Chronic secondary mitral regurgitation: General management and prognosis

INTRODUCTION — Secondary mitral regurgitation (MR; also known as functional MR) is MR caused by left ventricular (LV) disease (dilation, abnormal shape and/or dysfunction) and/or dilation of the left atrium (LA) and mitral annulus, generally with structurally normal or minimally thickened mitral valve leaflets and chords [1-3].

Secondary MR-associated LV dysfunction may be due to coronary artery disease (CAD) or (nonischemic) cardiomyopathy. In patients with CAD and secondary MR, LV dysfunction may be global or segmental (eg, inferolateral myocardial infarction [MI] with posterior leaflet tethering). Secondary MR caused by CAD (generally with MI) is also known as ischemic MR. Secondary MR associated with LA dilation is commonly associated with atrial fibrillation or heart failure (HF) with preserved ejection fraction [3,4].

By contrast, primary MR is caused by a primary abnormality of one or more components of the valve apparatus. Identification of the cause and type (primary or secondary) of MR is required for appropriate management of MR and associated conditions. Some individuals require management of both primary and secondary MR [1,3]. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

The management and prognosis of chronic secondary MR are presented here.

Related issues are presented separately:

●(See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

●(See "Pathophysiology and natural history of chronic mitral regurgitation".)

OVERVIEW OF MANAGEMENT — The approach to management of chronic secondary MR includes staging and serial monitoring, treatment of HF with reduced ejection fraction when present, management of other concurrent conditions (such as CAD and atrial fibrillation), and selection of candidates for mitral valve intervention (transcatheter edge-to-edge repair or mitral valve surgery) [1,2,5].

EVALUATION AND MONITORING

Staging — Staging of secondary MR is based upon symptoms, valve anatomy, and valve hemodynamics (severity of MR), which are associated with LV dysfunction (due to CAD or cardiomyopathy) and/or atrial and annular dilation (table 1) [1].

●Symptoms – Patients with secondary MR are commonly symptomatic due to HF with reduced ejection fraction, HF with preserved ejection fraction, and/or atrial fibrillation. Superimposed MR may cause further worsening of dyspnea, fatigue, and exercise intolerance [1,2]. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation", section on 'Clinical manifestations'.)

●Echocardiography – The severity of MR can be assessed quantitatively and semiquantitatively by Doppler echocardiography, as described in the table (table 1) [1]. Echocardiography is also helpful for assessing LV chamber size, wall thicknesses, global and regional function, and estimating pulmonary artery pressures. Transthoracic echocardiography (TTE) usually provides the necessary information. If TTE assessment of severity of MR is suboptimal, transesophageal echocardiography (TEE) may be helpful. (See "Echocardiographic recognition of cardiomyopathies" and 'Transesophageal echocardiography' below.)

Determining the cause of LV dysfunction — As secondary MR is caused by LV dilation and dysfunction and/or LA and annular dilation, evaluation of the severity and cause of LV and LA disease is also important. Identification of the cause (eg, CAD) impacts management and prognosis. Evaluation for CAD is performed even if chest pain is absent. Evaluation of the cause of LV dysfunction is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Evaluation of hibernating myocardium".)

Additional testing if needed

Transesophageal echocardiography — TEE is not indicated for routine follow-up of chronic secondary MR but is indicated when noninvasive imaging fails to determine the severity or cause of MR (including distinguishing primary from secondary MR) [1]. The severity of ischemic MR should be assessed under baseline conditions since variations in hemodynamic load and inotropic state can alter the severity of regurgitation.

TEE also has a role in evaluation prior to and during transcatheter or surgical mitral valve intervention to assess MR and the feasibility or success of mitral valve repair. Intraprocedural TEE assessment of MR severity can be misleading because of the LV pressure and volume unloading effects of general anesthesia. The severity of ischemic MR has been observed to decrease after induction of anesthesia, with the severity returning to baseline after combined intravenous volume loading to adjust preload and appropriate medications to return systolic pressure to baseline [6]. (See "Anesthesia for percutaneous cardiac valve interventions" and "Anesthesia for cardiac valve surgery".)

Cardiovascular magnetic resonance imaging — Cardiovascular magnetic resonance (CMR) imaging is not indicated for routine monitoring of MR but is indicated when echocardiography is not adequate to assess MR severity and LV and right ventricular (RV) volumes and systolic function [1]. CMR may also be helpful in evaluating ischemia (via stress CMR) and viability with the aid of delayed enhancement to assess for scar. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Regurgitant valve disease' and 'Determining the cause of LV dysfunction' above.)

Cardiac catheterization — Cardiac catheterization for hemodynamic assessment is indicated in selected patients with suboptimal or discordant noninvasive assessment or with an indication for coronary angiography to determine whether concomitant mitral valve and coronary artery interventions are indicated [1-3].

Serial assessment — Patients with chronic secondary MR require serial monitoring following initial evaluation and staging. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

The goals of monitoring are to assess changes in clinical status by history and physical examination and to assess changes in severity of MR and LV function by echocardiography, as these changes can occur in the absence of a change in symptoms. Secondary MR is often progressive since the regurgitant volume imposes a hemodynamic burden on the LV that leads to dilation and eccentric geometry, which may contribute to an increase in the severity of MR. (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

●Yearly visits – Routine follow-up of patients with significant valve disease includes annual history and physical examination [1]. Patients with secondary MR with LV systolic dysfunction should be followed as recommended for this principal disease process. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Follow-up and preventive care'.)

●Serial echocardiography – Serial TTE is performed to assess the severity of secondary MR, as well as LV size and function. We suggest a frequency of follow-up based upon the severity of MR and symptoms of HF:

•For progressive MR – Asymptomatic patients with mild or moderate MR (also known as progressive MR; identified by effective regurgitant orifice <0.40 cm², regurgitant volume <60 mL, and regurgitant fraction <50 percent) should undergo serial echocardiography as follows:

-For mild MR – Every three to five years

-For moderate MR – Every one to two years

•For severe MR – Patients with severe secondary MR (effective regurgitant orifice ≥0.40 cm² [may be ≥0.30 cm² with an elliptical regurgitant orifice area], regurgitant volume ≥60 mL, and regurgitant fraction ≥50 percent) should be seen at least every 6 to 12 months (sooner if symptoms worsen). Repeat TTE should be obtained at these visits. The six-month interval is preferred if stability of LV size, MR severity, or symptoms has not been documented.

GENERAL MANAGEMENT

Heart failure management

Recommendations for pharmacologic therapy — Patients with chronic secondary MR and HF with reduced ejection fraction (HFrEF) should receive standard evidence-based therapy for HFrEF, including an angiotensin system blocker (angiotensin receptor-neprilysin inhibitor, angiotensin converting enzyme [ACE] inhibitor, or single-agent angiotensin II receptor blocker [ARB]); beta blocker; mineralocorticoid receptor antagonist (MRA), if indicated; diuretic therapy as needed to treat volume overload; and other indicated medications. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

Asymptomatic patients with chronic secondary MR and LV systolic dysfunction (LV ejection fraction [LVEF] ≤40 percent) should receive standard therapy for asymptomatic LV dysfunction, including an angiotensin system blocker (ACE inhibitor or ARB) and beta blocker therapy. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

Efficacy of drug therapy — Randomized clinical trials in patients with HFrEF have shown that combination therapy including an angiotensin system blocker, beta blocker, MRA, and other agents can improve cardiac function, relieve symptoms, and enhance survival, as discussed separately (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

More limited data suggest that angiotensin system blockers (sacubitril-valsartan or ACE inhibitor) and beta blockers (carvedilol or metoprolol) also reduce LV volumes and the severity of secondary MR [7-13]. Treatment of volume overload may also be helpful, as illustrated by a study in patients with end-stage kidney disease in which ultrafiltration eliminated or reduced the severity of MR [14].

Exercise — In patients with chronic secondary MR, concerns regarding exercise are related to presence of MR as well as presence of CAD in patients with ischemic MR and the presence of cardiomyopathy in patients with nonischemic LV dysfunction. Exercise has a variable effect on the regurgitant fraction in patients with chronic MR [15]. The reduction in systemic vascular resistance may result in no change or a mild reduction in the regurgitant fraction. On the other hand, an elevation in blood pressure, as occurs with static exercise, can lead to marked increases in regurgitant volume and pulmonary venous pressure.

Evidence on the safety of exercise in patients with chronic secondary MR is scant, so exercise recommendations are based largely on expert opinion. The 2015 American Heart Association/American College of Cardiology (AHA/ACC) scientific statement on eligibility recommendations for competitive athletes includes recommendations for MR, CAD, and cardiomyopathy, but does not provide recommendations specifically targeting patients with chronic secondary MR.

●We suggest that patients with cardiomyopathy with secondary MR not participate in competitive sports, with the possible exception of low-intensity class IA sports (figure 1) in asymptomatic individuals.

●We suggest that patients with CAD and secondary MR not participate in competitive sports, with the possible exception of low-intensity class IA sports (figure 1) in asymptomatic individuals who have been screened by exercise testing on medications.

●We agree with the guidelines in prohibiting participation in competitive sports for patients with CAD in the following two settings:

•For at least three months after an acute MI or coronary revascularization procedure

•If they have increasing frequency of or worsening ischemic symptoms

Recommendations for exercise after mitral valve replacement or repair are discussed separately. (See "Overview of the management of patients with prosthetic heart valves", section on 'Exercise recommendations'.)

Pregnancy — MR during pregnancy is more commonly primary than secondary MR. For pregnant patients with secondary MR, maternal and fetal risks are primarily related to HF severity, LVEF, and pulmonary pressures, not MR severity. Peripartum cardiomyopathy is a cause of HF late in pregnancy (or during the five months after delivery) and may be associated with secondary MR, although the MR is not usually severe. Management of HF and MR during pregnancy, as well as peripartum cardiomyopathy, is discussed separately. (See "Management of heart failure during pregnancy" and "Peripartum cardiomyopathy: Treatment and prognosis" and "Pregnancy and valve disease", section on 'Mitral regurgitation'.)

Endocarditis prophylaxis generally not required — In accordance with the 2007 AHA guidelines on infective endocarditis and the 2020 ACC/AHA valvular heart disease guidelines [1,16], antibiotic prophylaxis is not recommended for patients with mitral valve disease (in the absence of prosthetic repair or replacement or history of infective endocarditis) [1,16]. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

MANAGEMENT OF CONCURRENT CONDITIONS — Patients requiring mitral valve intervention frequently have concurrent conditions that require management. These include CAD, atrial fibrillation, indications for pacing, and significant tricuspid regurgitation. Some of these conditions may be surgically managed at the time of mitral valve surgery (eg, surgical ablation for atrial fibrillation or coronary artery bypass surgery) or managed by catheter procedures, as discussed separately. (See "Surgical procedures for severe chronic mitral regurgitation" and "Atrial fibrillation: Surgical ablation" and "Chronic secondary mitral regurgitation: Intervention" and "Atrial fibrillation: Catheter ablation".)

Coronary artery disease — For patients with secondary MR, standard recommendations for management of CAD and coronary revascularization apply (including activity-limiting angina despite maximum medical therapy, significant left main CAD, or multivessel CAD with a reduction of LVEF and a large area of potentially ischemic myocardium). Revascularization may also reduce the severity of MR if a significant area of stunned or hibernating (ischemic yet viable) myocardium is present. (See "Chronic coronary syndrome: Overview of care" and "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention" and "Treatment of ischemic cardiomyopathy".)

The potential role of revascularization in reducing the severity of secondary MR caused by CAD is discussed separately. (See "Chronic secondary mitral regurgitation: Intervention", section on 'Coronary revascularization'.)

Atrial fibrillation — In patients with secondary MR, atrial fibrillation is managed according to standard recommendations, with specific considerations for patients with HF, as discussed separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "The management of atrial fibrillation in patients with heart failure" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".)

Pacemaker management — For patients with an indication for a permanent pacemaker, pacing strategies that may reduce MR include atrioventricular (AV) optimization and cardiac resynchronization therapy (CRT).

AV optimization — In patients who have a dual-chamber pacemaker, some studies suggest that AV optimization can reduce MR, but an impact on clinical outcomes has not been established. Several small studies have evaluated the impact of dual-chamber pacing with optimal AV delay on hemodynamic and clinical parameters in patients with significant MR [17-19]:

●In a prospective series of 20 patients with symptomatic complete AV block and dual-chamber pacemakers, optimal AV delay was determined by echocardiographic parameters [17]. The mean optimal AV delay was 98 ms, which reduced the severity of MR. Additionally, the cardiac output and systolic blood pressure improved.

●A trial enrolled 38 patients in sinus rhythm with HF and randomly assigned them to optimal medical therapy or optimal medical therapy with dual-chamber pacing [19]. AV delay was optimized according to echocardiographic parameters and generally ranged between 100 to 120 ms (in 14 of 19 patients). There were no differences between the two arms in most clinical endpoints, although the degree of MR and systolic LV diameter were both reduced in patients assigned to dual-chamber pacing.

Cardiac resynchronization therapy

Use — Patients with chronic secondary MR should receive CRT according to standard evidence-based guidelines for such therapy. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

CRT improves survival in selected patients with systolic HF and ventricular dyssynchrony. CRT often improves secondary MR in patients with ventricular dyssynchrony, and CRT is recommended in patients with secondary MR who meet criteria for CRT. However, careful patient selection is required for CRT, particularly in the setting of ischemic MR, since it may not be possible to pace scarred regions.

The benefits of CRT rapidly wane if therapy is discontinued [20]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

Effects of CRT — CRT often improves secondary MR in patients with ventricular dyssynchrony. The acute effects of CRT on secondary MR were evaluated in a study of 24 patients with biventricular (BiV) pacemakers [21]. The effective regurgitant orifice area (EROA) was assessed during BiV pacing and with BiV pacing turned off. Active CRT was associated with almost a 50 percent reduction in the EROA (25 to 13 mm²). Long-term benefits were noted in the CARE-HF and MIRACLE randomized trials of CRT [22,23]. Compared with controls, CRT produced significant reductions in LV end-systolic and end-diastolic dimensions and in mitral regurgitant jet area (eg, -2.7 versus -0.5 cm² at six months in MIRACLE) [23].

The preceding observations were made in patients with predominantly mild (1+) to moderate (2+) MR. The impact of CRT on moderate to severe MR (3+) to severe MR (4+) was evaluated in a study of 98 patients with indications for CRT [24]. In the 85 patients surviving to eight-month follow-up, significant improvement in MR (reduction by at least one grade) occurred in 42 patients (49 percent). An ischemic cause of HF was significantly more common in MR nonimprovers than among MR improvers (74 versus 48 percent). Survival rates were higher in MR improvers compared with MR nonimprovers (97 versus 88 percent at one year and 92 versus 67 percent at two years). MR improvement was an independent predictor of survival (hazard ratio 0.35, 95% CI 0.13-0.94). The findings suggest a significant benefit from CRT in this population and also highlight the importance of careful patient selection for this treatment, particularly in those with ischemic MR. Lack of response to CRT among patients with ischemic MR may be due to an inability to pace scarred regions. These issues are discussed in detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

MITRAL VALVE INTERVENTION — The role of mitral valve intervention (transcatheter or surgical) for secondary MR is discussed separately. (See "Chronic secondary mitral regurgitation: Intervention", section on 'Outcomes of mitral valve intervention'.)

PROGNOSIS — Among individuals with secondary MR, those with atrial dysfunction appear to have better survival than those with ventricular dysfunction [25]. In a study of 11,987 patients (median age 69) with secondary MR, 52 percent had isolated atrial dysfunction and 48 percent had ventricular dysfunction. Using data from 3522 matched pairs, the hazards of death were higher with ventricular dysfunction than with atrial dysfunction across severities of secondary MR.

With atrial dysfunction — While individuals with atrial functional MR generally have a better prognosis than those with ventricular functional MR, individuals with atrial functional MR are at higher risk of adverse outcomes than patients with primary MR. This was illustrated by a study of 283 patients with severe MR with preserved LVEF, which found that those with atrial functional MR had worse survival and higher risk of HF hospitalization than those with primary MR [26]. The presence of atrial functional MR was an independent predictor of mortality (adjusted odds ratio 2.61, 95% CI 1.17-5.83).

With ventricular dysfunction — Secondary MR associated with LV dysfunction is associated with adverse prognosis beyond that seen with LV dysfunction alone in patients with ischemic or nonischemic cardiomyopathy.

There are limited data from observational studies on the prognostic significance of secondary MR in patients with LV systolic dysfunction [27-29]. In a chart review of 1421 consecutive patients with LVEF ≤35 percent, patient survival at a mean follow-up of one year varied inversely with MR grade: 1004, 795, and 628 days with no to mild, moderate, and severe MR, respectively [28]. Severe MR was an independent predictor of mortality (relative risk [RR] 1.84). The severity of tricuspid regurgitation was also a predictor of mortality (RR 1.55) and often occurred with severe MR. Other predictors of poor outcome included CAD and cancer.

RV dysfunction may be a predictor of poor outcome among patients with secondary MR. In a prospective study of 356 chronic HF patients with LVEF ≤45 percent and moderate to severe MR, RV systolic function (as assessed by tricuspid annular plane systolic excursion) was an independent predictor of freedom from all-cause mortality or hospitalization for worsening HF [30]. Pulmonary artery systolic hypertension was a predictor of mortality upon univariate but not multivariate analysis, and pulmonary artery systolic pressure was not significantly different in the groups with and without evidence of RV systolic dysfunction.

Ischemic MR following MI is associated with increased mortality as well as risk of development of HF [31-44]. The degree of mortality risk is illustrated by the following observations:

●In an analysis from the CADILLAC trial of 1976 patients with an acute ST-elevation MI, 192 (10 percent) had mild MR and 58 (3 percent) had moderate to severe MR [35]. Patients with worse MR had significantly higher mortality rates at 30 days (1.4, 3.7, and 8.6 percent for no MR, mild MR, and moderate to severe MR, respectively) and at one year (2.9, 8.5, and 20.8 percent, respectively).

●A similar increase in risk over the longer term was noted in a prospective study of 303 patients with a previous Q-wave MI, 194 of whom had ischemic MR [39]. At five years, those with ischemic MR had a higher rate of cardiac mortality (50 versus 30 percent). The magnitude of the mortality risk correlated with the severity of the MR (figure 2).

●In a report limited to patients with a non-ST-elevation acute coronary syndrome, survival at 431 days decreased as the severity of MR increased [37]. MR was the only predictor of poor survival in multivariate analysis.

Ischemic MR is also an important predictor of the development of HF, even in patients with a normal LVEF at the time of the MI. The following observations were noted in different studies.

●At five years after ST-elevation MI, patients with ischemic MR had a much higher risk of HF than those without ischemic MR (53 versus 18 percent; adjusted RR 3.65) [44].

●At five years after MI, survival free of HF was related to the severity of MR in another report (74 and 35 percent with mild and moderate to severe MR, respectively) [36].

●The eventual risk of HF is increased in patients with MI and secondary MR independent of LVEF [38].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: What can go wrong after a heart attack? (The Basics)" and "Patient education: Mitral regurgitation (The Basics)")

●Beyond the Basics topic (see "Patient education: Mitral regurgitation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Secondary mitral regurgitation (MR; also known as functional MR) is MR caused by left ventricular (LV) disease (dilation, abnormal shape and/or dysfunction) and/or dilation of the left atrium (LA) and mitral annulus, generally with structurally normal or minimally thickened mitral valve leaflets and chords. (See 'Introduction' above.)

●Evaluation – Evaluation of patients with chronic secondary MR includes testing to determine the severity of MR, the cause of MR, and the cause of any associated LV dysfunction. The cause of MR and LV dysfunction impacts management and prognosis. (See 'Determining the cause of LV dysfunction' above.)

●Staging – Staging of secondary MR is based upon symptoms, valve anatomy, and valve hemodynamics (severity of MR), which are associated with LV dysfunction due to coronary artery disease (CAD) or cardiomyopathy (table 1). (See 'Staging' above.)

●Serial monitoring – Serial monitoring by clinical evaluation and echocardiography is warranted in patients with chronic secondary MR. As secondary MR is progressive, the goals of monitoring are to assess changes in clinical status, severity of MR, and LV function. (See 'Serial assessment' above.)

●Management – Management of chronic secondary MR includes the following components:

•Treatment of heart failure – First-line therapy for secondary MR caused by heart failure with reduced ejection fraction (HFrEF) is evidence-based management of HFrEF, including pharmacologic therapy as well as cardiac resynchronization therapy (CRT), as indicated. (See 'Heart failure management' above and 'Pacemaker management' above.)

•Management of concurrent conditions – Treatment of secondary MR includes assessment and management of concurrent conditions including coronary artery disease (CAD), atrial fibrillation, and disorders requiring pacemaker therapy. (See 'Management of concurrent conditions' above.)

●Prognosis – Among individuals with secondary MR, those with atrial dysfunction appear to have better survival than those with ventricular dysfunction. Secondary MR associated with LV dysfunction is associated with an adverse prognosis beyond that seen with LV dysfunction alone in patients with ischemic or nonischemic cardiomyopathy. (See 'Prognosis' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Sorin Pislaru, MD, who contributed to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic.