Medical Therapy for Functional Mitral Regurgitation
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Abstract
Functional mitral regurgitation (FMR) can be broadly categorized into 2 main groups: ventricular and atrial, which often coexist. The former is secondary to left ventricular remodeling usually in the setting of heart failure with reduced ejection fraction or less frequently due to ischemic papillary muscle remodeling. Atrial FMR develops due to atrial and annular dilatation related to atrial fibrillation/flutter or from increased atrial pressures in the setting of heart failure with preserved ejection fraction. Guideline-directed medical therapy is the first step and prevails as the mainstay in the treatment of FMR. In this review, we address the medical therapeutic options for FMR management and highlight a targeted approach for each FMR category. We further address important clinical and echocardiographic characteristics to aid in determining when medical therapy is expected to have a low yield and an appropriate window for effective interventional approaches exists.
Functional mitral regurgitation (FMR) is a consequence of left ventricular (LV) or atrial functional and anatomic remodeling, preventing adequate coaptation of the near structurally normal mitral valve (MV) leaflets. It can be broadly categorized into 2 groups: ventricular and atrial. In two-thirds of the cases, FMR develops in the setting of LV remodeling (LVR), most often in a dilated LV with reduced systolic function (ie, heart failure with reduced ejection fraction [HFrEF], ejection fraction [EF], ≤40%), or localized adverse LVR resulting in papillary muscle displacement, and less frequently as a result of ischemic papillary muscle dysfunction.1–6 In the remainder, FMR mainly results from atrial and annular dilatation, either due to atrial fibrillation/flutter (AF) or prolonged increase in left atrial (LA) pressures secondary to diastolic dysfunction (most often in heart failure with preserved EF [HFpEF], EF ≥50%; Table 1).3–7 A combination of these 2 categories is frequently observed in clinical practice.
| Mechanisms contributing to functional MR |
|---|
| LA forces |
| LA dilation (posterior>anterior) |
| Increased LA pressure causing LA stretch and fibrosis with altered atrial/annular dynamics |
| Mitral annular dilatation |
| Insufficient leaflet growth in relation to the above |
| Posterior leaflet bending and anterior leaflet flattening |
| Left ventricular forces |
| Increased LV sphericity causing apical and lateral displacement of papillary muscles with increased subvalvular traction and displacement of zone of coaptation |
| Poor LV contractility with slow rate of rise of intraventricular pressure (dp/dt) causing slow closure of leaflets |
| Mitral annular dilation |
| Cardiac electromechanical dyssynchrony |
| Dyssynchronous contraction of myocardial segments increasing tethering forces and decreasing closing forces |
| Diastolic MR resulting from improper MV closure with positive pressure gradient through MV during end diastole |
Mitral regurgitation (MR) of moderate or greater severity is present in 24% to 59% of patients with heart failure (HF),8–11 the incidence of which is rising with over 8 million adults in the United States expected to develop HF, a 46% predicted increase from 2012 to 2030.12 MR severity, when moderate or greater in HFrEF patients, is independently related to increased mortality and HF hospitalizations, which is the case even if MR is detected during acute decompensation of HF.13,14 Even lesser degrees of MR in patients with HF portends a poorer prognosis, albeit this relationship seems to be attenuated as LV dysfunction and exercise capacity grow worse.9,15–17 the presence of even mild FMR at discharge was associated with worse outcomes among hospitalized patients with HFpEF.18 The updated staging of FMR as per the 2020 American College of Cardiology/American Heart Association guidelines and the severity classification used in clinical trials (showing clinical benefit for patients whose FMR was classified under tier 1 or 2, but not tier 3, in a COAPT subanalysis study [Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation]) are compared in Table 2.19,20 The recent European Society of Cardiology/European Association for CardioThoracic Surgery guidelines have also recommended a similar stratification of severe FMR akin to their criteria for primary mitral regurgitation allowing for considerations for the crescent-shaped regurgitant orifice (effective regurgitant orifice area [EROA] cut off ≥30 mm2) and LV dysfunction (regurgitant volume [rVol] ≥45 mL in low-flow states; Table 2).21
| 2020 AHA guidelines for FMR staging | COAPT echocardiographic criteria | |||||
|---|---|---|---|---|---|---|
| Stage | Definition | Valve anatomy | Valve hemodynamics | Associated cardiac findings | Symptoms | |
| A | At risk of MR | Normal valve leaflets, chords, and annulus in a patient with CAD or cardiomyopathy | No MR jet or small central jet area <20% LA on Doppler; small vena contracta <0.30 cm | Normal or mildly dilated LV size with fixed (infarction) or inducible (ischemia) regional wall motion abnormalities; primary myocardial disease with LV dilation and systolic dysfunction | Symptoms attributable to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy | Non severe (COAPT Tier 3 criteria): EROA not measured or <0.2 cm2, with at least 2 of the following: rVol ≥45 mL/beat; regurgitant fraction ≥40%; vena contracta width ≥0.5 cm; proximal isovelocity surface area radius >0.9 cm but continuous wave Doppler of MR jet not done; large (≥6.0 cm) holosystolic jet wrapping around LA; peak E velocity ≥150 cm/s |
| B | Progressive MR | Regional wall motion abnormalities with mild tethering of mitral leaflet; annular dilation with mild loss of central coaptation of the mitral leaflets | EROA <0.40 cm2; rVol <60 mL; regurgitant fraction <50% | Regional wall motion abnormalities with reduced LV systolic function; LV dilation and systolic dysfunction attributable to primary myocardial disease | Symptoms attributable to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy | |
| C | Asymptomatic severe MR | Regional wall motion abnormalities or LV dilation with severe tethering of mitral leaflet; annular dilation with severe loss of central coaptation of the mitral leaflets | EROA ≥0.40 cm2; rVol ≥60 mL; regurgitant fraction ≥50% | Regional wall motion abnormalities with reduced LV systolic function; LV dilation and systolic dysfunction attributable to primary myocardial disease | Symptoms attributable to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy | |
| D | Symptomatic severe MR* | Regional wall motion abnormalities or LV dilation with severe tethering of mitral leaflet; annular dilation with severe loss of central coaptation of the mitral leaflets | EROA ≥0.40 cm2; rVol ≥60 mL; regurgitant fraction ≥50% | Regional wall motion abnormalities with reduced LV systolic function; LV dilation and systolic dysfunction attributable to primary myocardial disease | HF symptoms attributable to MR persist even after revascularization and optimization of medical therapy; decreased exercise tolerance; exertional dyspnea | Severe FMR responsive to TEER: COAPT Tier 1 criteria: EROA ≥0.3 cm2 or pulmonary vein systolic flow reversal. COAPT Tier 2 criteria: EROA ≥0.2 cm2 and <0.3 cm2, with any 1 of the following: rVol ≥45 mL/beat; regurgitant fraction ≥40%; vena contracta width ≥0.5 cm |
Therapeutic options vary depending on the underlying mechanism and severity of FMR.19,22 Therapies showing benefit for the treatment of FMR are (1) guideline-directed medical therapy (GDMT) including cardiac resynchronization therapy (CRT), (2) surgical repair/replacement, (3) mechanical circulatory devices or cardiac transplant, and more recently (4) multiple percutaneous MV repair modalities. However, medical management prevails as the mainstay of FMR treatment,9,21,23 especially when advanced right or left HF is present as outcomes of MV interventions tend to be worse in this setting.24,25 In this article, we review the medical management of FMR, including recognition of failure of medical therapy prompting interventions for valve repair.
Updated Evidence of Medical Therapy in FMR
Significance of GDMT in Treatment of FMR
GDMT plays a pivotal role in LV reverse remodeling (LVRR) in FMR and leads to reduction in severity and improved outcomes for both atrial and ventricular FMR: studies report 28% to 50% reduction in grade of FMR from baseline in patients receiving optimal or maximally tolerated doses of GDMT (including diuretics) in both ischemic cardiomyopathy and non-ischemic cardiomyopathy.26–28 Ventricular FMR mirrors LVR status,1,29 and suggestive evidence of LVRR secondary to GDMT is derived from LV EF (LVEF), LV end diastolic volume (LVEDV), and LV end systolic volume (LVESV) data.30 The discordant results of the COAPT and MITRA-FR (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) randomized control trials emphasize the importance of achieving optimization of GDMT before consideration of device therapy.31,32 While the COAPT trial demonstrated significantly lower rates of HF hospitalizations and all-cause mortality at 2 years, the MITRA-FR trial did not show a significant difference in the composite outcome of death from any cause or unplanned HF hospitalization at 1 year. In addition to differences in LV dimensions and degrees of MR thresholds used, a key difference between the trials was the optimization of GDMT in patients in COAPT study by an advanced HF specialist. In COAPT, randomization was permitted only for optimized patients on maximally tolerated doses of GDMT, with further dose uptitration as permitted on follow-up. Patients in the device arm were more likely to receive an ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI) and were started on/received increased doses of β-blocker (BB) therapy 2 years after the Mitraclip procedure.31 This potentially reflects the impact of suboptimal titration of GDMT among patients in MITRA-FR, in the absence of an advanced HF specialist guiding therapy, resulting in inclusion of patients who had not yet derived the full benefits of GDMT or who perhaps could not tolerate it, possibly signaling more advanced LV disease. It is also possible that GDMT with its demonstrated LVRR effects mitigated adverse LVR and severity of FMR in some of the MITRA-FR population before intervention, resulting in no significant differences detected between the two study arms. Moreover, continuation of strict titration of GDMT in COAPT post-implantation may also have impacted outcomes. These factors warrant further investigation. In a study evaluating patients with severe FMR treated with percutaneous MV replacement, <50% of the overall population was using >50% target dose of ACE inhibitor/ARB/ARNI or BBs. Post-percutaneous MV replacement, 33% underwent downtitration of GDMT, which was associated with poor survival. Contrary to these findings, patients with uptitrated/unchanged GDMT showed less recurrence of MR ≥3+, larger reduction in LVESV, and lower New York Heart Association class at follow-up.33
The armamentarium of approved medications available to tackle HFrEF includes ARNIs, ACE inhibitors, ARBs, BBs, SGLT2 (sodium glucose transporter-2) inhibitors (SGLT2i), loop diuretics, mineralocorticoid receptor antagonists (MRAs), hydralazine/isosorbide dinitrate, guanylate cyclase inhibitor vericiguat, and ivabradine. Updated evidence has shown immense additional benefits from initiation of a newly approved class of drugs, SGLT2i, across all HF spectrums.6,34 However, GDMT continues to remain underutilized in treatment of HF, both in inpatient and ambulatory settings.35–37 In the currently evolving era of device-based treatment of FMR, assuring GDMT before (and after) intervention is essential. Key studies are summarized in Table 3, with the approach to initiation and optimization of medications for GDMT summarized in Figures 1 and 2 and Table S1.16,34
| Author, country, year | Study type | Age, y | Sex (M), % | ICM, % | n | Drug vs comparison arm (if any) | Impact on FMR (study drug vs comparison) |
|---|---|---|---|---|---|---|---|
| Kang et al,38 United States, 2019 | RCT | 62.6±11.2 | 61 | 36 | 118 | ARNI vs valsartan | Significant reduction in EROA (30% vs 9%) and rVol (33% vs 12%) |
| Lowes et al,39 United States, 1999 | RCT | … | … | 59 | Carvedilol vs placebo | Reduction in MR ratioa at baseline and 4 mo compared with placebo | |
| Kotlyar et al,27 Australia, 2004 | POS | … | … | … | 257 | Carvedilol | Reduction of MR grade, 28% |
| Comin-Colet et al,40 Spain, 2002 | POS | … | 85 | 20 | 20 | Carvedilol | Significant reduction in grade and area of mitral regurgitant jet; reduction of MR grade, 80% |
| Capomolla et al, Italy,41 2000 | Cohort study | 53±9 | … | 62 | 90 | Carvedilol (vs matched control group) | Significant reduction in EROA and rVol in the carvedilol group |
| Tardif et al, multicenter,42 2011 | SHIFT substudy | 59.7±11 | 76 | 66 | 411 | Ivabradine vs placebo | Improvement in MR by 1 grade: 10% vs 8% |
| Seneviratne et al,43 Australia, 1994 | RCT | 71.6 (57–80)* | … | … | 23 | Captopril vs placebo | Significant reduction in MR area with incremental doses of 50–100 mg/d |
| Levine et al44 | POS | 60±13 | 84 | 37 | 19 | Lisinopril-isosorbide dinitrate | Improvement in MR grade to grade 0–1, 42% |
Figure 1. Suggested approach for titration of medical therapy in functional mitral regurgitation (FMR). Circular arrows: optimization of medical therapy, that is, uptitration to maximum doses achieved in clinical trials or maximally tolerated doses. ↓ points to the next step in consideration of treatment options. ACEI indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation/flutter; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, β-blocker; BP, blood pressure; Cr, creatinine; CRT-D, cardiac resynchronization therapy defibrillator; EF, ejection fraction; eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; HYD/ISDN, hydralazine/isosorbide dinitrate; K, potassium; LBBB, left bundle branch block; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; and SGLT2i, sodium glucose transport 2 inhibitor.
Figure 2. Targeted medical therapy for functional mitral regurgitation (FMR). Medical therapy including cardiac resynchronization therapy (CRT) targeting different aspects in treatment of FMR is portrayed. ACEI indicates angiotensin-converting enzyme inhibitor; Af, atrial fibrillation/flutter; ARB, angiotensin receptor blocker; ARNI, angiotensin neprilysin inhibitor; BB, β-blocker; GAG, glycosaminoglycan; GDMT, guideline-directed medical therapy; GLS, global longitudinal strain; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HYDRLZ/ISDN, hydralazine/isosorbide dinitrate; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; MV, mitral valve; and SGLT2i, sodium glucose transport 2 inhibitor.
Angiotensin Receptor Neprilysin Inhibitor
Since the PARADIGM-HF trial (Angiotensin-Neprilysin Inhibition Versus Enalapril in Heart Failure), focus had shifted to promote the early initiation and gradual uptitration of sacubitril/valsartan to achieve maximal cardiac benefits in HFrEF. Currently, direct-to-ARNI approach even in renin-angiotensin-aldosterone system inhibitor (RAASi) naive HF patients with close follow-up, as well as replacement of existing RAASi therapy with ARNI is recommended.34 LVRR effects of sacubitril/valsartan are well documented. The PROVE-HF trial (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) and EVALUATE-HF trial (Effects of Sacubitril/Valsartan Versus Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) demonstrated the impact of ARNI on reverse LVR.45–47 A recent meta-analysis supported these findings demonstrating superiority of ARNI over RAASi with improvements in LVRR index biomarkers and functional capacity noted in 3 months among patients with HFrEF.47
The PRIME trial (Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation) studied the efficacy of ARNI on FMR reduction in 117 patients randomized to receive ARNI or valsartan therapy for significant FMR (EROA >0.1 cm2) despite therapy with ACE inhibitor/ARB and BBs, at New York Heart Association class II to III and LVEF 25% to 50%.38 At 1 year, the ARNI group achieved 30% relative reduction in the primary end point of EROA (−0.058±0.095 versus −0.018±0.105 cm2; P=0.032) compared with the valsartan group irrespective of the cause of functional MR or baseline rhythm. Further, LV end systolic volume (LVESV) and LVEDV were significantly smaller in the sacubitril/valsartan group, and decrease in the LVEDV index alone was significantly greater in the sacubitril/valsartan group than in the valsartan group (mean difference of change, –7.0 [95% CI, −13.8 to −0.2] mL/m2; P=0.044). Similar results were obtained in secondary analysis among study completers with greater number of patients in the ARNI group showing significant reduction in FMR. ARNI ameliorates FMR through in several physiological pathways: first, it’s natriuretic effect leads to reduction of both preload and afterload; second, LVRR-mediated reduction in LV volume may lead to improved MV leaflet coaptation. Additionally, ARNI inhibits tissue growth factor beta more profoundly than ARBs, thus counteracting leaflet thickening—an important and underrecognized cause of FMR.48 Thus, ARNI appears to be an effective therapy for patients with ventricular FMR with EF ≤50, though its clinical benefit should be further studied.
In the PRIME trial, LA volume index significantly improved with therapy, while in PARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction), LA size was significantly reduced in the ARNI group.38,49 This is in line with animal models showing favorable atrial reverse remodeling with ARNI.50 However, no trials have demonstrated reduced annular size or reduction in atrial FMR, with the limitation that most studies assessing ARNI did not differentiate atrial or ventricular FMR. In PARAGON-HF (Angiotensin-Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction), the subgroup of patients deriving most benefit were women, patients with AF, and those with EF ≤57%, possibly mediated by a reduction of MR severity, albeit not explicitly assessed. This finding could be of interest for future research, especially given the higher likelihood of atrial rather than ventricular FMR in women.14,51
ACE Inhibitor/ARB
In addition to well-established morbidity and mortality benefits, RAASi agents reduce or prevent adverse LVR.52–58 A substudy of the SOLVD trial (Studies of Left Ventricular Dysfunction) highlighted the role of enalapril in inhibiting LVR by attenuation of progressive dilation and hypertrophy irrespective of the patients’ symptomatic status.53 V-HeFT (Valsartan in Heart Failure Trial) demonstrated favorable LVRR with Valsartan with reduction in LV end diastolic diameter and improvement in EF starting at 4 months and persisting for 2 years.54 However, there are scarce data demonstrating clear improvement in ventricular FMR with either ACE inhibitor or ARB therapy.43
Evidence for use of ACE inhibitor/ARB for atrial FMR is not substantiated. ACE inhibitor treatment was shown to attenuate loss of atrial microcapillaries and atrial structural remodeling in patients with chronic lone AF.59 There are equivocal data regarding ACE inhibitor and ARB for prevention of AF, but when used to treat hypertension, both agents prevented new-onset AF and progression from paroxysmal to chronic AF.60–62 This attenuation of remodeling and possible reduction in rate incidence of AF, along with the proven benefits of treating hypertension with this class of drugs, are compelling arguments to use these agents in patients with atrial FMR and any comorbidities justifying their use (eg, diabetes and coronary artery disease).
β-Blockers
BBs improve LVEF and survival for patients with HFrEF in sinus rhythm, with similar benefit observed in patients with HF with mid-range EF.63 Favorable outcomes of β-blockade are achieved through their antiarrhythmic, negative chronotropic and inotropic effects, as well as LVRR and are generally a dose-related phenomenon emphasizing the need for achieving target doses of this class.64–66
Evidence for effect of β-blockade on diminution of ventricular FMR in HFrEF is robust for carvedilol. Capomolla et al41 showed significant decrease in EROA (0.67±0.24 versus 0.13±10 cm2; P<0.0001) with concomitant significant reduction of regurgitate volume in the carvedilol group, accompanied by improvement in LVRR parameters of LVEF and LVESV index. FMR grade reduced in 80% of the study population (2.1±1.09 versus 0.75±0.72; P<0.0001) in a study by Colet et al,40 with significant reduction in FMR jet area (8.7±3.27 versus 2.7±2.89; P=0.001). Kotlyar et al showed that the extent of LVRR was independent of baseline grade of FMR or LV size. Moreover, they reported improvement in grade of FMR in 28% of patients, with the greatest extent of LVRR in patients whose FMR sustainably improved.27 Similarly, Lowes et al39 reported LVRR closely correlated with reduction of MR in 4 months of therapy that persisted at 1 year.
For patients with AF, there seems to be an improvement in LVEF, though the clinical benefit seems less than for patients in sinus rhythm, especially for milder systolic dysfunction.63,67 For HFpEF and atrial FMR, there are no clear data supporting the role of BBs, except for rate control and symptomatic relief for AF.
Sodium Glucose Transporter-2 Inhibitors
SGLT2is have shown remarkable outcomes irrespective of diabetes status in HFrEF treatment providing significant LV structural, morbidity, and mortality benefits.68 A recent meta-analysis of the DAPA-HF trial (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction) and EMPEROR-Reduced trial (Cardiovascular and Renal Outcomes With Empagliflozin in Heart Failure) showed 25% reduction in composite outcome of rehospitalization from HF or cardiovascular death and 13% reduction in all-cause mortality.68 Importantly, LVR indices including LVEF, LV mass index, LVEDV index, and LA volume index in HFrEF have also been shown to improve in patients treated with SGLT2i.69 No reports yet on SGLT2i effect on FMR are available; however, a rat model–based study evaluating the benefit of dapagliflozin in MR-induced myocardial dysfunction showed significant attenuation of cardiac fibrosis and endoplasmic reticulum stress, with improved hemodynamics evidenced by partial restoration of LVEF and end systolic pressure-volume relationship providing evidence for a possible role of SGLT2i on MR-induced HF.70 The results of the EFFORT clinical trial evaluating the role of ertugliflozin in treatment of FMR are expected in 2022.71 The above studies list a potential therapeutic benefit of SGLT-2 inhibitors for FMR. In the MITRA-FR and COAPT trials, SGLT2is were not part of the GDMT before intervention. Further studies analyzing outcomes of transcatheter edge-to-edge repair after inclusion of SGLT-2 inhibitors in GDMT preintervention could help address this question.31,32
Mineralocorticoid Receptor Antagonist
There is strong evidence for a positive role of MRAs on LVRR as evidenced by improvement of LVEF, LVESV, LVESV index, LVEDV, and LV mass index (LVMI).72–76 Recent evidence shows concurrent use of MRA with ARNI to be associated with further LVR indices including increase in LVEF, reduced EDV, and NT-proBNP (N-terminal pro-B-type natriuretic peptide).47 The augmented effects are attributed to effects of MRA on aldosterone antagonism leading to antifibrosis, afterload reduction, and diuresis.47,75 MRAs are also associated with decreased markers of collagen turnover signifying their role in decreasing wall stress.72–74,76,77 In HFpEF, there seem to be beneficial effects on HF hospitalization and possibly cardiovascular death, with a clearer response in women and patients with resistant hypertension.78–80 However, MRA effects of LVRR and specifically atrial FMR in patients with HFpEF or atrial fibrillation are not well described.
Role of Other GDMT Agents
V-HeFT I and A-HEFT (African American Heart Failure Trial) showed that addition of a fixed-dose combination of isosorbide dinitrate plus hydralazine to standard therapy for HF increases survival among Black patients with advanced HF.81,82 Further, a substudy of A-HEFT trial showed improvement in LVEF, LV end diastolic diameter, LV mass, and sphericity indices in patients receiving fixed-dose combination of isosorbide dinitrate plus hydralazine versus placebo.83 Levine et al44 showed a 42% reduction of FMR grade at 1-year follow-up associated with reduction in LV end diastolic diameter with uptitration of lisinopril-isosorbide dinitrate combination. In the SHIFT trial (Sub-Studies of the Ivabradine and Outcomes in Chronic Heart Failure), the selective sinus node inhibitor ivabradine reduced HF hospitalization and cardiovascular death in patients with HFrEF and heart rate >70 beats per minute.34 SHIFT and BEAUTIFUL (Randomized Trial of Ivabradine in Patients With Stable Coronary Artery Disease and Left Ventricular Systolic Dysfunction) demonstrated significant reduction in LVRR parameters of LVESV index, LVEDV index, LVEDV, and LVESV with improvement in LVEF. Greater decreases in heart rate were associated with further improvement in LVEF without a statistically significant effect on FMR.42,84 However, fixed-dose combination of isosorbide dinitrate plus hydralazine and ivabradine effects of LVRR and atrial FMR are not well described. The soluble guanylate cyclase stimulator vericiguat decreased the combined end point of HF hospitalization or cardiovascular death in patients with LVEF <45%; no clear influence on LVR or MR severity except a small increase in LVEF was observed to date.85,86
Cardiac Resynchronization Therapy
CRT is indicated for persistently symptomatic HFrEF patients despite GDMT with QRS >150 ms or QRS >130 ms with left bundle branch block morphology. Predictors for clinical and echocardiographic favorable response include left bundle branch block pattern, female sex, and non-ischemic cardiomyopathy.87–92 Nasser et al28 reported that the presence of left bundle branch block makes FMR less responsive to medical therapy, probably due to electromechanical dyssynchrony rather than loading conditions driving MR severity. Studies have shown up to 50% reduction in FMR on long-term (>6 months) follow-up with CRT therapy in both ischemic cardiomyopathy and non-ischemic cardiomyopathy.2,93 The MADIT-CRT trial (Cardiac Resynchronization Therapy for the Prevention of Heart Failure Events) and REVERSE trial (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) showed significant LVRR post-CRT implantation over a 12-month follow-up.94 Several large clinical trials and observational studies demonstrated improvements in quantitative markers of FMR severity as indicated by significant differences in jet area,95,96 EROA,93,97 vena contracta,97 and rVol.93 CRT effects are 2-fold. Acute reduction in FMR results from immediate synchronized contraction of PM bearing ventricular segments resulting in diminished tethering forces.1,93,98 Verheart et al98 demonstrated reduction in MR severity as assessed by vena contracta (vena contracta decrease, 0.8 mm; P≤0.0001), which was seen as early as 3 days, persisted at follow-up, and plays a prognostic role in LVRR. Long-term effects are achieved by means of minimizing global and local LV dyssynchrony, thereby improving LV dilation and sphericity, impacting mitral closing and tethering forces. Additionally, by causing atrioventricular synchrony, diastolic MR is mitigated.1 Whether baseline FMR grade impacts the response to CRT is controversial.98,99,93,100 However, there is clear prognostic implication of MR severity post-CRT pacing on survival, arrhythmic events, and future LVRR.93,97,101
In the CARE-HF trial (Cardiac Resynchronization in Heart Failure), CRT did not reduce AF incidence but did improve outcomes regardless of whether AF developed.102 Guarav et al103 found that in HFrEF patients with AF, CRT pacing improved LVEF similarly to patients in sinus rhythm but with lower functional improvement. For patients with AF, MR improvement with CRT was less common compared with those in sinus rhythm, despite similar LVRR with CRT, possibly due to significantly greater LA and annular volumes in the former.104 Atrial FMR response to CRT in patients with preserved EF is not well studied.
Adjunct Strategies in FMR
Emphasis must be laid to appropriately manage concurrent conditions in the setting of HF such as volume overload with diuretics, diabetes (SGLT2i), hypertension in accordance with GDMT for hypertension, encourage smoking cessation, restrict dietary sodium intake, and promote weight loss along with treatment of obstructive sleep apnea.6 Although current guidelines do not differentiate between treatment of atrial and ventricular FMR, certain strategies including restoration of sinus rhythm and surgical annuloplasty, often in conjunction with AF ablation (when EF is ≥50%), have proven beneficial in atrial FMR; however, evidence is still limited. Restoring and maintaining sinus rhythm can reduce LA volume and annular size, with significant reduction of FMR severity, irrespective of the presence of LV systolic dysfunction.105–107 Wu et al106 described utility of AF ablation in patients with and without LVSD, wherein longer duration of AF was associated with worse outcomes after ablation and freedom from recurrence was associated with improvement in MR severity. However, patient selection is important, as markedly enlarged LA limits catheter ablation success, for both sinus rhythm restoration and LA reverse remodeling with FMR diminution.108
Recognizing Failure of GDMT
While GDMT is the necessary first step, percutaneous or surgical anatomic repair of leaflets is warranted in a curated patient population with FMR refractory to medical therapy. Studies report a mortality of around 50% for patients with severe FMR treated with GDMT alone over long-term (>3 years) follow-up.109,110 Nasser et al28 reported progression to severe FMR from nonsevere FMR in 18% despite optimal GDMT, with sustained or worsening FMR grade—an independent prognosticator of adverse LVR and worse outcomes. Advanced age, renal insufficiency, atrial fibrillation, and functional status (New York Heart Association class III–IV) were independent predictors of all-cause death and HF hospitalization as reported by Agricola et al.109 Among CRT recipients, MR nonresponders had higher baseline tenting area, LVESV, and LVEDV.93,111 However, the optimal timing for percutaneous or surgical interventions for FMR is yet to be elucidated. Current valvular guidelines recommend transcatheter MV repair in persistently symptomatic (New York Heart Association class II–IV) stage D HF patients with severe FMR on optimized GDMT with appropriate anatomy as defined with LVEF between 20% and 50%, LVESD <70 mm, and pulmonary artery systolic pressure <70 mm Hg; surgical correction is only advised for patients with stage C or D HF undergoing concomitant coronary artery bypass grafting.19
Identifying patients in whom the pathology is primarily driven by valvular dysfunction over global adverse LVR is key for selecting patients who will potentially benefit from valvular correction.22,112,113 The prognostic significance of FMR diminishes in advanced HFrEF or in long-term follow-up wherein the severity of LVR and dysfunction dictates the clinical course.9,15,16 Several factors partake in this vital clinical distinction, namely functional class, LVEF, LVEDV, systolic blood pressures, EROA, and MR fraction. As suggested by Grayburn et al,22 hemodynamically insignificant FMR (EROA ≥0.2 cm2) occurring as a function of a severely remodeled LV with an elevated LVEDV (>220 mL or 120 mL/m2), proportionate to the degree of adverse LVR, is expected and is less likely to respond to valvular manipulation. Conversely, in a symptomatic patient despite optimal medical treatment, when clinical course is driven by FMR severity, in the setting of minimal LVR (ie, disproportionate FMR), valvular intervention is warranted.22
The results of the COAPT and MITRA-FR trials provide further insight into this highly debated postulation wherein patients with disproportionately severe FMR in the COAPT trial derived cardiovascular and mortality benefit from transcatheter edge-to-edge repair, as confirmed by lack of benefit even on long-term follow-up in the MITRA-FR trial.114 Key parametric differences included stricter inclusion criteria in the COAPT trial with regard to FMR severity (EROA >30 mm2; rVol >45 mL) and lesser adverse LVR indicated by LVESD ≤70 mm and LVEF 20% to 50%. Subsequent observational studies demonstrated similar results in a COAPT-like patient profile substantiating the above findings,24,25 but the theory was challenged in a subanalysis of MITRA-FR showing no benefit of transcatheter edge-to-edge repair in patients with an EROA/LVEDV ratio >0.15, possibly emphasizing utility of GDMT optimization.115 This discrepancy can also be explained by methodological limitations in accurate measurement and reproducibility of the semiquantitative echocardiographic parameters used for MR severity in the trials.116 Further, utilization of rVol/LVEDV ratio could potentially offset the limitations in EROA estimation.117 Coexisting TR occurring as a consequence of pulmonary hypertension with or without right ventricular (RV) dilation/dysfunction further impacts patient selection for transcatheter edge-to-edge repair. The COAPT trial excluded patients with moderate or severe RV dysfunction and systolic pulmonary pressure ≥70 mm Hg. Karam et al118 showed that RV dysfunction as evaluated by RV-PA uncoupling (tricuspid annular plane systolic excursion to systolic pulmonary pressure ratio, <0.274 mm/mm Hg) was a strong predictor of mortality. These findings were supported in a subsequent subanalysis of the COAPT trial with similar conclusions.119 Thus, a wholistic approach in the evaluation of patients suitable for valvular interventions with a team is vital for optimal outcomes. A helpful guide might be remembering that a typical ventricular FMR responsive patient to transcatheter MV repair would often have a rVol of 50%, LVEF of ≈30%, LVEDV of ≈220 to 250 mL, and consequently EROA of ≈0.4 cm with preserved RV-PA coupling.
Conclusions and Future Implications
GDMT optimization must be prioritized in all patients with FMR in an attempt to achieve target doses as attained in clinical trials19,120 (Figure 2). In HFrEF patients with ventricular FMR, it consists of RAASi preferentially ARNI, BBs with most evidence available for carvedilol, MRA with clearer evidence for spironolactone, SGLT2i, and when appropriate consideration of ivabradine, hydralazine, and vericiguat. CRT is an important aspect of therapy with strong evidence for its use when indicated, especially for patients in sinus rhythm. For patients with ischemic MR and HFpEF, consideration for revascularization and coronary artery disease medical treatment are appropriate. Patients with HFmrEF and ventricular FMR seem to derive benefit from similar regimen as GDMT for HFrEF, with most evidence for BBs, ARNI/ARB, and MRA. For patients with atrial MR and AF, restoration of sinus rhythm when feasible is advised, as well as RAASi therapy when concurrent indications exist. For patients with HFpEF and either atrial or ventricular FMR, evidence for SGLT2i, MRA, and ARNI/ARB seems promising through their effect on LVRR. These agents appear most important in subgroups that potentially derive the most benefit, namely LVEF <60% and women for ARNI. Patients who are refractory to GDMT or those developing recurrent severe symptomatic FMR should be evaluated for interventional therapy, keeping in mind that intervention should be done before LVR has progressed too far and when FMR is indeed the driver of symptoms, rather than LV dysfunction. Further research to identify demographic, clinical, RV, and LV functional parameters prognosticating FMR among patients solely receiving GDMT is indicated to select and risk stratify for different therapeutic interventions.
Article Information
Sources of Funding
None.
Supplemental Material
Table S1
| ACE | angiotensin-converting enzyme |
| AF | atrial fibrillation/flutter |
| ARB | angiotensin receptor blocker |
| ARNI | angiotensin neprilysin inhibitor |
| BB | beta blocker |
| CARE-HF | Cardiac Resynchronization in Heart Failure |
| COAPT | Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation |
| CRT | cardiac resynchronization therapy |
| EF | ejection fraction |
| EROA | effective regurgitant orifice area |
| FMR | functional mitral regurgitation |
| GDMT | guideline-directed medical therapy |
| HF | heart failure |
| HFpEF | heart failure with preserved ejection fraction |
| HFrEF | heart failure with reduced ejection fraction |
| LA | left atrium |
| LV | left ventricle |
| LVEDV | left ventricular end diastolic volume |
| LVEF | left ventricular ejection fraction |
| LVESV | left ventricular end systolic volume |
| LVR | left ventricular remodeling |
| LVRR | left ventricular reverse remodeling |
| MRA | mineralocorticoid receptor antagonist |
| MV | mitral valve |
| NT-proBNP | N-terminal pro-B-type natriuretic peptide |
| RAASi | renin-angiotensin-aldosterone system inhibitor |
| RV | right ventricle |
| rVol | regurgitant volume |
| SGLT2i | sodium glucose transport 2 inhibitor |
| V-HeFT | Valsartan in Heart Failure Trial |
Disclosures None.
Footnotes
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