Author + information
- Received February 23, 2019
- Accepted March 8, 2019
- Published online May 27, 2019.
- aDivision of Cardiology, Department of Internal Medicine and the Baylor Scott and White Heart and Vascular Hospital, Baylor University Medical Center, Dallas, Texas
- bImperial College, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Scott and White Heart and Vascular Hospital, 621 N. Hall Street, Dallas, Texas 75226.
Functional mitral regurgitation (MR) is present to varying degrees in most patients with chronic heart failure (HF) and left ventricular (LV) systolic dysfunction, and in ∼30% its magnitude is hemodynamically meaningful. A critical determinant of MR in these patients is the degree of LV dilatation. Remodeling and enlargement of the LV leads to displacement of the papillary muscles and widening and flattening of the mitral annulus, which (together with a reduction in closing forces) impairs the coaptation of the mitral valve (MV) leaflets.
However, independent of LV end-diastolic volume (LVEDV), ventricular dyssynchrony contributes importantly to functional MR. In patients with meaningful QRS prolongation, dyssynchrony causes unequal contraction of papillary muscle bearing walls, preventing coordinated closure of the MV leaflets; amelioration of the conduction delay by cardiac resynchronization reduces MR. Additionally, irrespective of the presence of electric conduction delay, localized LV remodeling can cause apical and posterior displacement of the papillary muscles and dyssynchronous contraction of the leaflet-supporting structures independent of global LV dysfunction (Online Appendix).
These observations suggest that patients with functional MR and HF include the following: 1) those whose MR can be entirely explained by the MV distortions produced by LV enlargement; and 2) those who had regional LV dysfunction inordinately interferes with the synchronous contraction of the papillary muscle segments that support normal MV coaptation. We refer to the first group as having MR that is “proportionate” to LV enlargement and the second group as having MR that is “disproportionate” to LVEDV (i.e., the severity of MR is greater than predicted by LV volumes) (1).
Characterization of Proportionate and Disproportionate MR
According to the Gorlin hydraulic formula, there is a linear relationship between the effective regurgitant orifice area (EROA) and LVEDV, such that increasing degrees of MR are expected as the LV dilates. Therefore, in patients with LV systolic dysfunction, values for EROA cannot be interpreted in isolation, but must be considered in the context of the LVEDV (1). An EROA of 0.2 cm2 is expected when the LVEDV is >200 ml, and when the LV ejection fraction is 30% an EROA of 0.4 cm2 can be explained solely by LV enlargement if the LVEDV is >250 ml. These patients have proportionate MR. In contrast, if the EROA is 0.4 cm2 but the LVEDV is <200 ml, the severity of MR cannot be explained by the LVEDV (i.e., the patient has disproportionate MR) (Figure 1).
Effect of Drug Therapy for HF on Functional MR
Neurohormonal antagonists that are prescribed to reduce morbidity and mortality in patients with chronic HF lead to a decrease in LVEDV, which can be expected to reduce MR if the degree of MR is proportionate to the LVEDV. Angiotensin-converting enzyme inhibitors and receptor blockers decrease the magnitude of MR, typically in those with mild-to-moderate MR. This benefit often required high doses of these agents, and higher doses were often specifically prescribed to patients who had greater pretreatment LVEDV. Furthermore, in a double-blind randomized trial, adding a neprilysin inhibitor to an angiotensin receptor blocker led to a reduction in MR in patients with mild-to-moderate MR and a LVEDV >200 ml. In the only study of patients with HF and severe MR, who received lisinopril and isosorbide dinitrate (target doses of 80 mg and 480 mg daily, respectively), ∼40% showed improvement of MR from 3–4+ to 0–1+ after 12 months (Online Appendix).
Similarly, beta-blockers are effective in ameliorating functional MR in patients with an ischemic or nonischemic cardiomyopathy. In a double-blind placebo-controlled trial of 165 patients with HF, reduced ejection fraction, and LVEDV ∼200 ml, metoprolol (150 mg daily for 6 months) decreased LVEDV and reduced the severity of functional MR; >40% of treated patients (vs. <20% of the control group) showed meaningful decreases in MR, whereas <5% of treated (vs. 15% of the control) patients experienced worsening MR. In a second trial, metoprolol reduced LV end-diastolic dimensions from 73 to 64 mm and decreased the MR grade from nearly 2+ to 0–1+. In a double-blind placebo-controlled trial, carvedilol (50 mg daily) improved LV geometry and reduced the severity of MR by 50%; the benefits emerged after 4 months and were maintained for 1 year. In 257 patients with chronic HF and LV dysfunction, carvedilol reduced LVEDV and the severity of MR for up to 2 years; 30% had meaningful decreases in EROA. These effects were most marked in patients with the greatest pretreatment LV dilatation (i.e., LV end-diastolic dimension >37 mm/m2), corresponding to a LVEDV of ∼250 ml. Similarly, 80% of patients with chronic HF, LVEDV of 230 ml, and 2+ regurgitation experienced improvement in MR with carvedilol after 1 year. In the only study of beta-blockade that focused on severe MR, which enrolled 45 patients with HF and striking LV enlargement (LV end-diastolic dimension ∼75 mm and EROA ∼0.6 cm2), carvedilol reduced EROA by 80% after 6 months (Online Appendix).
Nasser et al. (2) evaluated the effect of maximally tolerated doses of neurohormonal antagonists in 163 patients with HF and a reduced ejection fraction who were treated for ≥4 years; ∼30% to 35% had severe MR (3+ or 4+) at baseline. During follow-up, ∼40% of those with severe MR experienced a sufficient decrease in regurgitant flow such that they were considered to have non-severe MR. Importantly, the absence of left bundle branch block was the primary predictor of a favorable response to drug therapy; those with marked QRS prolongation often showed worsening MR despite medical management (2). Because intraventricular conduction delay characterizes patients with disproportionate MR, these observations suggest that neurohormonal antagonists yield the greatest benefits in those with proportionate MR. Conversely, because disproportionate MR is not primarily determined by LV dilatation, it does not respond well to agents that act primarily through a reduction in LV chamber size.
Effect of Transcatheter MV Repair in Systolic HF
In patients with disproportionate MR, treatment might best be directed toward amelioration of dyssynchrony (e.g., with cardiac resynchronization therapy when the QRS duration is meaningfully prolonged) or to the MV itself (using transcatheter techniques to achieve MV leaflet approximation).
Two randomized trials have reported the effects of transcatheter MV repair in patients who had severe functional MR, HF, and reduced ejection fraction (3,4). Both trials randomly assigned participants to the procedure or to a control group that received only medical therapy. In the 307 patients enrolled in the MITRA-FR (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation) trial (3), MV repair did not reduce the combined risk of death or hospitalization for HF. In contrast, in the 614 patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial (4), MV repair decreased all-cause mortality as well as the combined risk of death or hospitalization for HF. These benefits were apparent as early as 2 months following randomization.
The trials enrolled 2 distinctly different groups of patients (Table 1). The MITRA-FR study allowed the participation of patients with an EROA of 0.2 cm2 as well as patients with marked LV dilatation, whereas both types of patients were excluded in COAPT. Consequently, prior to randomization, the average patient in MITRA-FR had an LVEDV of 252 ml and an EROA of 0.31 cm2. More than 50% had an EROA <0.3 cm2, and only 16% had an EROA of ≥0.4 cm2. In contrast, at baseline, the average patient in COAPT had a LVEDV of only 192 ml, but had an EROA of 0.41 cm2. Only 14% had an EROA of <0.3 cm2, but 41% had an EROA of ≥0.4 cm2 (Table 1). When the patients in COAPT are compared with those in MITRA-FR, their EROA was ∼30% greater but their LV volumes were ∼30% smaller. Accordingly, the patients in COAPT had severe and disproportionate MR, whereas the patients in MITRA-FR had severe and proportionate MR or non-severe MR (Figure 1). The annual risk of death or hospitalization for HF was similar in the control groups in the 2 trials; these events were related to severe LV remodeling in the MITRA-FR trial but to functional MR in the COAPT trial.
Differences in LVEDV at baseline also influenced procedural success and risks (Table 1). In the COAPT trial, the proportion of patients with severe MR was 5% immediately post-procedure and remained at 5% after 1 year. In contrast, in the MITRA-FR trial, the proportion of patients with severe post-procedural MR was 9% and increased to 17% at 1 year. Procedural complications were reported in 14.6% of the MITRA-FR patients, but in only 8.5% of the patients in the COAPT trial. Therefore, it seems likely that marked LV dilatation might complicate the procedural placement of MV clips, and these clips may be less likely to maintain leaflet coaptation if the LV is markedly enlarged.
Importantly, transcatheter MV repair does not obviate the need for (and may facilitate the use of) intensive therapy with neurohormonal antagonists. Before the procedure, maximization of drug treatments may ameliorate the severity of proportionate MR; drug nonresponders are likely to have disproportionate MR, thus selecting for patients who preferentially benefit from transcatheter MV repair. Intriguingly, medical therapy may also play an important role after placement of MV clips. Following mechanical coaptation, systolic blood pressure often rises, allowing neurohormonal antagonists to be further up-titrated. In the COAPT trial, background therapy was intensified to a greater degree in patients who had the procedure, as compared with the control group. This intensification of neurohormonal antagonists may help to maintain reversal of LV remodeling, which may preserve the ability of the MV clips to keep regurgitant flow in check, thus explaining the low incidence of recurrent severe MR in the COAPT trial.
Of note, the COAPT trial was designed as a confirmatory study to evaluate a hypothesis generated from an earlier randomized trial (EVEREST II [Endovascular Valve Edge-to-Edge Repair Study]) that compared transcatheter MV repair with conventional surgery. In that trial, as compared with surgery, percutaneous clipping of the MV leaflets produced a similar reduction in the severity of MR and LV volumes, but with a lower risk of major adverse events (5). Post hoc analyses indicated that the responses in patients with functional MR and with degenerative MV disease were similar. Importantly, the entry criteria for EROA and LV volumes for EVEREST II were similar to those of the COAPT trial, and, thus, the patients with functional MR in EVEREST II had features of severe but disproportionate MR (Figure 1). Therefore, it is reasonable to view the findings of the COAPT trial as confirmatory.
In patients with HF and a reduced ejection fraction, functional MR is common, is typically not severe, and generally improves with neurohormonal antagonists. When functional MR is severe, the MR may be proportionate or disproportionate to LV volumes. Patients with severe and proportionate MR respond to intensification of drug therapy, whereas those with ventricular dyssynchrony and disproportionate MR benefit preferentially from transcatheter MV repair, which may allow for further intensification of drug treatment.
Dr. Packer has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Gilead, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. Grayburn has received research grant funding from Abbott Vascular, Edwards Lifesciences, Medtronic, and Boston Scientific; and consulting fees from Abbott Vascular, Edwards Lifesciences, Medtronic, and Neochord; and Echo Core Lab contracts from Edwards Lifesciences, Neochord, Cardiovalve, and W.L. Gore.
- Received February 23, 2019.
- Accepted March 8, 2019.
- 2019 American College of Cardiology Foundation
- Grayburn P.A.,
- Sannino A.,
- Packer M.
- Nasser R.,
- Van Assche L.,
- Vorlat A.,
- et al.
- Obadia J.F.,
- Messika-Zeitoun D.,
- Leurent G.,
- et al.
- Stone G.W.,
- Lindenfeld J.,
- Abraham W.T.,
- et al.
- Ailawadi G.,
- Lim D.S.,
- Mack M.J.,
- et al.,
- for the EVEREST II Investigators