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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018
AFRICA
59
that this drug caused worsening left ventricular dimensions
and function in animal subjects with primary MR. By contrast,
treatment of dogs with the selective beta-blocker atenolol
improved left ventricular remodelling,
90
whereas treatment
with metoprolol in animals and humans have had mixed
results.
108,180,196,197,199,200
Thirdly, an important question is whether patients presenting
in more advanced stages of left ventricular remodelling will
respond to anti-remodelling therapy or whether the wall stresses
determined by the Laplace law will outweigh any potential
beta-blocker effect. In this regard, the findings of Pat
et al
.
200
are interesting because although there were improvements in
cardiomyocyte contractility and beta-receptor responsiveness,
left ventricular remodelling was not attenuated by metoprolol. It
was postulated that
β
-AR blockade failed to preserve interstitial
collagen loss and therefore failed to prevent ongoing myocyte
slippage. There appears to be a strong early adrenergic response
to chronic primary MR,
56
and beta-blocker therapy before onset
of left ventricular dilatation may have more benefit.
Lastly, in patients with rheumatic mitral valve disease, there is
a possibility that rheumatic fever causing rheumatic carditis may
have long-lasting effects on the myocardium, attenuating reverse
remodelling by beta-blockers.
Conclusion
Left ventricular remodelling in response to the volume load
created by chronic primary MR is a complex process that stems
from excessive diastolic stretch of myocytes. Excessive stretch
triggers activation of numerous signal transduction pathways,
resulting in an initial adaptive remodelling process in the form
of eccentric hypertrophy. However, chronic activation of these
pathways results in abnormal increases in ROS, catecholamines,
angiotensin II and inflammatory cytokines. This is followed by
a transition to adverse remodelling involving cardiomyocyte
apoptosis and interstitial collagen loss, common to all forms of
heart failure.
Limited data do not support the routine long-term use of
afterload-reducing agents for the treatment of chronic primary
MR. By contrast, there is pre-clinical data demonstrating that
β
-AR blockade reverses remodelling caused by the volume
overload of chronic primary MR, and there are some recent
clinical data to support this hypothesis. However, some studies
demonstrated worsening left ventricular remodelling with beta-
blocker therapy. Whether these contrasting outcomes are related
to differences in beta-blockers, varying experimental models
or differences in timing of therapy will need clarification.
Ultimately, further studies are required to elucidate the exact
mechanisms involved, and large randomised clinical trials are
needed to clarify the role of these agents for patients with chronic
primary MR.
The authors thank Drs Eric Klug and Thomas Kalk for their valuable
comments, and Dr Lindsay McCutcheon for help with the artwork.
References
1.
Vahanian A, Alfieri O, Andreotti F,
et al
. Guidelines on the manage-
ment of valvular heart disease (version 2012): the Joint Task Force on
the Management of Valvular Heart Disease of the European Society of
Cardiology (ESC) and the European Association for Cardio-Thoracic
Surgery (EACTS).
Eur J Cardiothorac Surg
2012;
42
(4): S1–44.
2.
Ciarka A, van de Veire N. Secondary mitral regurgitation: pathophysiol-
ogy, diagnosis, and treatment.
Heart
2011;
97
(12): 1012–1023.
3.
Foster E. Clinical practice. Mitral regurgitation due to degenerative
mitral-valve disease.
N Engl J Med
2010;
363
(2): 156–165.
4.
Sliwa K, Mocumbi AO. Forgotten cardiovascular diseases in Africa.
Clin Res Cardiol
2010;
99
(2): 65–74.
5.
McMurray JJ, Adamopoulos S, Anker SD,
et al
. ESC guidelines for
the diagnosis and treatment of acute and chronic heart failure 2012:
The Task Force for the Diagnosis and Treatment of Acute and Chronic
Heart Failure 2012 of the European Society of Cardiology. Developed
in collaboration with the Heart Failure Association (HFA) of the ESC.
Eur Heart J
2012;
33
(14): 1787–1847.
6.
Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling:
mechanisms: part 1 of 2.
Circulation
2013;
128
(4): 388–400.
7.
Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac
fibrosis.
Cell Mol Life Sci
2014;
71
(4): 549–574.
8.
Otto CM, Prendergast B. Aortic-valve stenosis – from patients at risk to
severe valve obstruction.
N Engl J Med
2014;
371
(8): 744–756.
9.
Carabello BA, Crawford FA. Valvular heart disease.
New Engl J Med
1997;
337
(1): 32–41.
10. Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation.
Lancet
2009;
373
(9672): 1382–1394.
11. Avierinos JF, Gersh BJ, Melton LJ, 3rd,
et al
. Natural history of
asymptomatic mitral valve prolapse in the community.
Circulation
2002;
106
(11): 1355–1361.
12. Enriquez-SaranoM, Avierinos JF,Messika-ZeitounD,
et al
. Quantitative
determinants of the outcome of asymptomatic mitral regurgitation.
N
Engl J Med
2005;
352
(9): 875–883.
13. Ross J Jr, Sonnenblick EH, Taylor RR, Spotnitz HM, Covell JW.
Diastolic geometry and sarcomere lengths in the chronically dilated
canine left ventricle.
Circ Res
1971;
28
(1): 49–61.
14. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hyper-
trophy in the human left ventricle.
J Clin Invest
1975;
56
(1): 56–64.
15. Dell’italia LJ, Balcells E, Meng QC,
et al
. Volume-overload cardiac
hypertrophy is unaffected by ACE inhibitor treatment in dogs.
Am J
Physiol
1997;
273
(2 Pt 2): H961–970.
16. Matsuo T, Carabello BA, Nagatomo Y,
et al
. Mechanisms of cardiac
hypertrophy in canine volume overload.
Am J Physiol
1998;
275
(1 Pt
2): H65–74.
17. Kerckhoffs RC, Omens J, McCulloch AD. A single strain-based growth
law predicts concentric and eccentric cardiac growth during pressure and
volume overload.
Mech Res Commun
2012;
42
: 40–50.
18. Spinale FG, Ishihra K, Zile M, DeFryte G, Crawford FA, Carabello BA.
Structural basis for changes in left ventricular function and geometry
because of chronic mitral regurgitation and after correction of volume
overload.
J Thorac Cardiovasc Surg
1993;
106
(6): 1147–1157.
19. Wisenbaugh T, Spann JF, Carabello BA. Differences in myocardial
performance and load between patients with similar amounts of chronic
aortic versus chronic mitral regurgitation.
J Am Coll Cardiol
1984;
3
(4):
916–923.
20. Imamura T, McDermott PJ, Kent RL, Nagatsu M, Cooper Gt,
Carabello BA. Acute changes in myosin heavy chain synthesis rate in
pressure versus volume overload.
Circ Res
1994;
75
(3): 418–425.
21. Urabe Y, Mann DL, Kent RL,
et al
. Cellular and ventricular contractile
dysfunction in experimental canine mitral regurgitation.
Circ Res
1992;
70
(1): 131–147.
22. Tsutsui H, Ishihara K, Cooper Gt. Cytoskeletal role in the contractile
dysfunction of hypertrophied myocardium.
Science
1993;
260
(5108):