Adrian Bucsa1, Daniela-Noela Radu1, Roxana Enache1,2, Monica Rosca1,2, Andreea Calin1,2, Lucian Predescu1, Bogdan A. Popescu1,2
1 „Prof. Dr. C. C. Iliescu” Emergency Institute of Cardiovascular Diseases, Bucharest, Romania
2 „Carol Davila” University of Medicine and Pharmacy, Euroecolab, Bucharest, Romania
Abstract: Secondary ischemic mitral regurgitation (MR) is becoming increasingly frequent nowadays, as ischemic heart disease is more prevalent than before, even at young ages. We present the case of a 33-year-old patient with ischemic heart disease and secondary ischemic MR, whose management plan was established by a Heart Team including cardiologists, in-terventional cardiologist and cardiac surgeon. Optimal medical therapy and percutaneous myocardial revascularization were the chosen treatment options, with relief of symptoms and mild improvement of MR. Taking into consideration that there is no clear evidence of a certain advantage from a mitral valve intervention in this setting, the chosen strategy in this case was close follow-up of the patient. In conclusion, secondary MR needs to be carefully evaluated; until new studies and evidences emerge regarding the optimal treatment, every case requires a personalized plan of management. Keywords: ischemic mitral regurgitation, ischemic heart disease.
Mitral valve regurgitation (MR) represents nowa-days almost one third of the acquired left-sided valve pathology in developed countries. The main classifica-tion of MR is primary and secondary1. Secondary MR, also known as functional MR, occurs when the valve leaflets and chordae are structurally normal, but lea-fl et coaptation is restricted by abnormal alterations in left ventricle (LV) geometry2. An increasingly frequent cause of secondary MR is ischemic heart disease; chro-nic functional ischemic MR represents a true challenge concerning diagnosis and management.3
A 33-year-old male presented with progressively aggravated dyspnea and unproductive cough on mo-derate exertion within the last 6 months. He had relevant family history (his father died of myocardial infarction at the age of 51) and his own medical histo-ry revealed recently diagnosed arterial hypertension stage II and type 1 insulin-dependent diabetes mellitus with multiple microvascular complications (macroal-buminuria, distal sensory polyneuropathy).
Upon current admission, the clinical examination revealed no pathological signs, except for a grade III/VI systolic murmur that was heard with maximum inten-sity in the mitral area and radiated over the entire pre-cordium. Resting ECG showed sinus rhythm and left ventricular (LV) hypertrophy with left ventricular stra-in. Laboratory studies revealed mild fasting hypergly-cemia, hypertriglyceridemia and a NT-proBNP value of 240 pg/ml. Transthoracic echocardiography show-ed left ventricular hypertrophy with normal diameters and volumes, with hypokinesia of basal-inferolateral, basal and mid-anterolateral segments and akinesia of basal-inferior interventricular septum and basal- in-ferior segments. The LV ejection fraction was within normal limits, with longitudinal systolic LV dysfuncti-on and LV diastolic dysfunction (pseudonormal mitral flow). Moderate MR was noted, with posterior mi-tral leaflet restriction and an eccentric regurgitant jet towards the left atrium posterior wall (Figure 1, Figure 2, Figure 3). The estimated pulmonary artery systolic pressure was 58 mmHg. Coronary angiography was performed, revealing a 40% stenosis of the proximal left anterior descending artery (LAD), 50-60% stenosis of the mid LAD, 80% stenosis of the second obtu-se marginal branch (OM2) and hypoplastic, diffusely infiltrated right coronary artery (RCA) (Figure 4). Taking into consideration the LV hypertrophy and the presence of systemic hypertension in a young patient, an abdominal aorta angiography was also performed, including the renal arteries, with no significant lesions found. Stress echocardiography was performed to assess the indication of myocardial revascularization in a patient without angina. It showed worsening of the wall motion abnormalities in the inferior, infero-lateral and inferior interventricular septum segments and worsening of MR, with severe MR during exercise. There was also an increase in pulmonary artery systo-lic pressure, reaching 70 mmHg during the test. Thus, the LAD stenoses were interpreted as haemodyna-mically nonsignificant and myocardial revascularizati-on was indicated only for the marginal branch. After a Heart Team discussion of the case the first option was percutaneous coronary intervention (PCI) of the OM2. This was performed with a drug-eluting stent (DES), with good final result (Figure 5). The medical treatment recommended included: beta blocker, an-giotensin receptor blocker, diuretic, calcium channel blocker, statin and double antiplatelet therapy (clo-pidogrel and aspirin).
One month later, the patient described improve-ment of effort tolerance after angioplasty. A stress echocardiography test was performed, showing no signs of myocardial ischemia, but with the same aspect regarding MR as in the previous evaluation (modera-te MR at rest, severe MR at exercise). Considering that the patient was asymptomatic, with normal LV dimensions, normal LV systolic function, improvement of LV kinetics, conservative treatment was decided, with follow up.
Three months later, the patient presented at the Emergency Department for retrosternal chest pain at moderate exertion in the last two weeks, the last episode in the day of admission. Coronary angiogra-phy was performed revealing patent OM2 DES, but significant progression of the proximal LAD lesions: 90% stenosis and serial significant stenoses of the mid LAD (Figure 6). Three DE stents were implanted in the proximal and mid-LAD, with optimal procedural result and without complications (Figure 7). Platelet response to aspirin and clopidogrel was tested, with optimal result. A month later, the patient was asymp-tomatic; transthoracic echocardiography revealed im-provement of MR (mild to moderate at rest).
Four months after the last angioplasty, another stress echocardiogram was perfomed, showing new exercise-induced wall abnormalities of the anterior segments and worsening of MR during exercise (se-vere). In this context, a third coronary angiography evaluation was considered necessary. No new steno-ses were revealed. Therefore, taking into consideration that the patient was asymptomatic, with normal LV dimensions and ejection fraction, normal left atrial volume, optimal medical therapy with aggressive risk factor modifi cation were recommended and close follow-up of the patient.
Figure 1. Transthoracic echocardiography, parasternal long axis view, 2D and color Doppler: moderate MR is visible, with posterior mitral cusp restriction and an eccentric regurgitation jet to left atrium posterior wall.
Figure 2. Transthoracic echocardiography, apical four chamber view, color Doppler: visualization of moderate MR with vena contracta of 4 mm.
Figure 3. Transthoracic echocardiography, apical three chamber view, color Doppler: eccentric MR jet to left atrium posterior wall is seen.
Figure 4. Coronary angiography reveals 40% stenosis of the proximal left anterior descending artery (LAD), 50-60% stenosis of the mid LAD, 80% stenosis of second obtuse marginal branch (arrow).
Figure 5. Percutaneous coronary intervention of the second obtuse marginal branch with a drug-eluting stent, with good final result (arrow).
Figure 6. Repeated coronary angiography reveals permeable drug eluting stent on the second obtuse marginal branch, but significant progression of proximal LAD lession- 90% stenosis (arrow) and serial stenoses of the mid LAD.
Figure 7. Percutaneous coronary intervention of the proximal and mid LAD with three drug-eluting stents, with good final result.
Chronic secondary ischemic MR is the most common subtype of ischemic MR, being characterized by an im-balance between tethering forces and closing forces of the mitral valve, resulting in 95% of the cases from a type IIIb dysfunction (according to Carpentier’s types of MR)- restricted systolic leaflet motion3. The mecha-nism of ischemic functional MR has been described in great detail by Levine and Schwammenthal.4 The pa-pillary muscles, normally parallel to the LV long axis and perpendicular to the leaflets, are displaced by the myocardial segments underlying them in an outward and/or apical direction in ischemic heart disease, re-stricting leaflet closure in systole. The posterior leaflet is more frequently affected and particularly the poste-romedial scallop4.
A special subgroup of functional MR is represen-ted by those patients who have isolated infero-basal myocardial infarction with consecutive posterior leaflet tethering, but with preserved ejection fraction. In these cases heart failure symptoms can be explained by functional MR alone, and not by LV dysfunction1.
Echocardiography remains the most important method of diagnosis and evaluation of secondary MR. A comprehensive approach is recommended, combi-ning quantitative parameters, such as effective regur-gitant orifice area (EROA) and regurgitant volume (RV) with qualitative parameters such as mitral filling pattern, pulmonary vein flow pattern, density of the MR signal on continuous wave Doppler, left atrial size, pulmonary artery pressure.1,5 Compared to primary MR, lower thresholds have been established to define severe secondary MR (20 mm2 for EROA and 30 ml for RV)6.
Secondary MR is characteristically dynamic during exercise, therefore stress echocardiography can pro-vide important prognostic information; it has been shown that an increase in the severity of MR defi ned as an increase of EROA more than 13 mm2 and incre-ased pulmonary artery pressure during exercise (≥60 mmHg) identifies a subgroup of patients at higher risk of cardiac events2,7.
Regarding prognosis, several observational studies have shown that secondary MR is a poor prognostic element in patients with LV dysfunction compared to those who do not have secondary MR1. Trichon et al have studied 2057 patients with ischemic MR and chronic LV systolic dysfunction showing that MR is an independent predictor of mortality. The severity of MR plays an important role as there were signifi cant differences in survival at one, three and five years in patients with moderate to severe versus those witho-ut MR or with mild MR8 and it may lead to the deve-lopment of MR. The frequency of MR and its relation to survival in patients with LV systolic dysfunction has not been completely characterized. We analyzed the histories, coronary anatomy, and degree of MR in pa-tients with symptomatic heart failure and LV ejection fraction <40% who underwent cardiac catheterization between 1986 and 2000. Cox’s proportional hazards modeling was used to assess the independent effect of MR on survival. Two thousand fifty-seven patients met study criteria; MR was common in this cohort (56.2%. Nevertheless, it is unclear if prognosis is inde-pendently affected by MR compared to LV dysfunction as there are no proofs of a survival benefit due to reduction of secondary MR9.
The management of secondary ischemic MR re-quires integration of several parameters: clinical (e.g. symptoms of heart failure, comorbidities) and echocardiographic (e.g. MR severity at rest and dynamic change during exercise, presence of mitral valve com-plex anomalies, the origin and direction of the regur-gitant jet, the degree of LV remodelling, the coexis-tence of LV dyssynchrony, the presence and extent of viable myocardium)3. In contrast to primary MR, there is currently no clear evidence that the correction of secondary MR improves survival, therefore its ma-nagement is challenging9. Guideline-directed medical treatment remains the first option, aiming to reduce symptoms, to prevent myocardial infarction and to re-vert or delay the LV remodelling process. Angiotensin converting enzyme inhibitors, beta-blockers, spirono-lactone, titrated diuretic therapy should be prescribed according to the current recommendations3,9. Furt-hermore, besides medical treatment, inappropriate tethering can be addressed by surgery involving the mitral valve or LV reshaping, whereas coronary revascularization or cardiac resynchronisation therapy can potentially reduce tethering as well as increase mitral valve closing forces3.
Patients with secondary ischemic MR should under-go appropriate revascularization. Nevertheless, there are issues regarding MR relief by revascularization alone in chronic coronary artery disease. Aklog et al noted that moderate or severe MR persisted in 77% of revascularized patients4,10. Percutaneous or surgical revascularization is associated with improved survival compared to medical therapy alone in patients with MR8, but the proper way of revascularization is still controversial. Surgery has potential benefits of achie-ving more complete revascularization and improving MR more effectively by a mitral valve procedure at the time of coronary artery bypass graft (CABG). Howe-ver, surgical revascularization has a higher procedural risk compared with percutaneous coronary interven-tion (PCI), and it is unclear whether MR is merely a marker for more advanced left ventricular (LV) dys-function or whether IMR itself should be a target for therapy11. Kang et al conducted a nonrandomized study of 185 patients who underwent myocardial re-vascularization by PCI or CABG. A propensity-mat-ched analysis showed that cardiac events were fewer in the CABG subgroup11. However, about 90% of pa-tients in this study had multivessel coronary artery di-sease, and CABG was the preferred treatment option for patients with 3-vessel disease.
Surgery in secondary MR has limited indications when concomitant revascularization is not an option, as it is hampered by a signifi cant operative mortality, high rates of recurrent mitral regurgitation and no survival benefit9,12. It should be considered when pati-ents are already scheduled for CABG or other cardiac surgery or when symptoms persist and are attributa-ble to MR, despite optimal medical therapy1,9.
The presented case illustrates the aspects discussed above. In a young man with ischemic coronary disease and secondary moderate MR, the management plan was established by a Heart Team including cardiolo-gists, interventional cardiologists and cardiac surge-ons. Optimal medical therapy and percutaneous myo-cardial revascularization were chosen, with relief of symptoms and mild improvement of MR. In conclusion, secondary MR needs to be closely and carefully assessed. Until new evidences emerge regarding the optimal treatment, every case requires a personalized management plan.
Secondary ischemic MR is a complex condition. The imaging diagnosis and assessment of secondary ische-mic MR involves mainly echocardiography, with an important role played by stress echocardiography in terms of prognosis. The treatment should first be di-rected to the underlying LV dysfunction using guideli-ne-directed medical therapy. Other methods could be added as needed (e.g. coronary revascularization and/ or CRT). Mitral valve surgery should be indicated only when a clear benefit is foreseen.
Conflict of interest: none declared.
1. Benjamin MM, Smith RL, Grayburn PA. Ischemic and Functional Mi-tral Regurgitation in Heart Failure: Natural History and Treatment. Current Cardiology Reports 2014;16(8):517.
2. Călin A, Ginghină C. Regurgitarea mitrală. În: Ginghină C. Mic tratat de cardiologie- ediţia a II-a. Editura Academiei Române, Bucureşti, 2017; 553-576.
3. Lancellotti P, Marwick T, Pierard LA. How to manage ischaemic mi-tral regurgitation. Heart 2008;94(11):1497-502
4. Levine RA, Schwammenthal E. Ischemic Mitral Regurgitation on the Threshold of a Solution: From Paradoxes to Unifying Concepts. Cir-culation 2005;112(5):745-758.
5. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgita-tion: an executive summary from the European Association of Car-diovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14(7):611-44.
6. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103(13): 1759-1764.
7. Lancellotti P, Troisfontaines P, Toussaint A-C, Pierard LA. Prognos-tic importance of exercise-induced changes in mitral regurgitation in patients with chronic ischemic left ventricular dysfunction. Circula-tion 2003;108(14):1713-1717.
8. Trichon BH, Felker GM, Shaw LK, Cabell CH, O’Connor CM. Re-lation of frequency and severity of mitral regurgitation to survival
among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91(5):538-543.
9. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38(36): 2739-2791.
10. Aklog L, Filsoufi F, Flores KQ, et al. Does coronary artery bypass grafting alone correct moderate ischemic mitral regurgitation? Cir-culation 2001;104(12 Suppl 1):I68-75.
11. Kang D-H, Sun BJ, Kim D-H, et al. Percutaneous versus surgical re-vascularization in patients with ischemic mitral regurgitation. Circu-lation 2011;124(11 Suppl):S156-162.
12. Mihaljevic T, Lam B-K, Rajeswaran J, et al. Impact of mitral valve an-nuloplasty combined with revascularization in patients with function-al ischemic mitral regurgitation. J Am Coll Cardiol 2007;49(22):2191-2201.