Download The role of coronary microvascular disorder in congestive heart failure

Am J Physiol Heart Circ Physiol 308: H814–H815, 2015;
doi:10.1152/ajpheart.00118.2015.
Editorial Focus
The role of coronary microvascular disorder in congestive heart failure
Georges E. Haddad, Sana Chams, and Nour Chams
Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, District of Columbia
Address for reprint requests and other correspondence: G. E. Haddad, Dept.
Physiology and Biophysics, College of Medicine, Howard Univ., 520 W. St.
NW, Washington, DC 20059 (e-mail: [email protected]).
H814
play(s) a key role in the development of heart failure: myocytes, extracellular matrix, and/or vasculature?
Coronary arterial disease is a main cause of heart failure. But
most published research and techniques have been focusing on
coronary arterial main branches, and only recently has microvascular dysfunction been getting more attention (6, 14, 16).
Coronary microvascular dysfunction was observed in patients
with hypertrophic cardiomyopathy. But its detailed role in
heart failure is not very clear because accurate quantitative
assessment of microvascular function and myocardial ischemia
is not easily feasible in clinical practice and bench research,
especially in rodents (1, 12). Microvascular obstruction, index
of microcirculatory resistance, and hyperemic microvascular
resistance were widely used parameters to identify microcirculation dysfunction. Invasive methods were based on principle of thermodilution or Doppler flow with guide wires (1),
whereas noninvasive positron emission tomography (PET)
served as a gold standard for noninvasive assay of myocardial
blood flow (5, 11). However, there is no solid proof to directly
correlate coronary microvascular dysfunction to ischemic heart
failure in vivo in human patients and animals to date, which is
probably due to the lack of proper model and the need for more
advanced finer techniques.
In this current issue of the American Journal of PhysiologyHeart and Circulatory Physiology, Chen and colleagues (8)
reported their serial studies on coronary arterial disorder in
congestive CHF in rats. The authors showed successive vascular changes of coronary arteries from main, middle, and
small arterial branches to arterioles and capillaries in the CHF
model. Heart failure was induced by chronic aortic constriction
with ischemia-reperfusion followed by aortic debanding. Their
main hypothesis is that the development of heart failure is
associated with vascular disorders that occur in not only main
branches of the coronary artery but also arterioles and capillaries. The capillary structural disorders found in CHF hearts
were diverse to include stenosis, nonlinear arrangement, curled
shape, drastic changes in diameter, proliferation, and roughened surface texture. Capillary disorder can be one of the
critical contributing factors to the energy starvation that leads
to the reduction of intrinsic contractile properties of the underlying myocytes. However, it is still a big challenge to simultaneously assess myocardial contractility and microvascular
blood flow in rodent animals.
Future studies on the role of coronary microcirculation
disorder (CMD) in CHF should involve the assessment of 1)
the correlation between the degree and range of CMD and heart
failure, specifically, the impact of the regional CMD on the
global cardiac pumping function of the heart (contractility) by
using invasive and noninvasive techniques; 2) the relationship
between narrowing (atherosclerotic) of the main arteries and
the impact on distal and proximal capillary disorders, which
assess the importance of the global coronary blood flow reserve
to the regional blood flow disorder, as well as to microvascular
and endothelial dysfunction; and 3) an evaluation of the impact
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heart failure are coronary heart disease
(coronary artery atherosclerosis), hypertension, cardiomyopathy, and heart valve disease (4). Accordingly, the most common models of heart failure are coronary arterial occlusion,
temporally (partially) or permanently (completely); aortic constriction or high-salt feeding; gene-deficient and knockout
models; and mitral, aortic regurgitation (10). Each model of
heart failure has its pros and cons versus the respective human
condition. Left anterior descending artery ligation is the most
widely used model; however, in the myocardial infarction
model, distal myocardial tissue to the occlusion site was almost
normal, especially in rodent animals, even a couple of months
postocclusion (7). Aortic constriction offers a good model for
myocyte hypertrophy in mice, rats, swine, and dogs. However,
the occurrence of congestive heart failure (CHF) post-aortic
constriction depends on the degree of aortic stenosis and the
overload duration (3). Left ventricle function could be preserved up to 4 mo post-aortic banding (even with 72% aortic
constriction) with collagen fiber accumulation in the interstitial
and perivascular space (7). Despite that, gene-deficient and
knockout rodent models were globally used in heart failure
research, and no individual gene-deficient and knockout models could bring a breakthrough in the treatment of heart failure,
probably because of a simple reason: heart failure is not a
disease induced by monogene/protein (4).
Advances in heart failure treatment have been mostly
achieved in surgical progress, like coronary artery stents,
bypass, heart assistant devices, or heart transplantation. However, limitations associated with angioplasty and stent have
been the restenosis that can occur within 6 mo after the initial
procedure. The chance of restenosis is from 25 to 40% (9).
Heart failure research in pharmacological management has
been largely dispirited. There have been many advances in
studying myocyte contractility, but inotropic agents just could
not improve cardiac dysfunction. The fibrosis inhibitors such
as the angiotensin-converting enzyme inhibitor, like candesartan (15) and irbesartan, did not show a beneficial effect in a
patient with CHF (13, 18). To date, there is no single drug
regimen that could effectively reverse cardiac dysfunction.
Despite the fact that gene therapy and stem cells therapy offer
great promise for heart failure treatment, uncertainties and
controversies still remain, including the high-yield transgene
expression/stem cell implantation in the heart and long-term
utility. In that regard, the obvious question is, What type of
cells can be regenerated to strengthen cardiac performance:
myocytes or endothelial cells (capillaries)? Do the regenerated
cells or repaired LV part (ischemic area or remote area) play a
key role in the overall progression of the heart failure and to
what extent (2, 17)? This largely addresses our predicament in
understanding heart failure: Which cardiac component(s)
COMMON CAUSES OF
Editorial Focus
H815
of novel therapies, such as AAV.VEGFa transgene, stem cell
therapies, and antiangina (ivabradine and ranolazine) therapies.
9.
GRANTS
This work was supported in part by Research Centers in Minority Institutions Division of Research Infrastructure Grants 1 R15 AA019816-01A1 and
8 G12MD007597.
10.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
11.
G.E.H. conception and design of research; G.E.H. and S.C. analyzed data;
G.E.H., S.C., and N.C. interpreted results of experiments; G.E.H., S.C., and
N.C. drafted manuscript; G.E.H., S.C., and N.C. edited and revised manuscript;
G.E.H. approved final version of manuscript.
12.
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