a relatively small number of readily available preoperative patient characteristics have the potential to predict those patients who are good candidates for durable mitral valve repair in the setting of ischemic mitral regurgitation. Most importantly, basal aneurysms or dyskinesias are specific predictor of MR recurrence after repairs.

Taken together, these three studies confirm the complexity of treating ischemic MR as well as its high morbidity and mortality. The dynamic interplay of ventricular remodeling, annular dilation, papillary muscle displacement, and leaflet tethering requires a nuanced and tailored approach to treating the individual patient with this complex ventricular-based disease. Given the recent efforts of the CTSN investigators to inform long-standing biases and clarify treatment approaches, we now know that CABG candidates with moderate MR will not benefit from simultaneous mitral valve repair in the short run, and every patient with severe symptomatic ischemic MR should not undergo attempt at valve repair. Nevertheless, the story is still unfolding. While it is increasingly apparent that the "one size fits all" approach does not apply to the treatment of ischemic MR, it is also clear that repair techniques will need to be expanded to include more complex subvalvular maneuvers that directly address leaflet tethering.^12,13

Mitral Valve Prolapse: Papillary Stitch

References

1. Borger MA, Alam A, Murphy PM, Doenst T, David TE. Chronic ischemic mitral regurgitation: repair, replace, or rethink? Ann Thorac Surg 2006;81:1153-61.
2. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation 2005;111:295-301.
3. Trichon BH, Felker GM, Shaw LK, Cabell CH, O'Conner CM. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91:538-43.
4. Rossi A, Dini FL, Faggiano P, et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure: a quantitative analysis of 1256 patients with ischaemic and nonischaemic dilated cardiomyopathy. Heart 2011;97:1675-80.
5. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitaiton: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759-64.
6. Kumanohoso T, Otsuji Y, Yoshifuku S, et al. Mechanism of high incidence of ischemic mitral regurgitation in patients with inferior myocardial infarction: quantitative analysis of left ventricular and mitral valve geometry in 103 patients with prior myocardial infarction. J Thorac Cardiovasc Surg 2003;125:135-43.
7. Smith PK, Puskas JD, Ascheim DD, et al. Surgical treatment of moderate ischemic mitral regurfitation. N Engl J Med 2014;371:2178-88.
8. Di Donato M, Castelvecchio S, Menicanti L. End-systolic volume following surgical ventricular reconstruction impacts survival in patients with ischaemic dilated cardiomyopathy. Eur J Heart Fail 2010;12:375-81.
9. Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 2005;111:2837-49.
10. Acker MA, Parides MK, Perrault LP, et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 2014;370:23-32.
11. Kron IL, Hung J, Overbey JR, et al. Predicting recurrent mitral regurgitation after mitral valve repair for severe ischemic mitral regurgitaiton. J Thorac Cardiovasc Surg 2015;149:752-761.
12. Borger MA, Murphy PM, Alam A, et al. Initial results of the chordal cutting operation for ischemic mitral regurgitation. J Thorac Cardiovasc Surg 2007;133:1483-92.
13. Fattouch K, Castrovinci S, Murana G, Dioguardi P, Guccione F, Nasso G, et al. Papillary muscle relocation and mitral annuloplasty in ischemic mitral valve regurgitation: midterm results. J Thorac Cardiovasc Surg 2014;148:1947-40.

Keywords: Aneurysm, Arrhythmias, Cardiac, Body Mass Index, Coronary Artery Bypass, Coronary Artery Disease, Coronary Disease, Dyskinesias, Heart Failure, Mitral Valve, Mitral Valve Insufficiency, Myocardial Infarction, Myocardial Ischemia, Papillary Muscles, Percutaneous Coronary Intervention, Quality of Life, ROC Curve, Randomized Controlled Trials as Topic, Stroke, Surgeons, Systole, Ventricular Remodeling, Thoracic Surgery

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