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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018 AFRICA 57
Beta-blockade therapy for chronic primary MR
At present there is no proven medical therapy for chronic
primary MR. Surgery is the mainstay of treatment for severe
MR1 but carries peri-operative risk, and patients are potentially
subjected to a life-time risk of anticoagulation if they undergo
mitral valve replacement. Many patients in the developing world
are from poor and rural backgrounds where access to regular
medication and regular anti-coagulation assessment is difficult.
A medication that could limit or even reverse left ventricular
dysfunction associated with the volume-loaded state of chronic
severe MR would be extremely beneficial to these patients, even
if only to delay the need for surgical intervention. This would
especially be true in women of child-bearing age. Warfarin
is teratogenic and many women with prosthetic valves have
complicated pregnancies related to the teratogenic effects of
warfarin or the risks related to bleeding during pregnancy.
Persistent, and often worsened, postoperative left ventricular
dysfunction is a major cause of morbidity and mortality in these
patients,133 although this is not a universal finding, especially
when patients are referred for early surgery.181-183 Nevertheless, a
means to improve left ventricular function in the peri-operative
period might improve the postoperative morbidity and mortality
rates associated with left ventricular dysfunction.
Current guidelines1,184 recommend surgery for patients with
severe pulmonary hypertension on presentation or a progressively
dilating LV, even if they are asymptomatic. However, timing of
surgery is uncertain185,186 and there is no clear guideline as to the
urgency of the surgery in asymptomatic patients without overt
left ventricular systolic dysfunction (LVEF < 60%). Several
studies support early surgery for chronic primary MR.187-189
Enriquez-Sarano et al.12 showed that patients with an effective
regurgitant orifice area of at least 40 mm2, as assessed by
echocardiography, should promptly be considered for cardiac
surgery. Barbieri et al.190 found that asymptomatic patients with
evidence of pulmonary hypertension (> 50 mmHg at rest) should
undergo prompt surgery. However, there is also evidence that
asymptomatic patients with severe MR can be followed until
they become symptomatic or demonstrate echocardiographic
signs of left ventricular dysfunction.132,191
How these patients should be managed in the interim is
unclear but it is important that patients are not left untreated
until irreversible left ventricular remodelling has taken place. In
resource-limited hospitals, patients who do not need emergency
surgery often wait several months before they undergo surgery,
by which time there has been progressive advancement of
ventricular remodelling, leading to permanent impairment of
function. Medical therapy that could reverse or at least attenuate
LV remodelling may improve outcomes in these patients.
To date, there is little evidence to support medical therapy in
the treatment of patients with organic valve disease,1,119,192 or in
the reversal or attenuation of LV remodelling, which may delay
the need for surgery in asymptomatic patients.193 Vasodilator
therapy, which reduces peripheral vascular resistance and left
ventricular afterload,119 has generally not improved outcomes in
patients with MR or in experimental MR canine models.15,122,145,194
Although several small studies from the 1970s to the 1990s
showed benefit of vasodilator therapy in acute MR,144 small
human studies from the same period failed to show long-term
benefit.195 One retrospective study, however, demonstrated an
improvement in echocardiographic LVEF in patients treated
with afterload-reducing agents.146 However, there are no large
randomised studies assessing long-term vasodilator therapy,
including ACE inhibitors, in humans.
There is some clinical evidence to support the concept that
β-AR blockade may attenuate remodelling in patients with
primary MR (Table 1). Stewart et al.196 recruited 25 patients with
moderate or severe degenerative MR and randomly assigned
the participants to the β1-AR blocker metoprolol, or placebo
for approximately two weeks. Left ventricular function was
assessed at baseline and on study completion by cardiac magnetic
resonance imaging. They found that the β 1-AR blocker resulted
in a decrease in left ventricular work and an increase in forward
stroke volume.196 Mitral annular dimensions also appeared to
improve over the two-week period in the same cohort of patients.197
A retrospective observational study involving 895 patients in
California showed that participants on β1-AR blocker therapy
with severe MR and normal left ventricular function had a
significantly lowered mortality hazard, regardless of the presence
of hypertension or coronary artery disease.198 Ahmed et al. 199
published the results of the first randomised, controlled phase
IIb trial of beta-blockade in patients with chronic degenerative
MR. Thirty-eight asymptomatic patients with moderate-to-
severe isolated MR were randomised to either placebo or long-
acting metoprolol for two years. Cardiac magnetic resonance
analysis showed that patients randomised to the β-AR blocker
had significantly better LVEFs after two years of therapy.
By contrast, there are several pre-clinical and clinical studies
demonstrating that beta-blocker therapy actually worsens left
ventricular dimensions and function in chronic primary MR
(Table 1).108,146,197,200,201 A recent, longer-term (23 to 35 weeks) study
in rats found that echocardiographic measures of left ventricular
remodelling were not improved by carvedilol.201 In fact, left
ventricular dimensions, ejection fraction and survival were
significantly lower with long-term carvedilol use.
Similarly, in a four-month dog model, extended-release
metoprolol succinate failed to attenuate the adverse global
left ventricular remodelling and ECM loss, but did preserve
cardiomyocyte function.200 Interestingly, all dogs treated with
β-1-receptor blocker (n = 6) survived to four months, whereas
only five out of nine of the untreated dogs survived to four
months. Similarly, Sabri et al.108 found that, despite reductions
in interstitial collagen degradation and reductions in adverse
remodelling-related intracellular signalling, extended-release
metoprolol succinate failed to attenuate left ventricular dilatation
or decline in left ventricular function.
A retrospective echocardiographic study in 134 human
subjects with moderate-to-severe MR (67% degenerative and
20% ‘non-specific thickening’) found that patients exposed to
beta-adrenergic blockade developed worsening of their ejection
fraction over a mean of 20 months of follow up.146 Finally, despite
improvements in left ventricular work and annular dimensions,197
in patients treated over a short period with metoprolol, there
were significant increases in left ventricular end-systolic and
end-diastolic volume with no significant change in LVEF or
regurgitant volume. 196
At the present time, there are no recommendations regarding
medical therapy in chronic primary MR. Afterload reduction
has not consistently been shown to improve long-term
outcomes.15,122,145,146,195 Data from heart failure trials158,169,170 as well
as from animal models90 and human trials199 suggest a role for