Evaluation of Secondary MR

Secondary MR can be divided into four clinical groups that help define clinical prognosis and can assist in guiding therapy: (1) At risk of secondary MR; (2) Progressive secondary MR; (3) Asymptomatic severe secondary MR; and (4) Symptomatic severe secondary MR [14]. Diagnostic evaluation of MR is performed by echocardiography (both transesophageal and transthoracic), magnetic resonance imaging (MRI), or LV angiography. Transesophageal echocardiography and MRI most often accurately identify the underlying cause and mechanism of MR. All 3 methods allow estimation of LV volume, function, and sphericity; pulmonary artery pressure; right ventricular function; and tricuspid regurgitation.

The echocardiographic or angiographic severity of MR is classified as mild, moderate, or severe [15]. Qualitative findings include MV morphology and the color-flow and continuous-wave signals of the MR jet. Semiquantitative measures are the effective regurgitant orifice area (EROA), regurgitant volume, and regurgitant fraction [1]. Enlarged LA and LV chamber size and increased pulmonary artery pressure support the diagnosis of severe MR.

Conventional 2-dimensional (2D) assessment for MR quantification relies on measuring the MR jet core at its vena contracta. Therefore, MR severity can be significantly underestimated when the orifice is elliptical (which is common in secondary MR) [4], a problem that is compounded if multiple jets are present. Three-dimensional (3D) echocardiography overcomes this limitation by permitting direct planimetry of the vena contracta, regardless of orifice shape or the number of jets [16]. Conversely, both 2D and 3D color flow Doppler tend to overestimate the orifice area because they cannot resolve the high velocity jet core because of aliasing and blooming artifacts. Secondary MR severity also varies during the cardiac cycle and can peak in early or late systole. This further complicates the evaluation, which is traditionally done in midsystole. No single variable is sufficient to quantify the degree of MR, so multimodality assessment with both 2D and 3D echocardiography is optimal [17].

Exercise echocardiography is sometimes useful when symptoms appear disproportionate to resting MR severity [20]. Exercise results in greater preload and afterload, a more spherical ventricle, increased coaptation distance, and systolic expansion of the mitral annulus. Such changes can occur in the absence of ischemia [21] and increase the patient’s risk of acute pulmonary edema [22]. Patients with exercise-induced severe MR may be at heightened risk for death or HF hospitalization [23]. Quantitatively, an exercise-induced EROA increase of ≥13 mm² is associated with elevated morbidity and mortality rates. Exercise echocardiography can also reveal increased pulmonary artery pressure and reduced LVEF, both of which are associated with LV dysfunction and poor prognosis after MV surgery [24, 25]. Exercise can also induce greater LV dyssynchrony with increased MR. However, the predictive value of exercise echocardiography is imperfect, given the technical issues of measuring key variables either during or immediately after exercise.

Echocardiography is also useful for determining the likelihood of successful MV repair by either surgical or transcatheter procedures (e.g., MitraClip placement ) [26]. In a group of 300 patients with severe MR who underwent MitraClip implantation (68% of whom had secondary MR), the procedure failed to reduce MR to ≤2+ in 31 patients (10.3%). By multivariable analysis, predictors of failed MitraClip placement included greater EROA (odds ratio [OR]: 1.21 per 10 mm² increase, p = 0.005) and a baseline transmitral pressure gradient ≥4 mm² (OR: 1.26, p = 0.03). Success rates were similar in patients with primary and secondary MR [27].

Cardiac magnetic resonance (CMR) imaging and multidetector row computed tomography (MDCT) can provide complementary information to echocardiography in patients with MR. CMR can accurately quantify the degree of MR [28]. Given its high spatial resolution, MDCT can accurately depict MV morphology [29]. Both techniques can be used to make volumetric measurements of chamber dimensions, evaluate ventricular function, and assess myocardial fibrosis.

Therapy for Secondary MR

The goals of therapy for secondary MR are to relieve symptoms, improve quality of life, reduce HF hospitalizations, and potentially improve patient survival. Often, therapy is directed at the underlying LV dysfunction; these treatments include guideline-directed medical therapy for HF and biventricular cardiac resynchronization therapy (CRT) when appropriate. Coronary revascularization may also help patients with extensive ischemia and preserved myocardial viability, although it rarely markedly reduces or eliminates secondary MR. Regarding surgical and transcatheter MV repair, it is unclear how well these interventions interrupt the progressive cycle of LV volume overload → LV dilation → secondary MR → increasing LV volume overload and dilation → increasing MR.

Carvedilol or metoprolol , combined with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers, is sometimes helpful for patients with LV dysfunction and secondary MR. By reducing LV remodeling, maximal guideline-directed medical therapy sometimes reduces MR in severe cases. However, few studies have examined the effect of medical therapies on secondary MR. In a randomized trial that involved 59 patients with HF and severe dilated cardiomyopathy, treatment with carvedilol versus placebo resulted in reduced LV mass sphericity and improved systolic function. The severity of MR, assessed by the ratio of MR jet area/LA area, increased during follow-up in the placebo group but decreased in the carvedilol group (p = 0.04) [30]. In the largest randomized trial, among 138 patients with dilated cardiomyopathy who were taking stable doses of digoxin, diuretic agents, and ACEI, metoprolol (titrated to 50 mg, 3 times a day) produced greater 6-month reductions in LV end-diastolic and end-systolic volumes and secondary MR than did placebo [31]. However, MR improved in only ~42% of metoprolol-treated patients (vs. 20% of control-group patients), and there were no significant differences in symptoms or in rates of cardiac readmission or death during follow-up.

There is limited information about whether ACEIs and other agents reduce secondary MR. In a small study of 19 patients with severe dilated cardiomyopathy (mean LVEF ~20%) and 3+/4+ MR who were taking stable doses of digoxin and diuretic agents, the mean lisinopril dose was up-titrated from 16 to 55 mg/day, and isosorbide from 30 to 286 mg/day. At 12-month follow-up, MR had decreased to grade 0/1+ in 8 patients (42%) and remained 3+/4+ in the other 11. LVEF improved in both groups but to a greater degree in the MR responders, and the LV end-diastolic dimensions decreased in the responders but increased in the non-responders [32].

CRT

CRT is a recommended treatment for selected HF patients with LV dyssynchrony. CRT is a Class I recommendation for patients in sinus rhythm with New York Heart Association (NYHA) functional class II to IV symptoms, LVEF ≤35%, left bundle branch block (LBBB), and QRS duration ≥150 ms despite receiving guideline-directed medical therapy. CRT may also be useful in patients with LVEF ≤35%, sinus rhythm, non-LBBB pattern, and QRS duration ≥150 ms, and in those with LBBB and QRS duration 120–149 ms (Class IIa indications) [33, 34]. Randomized trials of CRT with or without a defibrillator have shown that it improves both survival and HF rehospitalization rates [35], reduces LV end-diastolic and end-systolic dimensions, and increases LVEF.

The effect of CRT on secondary MR is inconsistent, although most studies show that overall MR severity decreases with restoration of synchronous ventricular contraction and LV remodeling. In the sham-controlled MIRACLE (Multicenter InSync Randomized Clinical Evaluation) trial involving 450 NYHA functional class III/IV HF patients with LVEF ≤35% and QRS duration ≥130 ms, CRT resulted in reductions in LV end-diastolic and end-systolic volumes, improved LVEF, and sustained reductions in MR (assessed by the relative size of the mitral jet area in the LA) [36]. In a study of 63 patients with HF and moderate to severe MR, MR improved by ≥1 grade in 43% of patients, and an additional 20% had late improvement at 6 months [34]. Improvement of severe secondary MR is associated with better prognosis, but this improvement occurs in no more than one-half of patients after CRT [33].

Mechanical Therapy

Surgical options

As noted, secondary MR is so named because it is secondary to disease of the LV not of the valve itself. Heart failure associated with secondary MR has a worse prognosis than heart failure without MR [37, 38]. However it was unclear whether the presence of MR was merely a marker of LV dysfunction or was itself contributing to the pathology of heart failure and thus a target for therapy. Indeed surgical approaches to secondary MR have failed to demonstrate improved survival over medical therapy although some reported improved symptoms [39–43]. Recently 2 large randomized trials of the MitraClip (Fig. 7.3) have helped clarify the issue. MitraClip is a percutaneously inserted device that clips the mitral leaflets together at their midbellies, creating a figure of 8 orifice, reducing MR. In the Mitra-FR trial [44] patients with moderate to severe MR and severe LV dilitaiton were randomized to standard therapy versus standard therapy + the MitraClip. The MitraClip caused no reduction in repeated hospitlalizations or mortality. In the COAPT trial [45] patients with severe MR and modest LV dilitation who were still symptomatic after very aggressive medical therapy were randomized to receive aggressive medical therapy versus agressive medical therapy + the MitaClip. The results were virtually opposite to those of Mitra FR. The clip reduced both rehospitalizations and mortality. Only 3 patients needed to be treated to avoid 1 rehoapitalization and only 6 needed to be treated to avoid 1 death. The results of the 2 trials are in fact complementary. They indicate that patients with very severe MR and only modest LV dilitaiton who are symptomatic despite aggressive medical therapy benefit from the clip whereas patients with less severe MR yet more LV dysfucntion fail to benefit. Thus in this group of patients MR is not only a marker of LV dysfucntion but also contibutes to the pathology of the disease and thus is a target for therapy. In patients with less severe MR, the MR is not a target. On this basis there is now FDA approval for the use of MitraClip for the treatment of severe symptomatic secondary MR.

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