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A novel mouse model of lipotoxic cardiomyopathy
Chiu H-C, Kovacs A, Ford DA, et al. J Clin
Invest. 2001;107:813–822.
Inherited and acquired cardiomyopathies are associated with marked
intracellular lipid accumulation in the heart. To test the hypothesis
that mismatch between myocardial fatty acid uptake and utilization
leads to the accumulation of cardiotoxic lipid species, and to
establish a mouse model of metabolic cardiomyopathy, Chiu et al
generated transgenic mouse lines that overexpress long-chain acyl-CoA
synthetase in the heart (MHC-ACS). This protein plays an important
role in vectorial fatty acid transport across the plasma membrane.
MHC-ACS mice demonstrate cardiac-restricted expression of the
transgene and marked cardiac myocyte triglyceride accumulation.
Lipid accumulation is associated with initial cardiac hypertrophy,
followed by the development of left ventricular dysfunction and
premature death. Terminal deoxynucleotidyl transferase-mediated
dUTP nick-end labeling staining and cytochrome c release in transgenic
heart suggest that a cardiac myocyte death occurs, in part, by
lipid-induced programmed cell death. Taken together, the authors’
data demonstrate that the fatty acid uptake/utilization mismatch
in the heart leads to accumulation of lipid species toxic to cardiac
myocytes. This novel mouse model will provide insight into the
role of perturbations in myocardial lipid metabolism in the pathogenesis
of inherited and acquired forms of heart failure.
Lipotoxic heart disease in obese rats:
implications for human obesity
Zhou YT, Grayburn P, Karim A, et al. Proc
Natl Acad Sci USA. 2000;97(4):1784–1789.
To determine the mechanism of the cardiac dilatation and reduced
contractility of obese Zucker diabetic fatty rats, myocardial
triacylglycerol (TG) was assayed chemically and morphologically.
TG was high because of underexpression of fatty acid oxidative
enzymes and their transcription factor, peroxisome proliferator-activated
receptor-a. Levels of ceramide, a mediator of apoptosis, were
two to three times those of controls, and inducible nitric oxide
synthase levels were four times greater than normal. Myocardial
DNA laddering, an index of apoptosis, reached 20 times the normal
level. Troglitazone therapy lowered myocardial TG and ceramide
and completely prevented DNA laddering and loss of cardiac function.
The authors conclude that cardiac dysfunction in obesity is caused
by lipoapoptosis and is presented by reducing cardiac lipids.
Commentary
These two papers describe a new and potentially very important
form of cardiovascular disease, ‘lipotoxic heart disease’ or ‘lipotoxic
cardiomyopathy’. The concept is that abnormally high circulating
fatty acid levels or excessive uptake of fatty acids by the heart
can lead to the development of a cardiomyopathy or heart failure
associated with accumulation of intracellular lipid and accelerated
apoptosis (programmed cell death). This form of cardiomyopathy
has potential clinical relevance in obesity or diabetes and insulin
resistance syndromes, often termed ‘metabolic syndrome X’. It
also may be relevant in various genetic disorders of abnormal
fatty acid metabolism.
The papers highlight the need for further research to better understand
the cellular events that contribute to lipotoxic cardiomyopathy,
as well as the potential to develop therapeutic interventions
to treat these cardiomyopathies.
G.D. Lopaschuk
No-flow ischemia inhibits insulin signaling
in heart by decreasing
intracellular pH
Beauloye C, Bertrand L, Krause U, et al.
Circ Res. 2001;88(5):513–519.
Insulin signaling is initiated by its binding to the insulin receptor.
This activates the tyrosine kinase activity of the receptor, leading
to insulin receptor autophosphorylation and to subsequent phosphorylation
of insulin receptor substrates. This in turn activates downstream
components of the signaling pathway which mediate some of the
metabolic effects of insulin including recruitment of insulin-sensitive
glucose transporters GLUT4 to the plasma membrane.
Beauloye et al studied the insulin response of ischemic myocardium
by analyzing insulin signaling in isolated perfused rat hearts
submitted to no-flow ischemia. Intracellular pH was measured in
these hearts by nuclear magnetic resonance spectroscopy.
Commentary
The important conclusion reached from this study is that there
is an inhibition of insulin signaling during severe ischemia,
and that this inhibition parallels the development of intracellular
acidosis (at intracellular pH values below 6.75). Therefore, inhibition
of insulin signaling is expected to depend on the severity and
duration of ischemia. Inhibition of insulin signaling by severe
ischemia may indicate that all insulin effects are abolished.
Conversely, insulin signaling was soon fully restored on reperfusion,
suggesting that the hormonal effects could resume as normal intracellular
pH recovers.
The implications of these findings on cell protection, heart function,
glucose metabolism, or other heart responses to insulin remain
to be investigated.
D. Feuvray
Hypertrophied rat hearts are less responsive
to the metabolic and
functional effects of insulin.
Allard MF, Wambolt RB, Longnus SL, et al.
Am J Physiol Endocrinol Metab. 2000;279(3): E487–E493.
The authors determined the effect of insulin on the fate of glucose
and contractile function in isolated working hypertrophied hearts
from rats with an aortic constriction (n = 27) and control hearts
from sham-operated rats (n = 27). Insulin increased glycolysis
and glycogen in control and hypertrophied hearts. The change in
glycogen was brought about by increased glycogen synthesis and
decreased glycogenolysis in both groups. However, the magnitude
of change in glycolysis, glycogen synthesis, and glycogenolysis
caused by insulin was lower in hypertrophied hearts than in control
hearts. Insulin also increased glucose oxidation and contractile
function in control hearts but not in hypertrophied hearts. Protein
content of glucose transporters, protein kinase B, and phosphatidylinositol
3-kinase was not different between the two groups. Thus, hypertrophied
hearts are less responsive to the metabolic and functional effects
of insulin. The reduced responsiveness involves multiple aspects
of glucose metabolism, including glycolysis, glucose oxidation,
and glycogen metabolism. The absence of changes in content of
key regulatory molecules indicates that other sites, pathways,
or factors regulating glucose utilization are responsible for
these findings.
Commentary
Decreased insulin responsiveness of skeletal muscle
is a hallmark of type 2 diabetes, which is associated with increased
cardiovascular morbidity and mortality. The subcellular mechanism
leading to impaired insulin stimulation is largely unknown and
may differ among tissues. The study by Allard et al demonstrates
that left ventricular hypertrophy in response to pressure overload
in nondiabetic rats elicits insulin resistance in the myocardium,
with reduced glycolysis, glycogen synthesis, and glucose oxidation.
The consequences of reduced insulin responsiveness on myocardial
function and survival are presently not known. However, the findings
of this study may be of clinical importance because hypertrophied
and failing myocardium relies more on glucose metabolism than
does normal myocardium. Stimulation of glucose oxidation and/or
restoration of insulin responsiveness may be a target for therapeutic
intervention.
R. Lerch
Myoblast transplantation for heart failure
Menasché P, Hagege AA, Scorsin M, et al.
Lancet. 2001;357(9252):279B280.
Intramyocardial skeletal muscle transplantation has been shown
experimentally to improve heart function after infarction. Menasché
et al report success with this procedure in a patient with severe
ischemic heart failure. They implanted autologous skeletal myoblasts
into the postinfarction scar during coronary artery bypass grafting
of remote myocardial areas. Five months later, there was evidence
of contraction and viability in the grafted scar on echocardiography
and PET. Although encouraging, this result requires validation
by additional studies.
Commentary
Myocytes are terminally differentiated cells, which means that
lost cells cannot be replaced by mitosis. Accordingly, transplantation
of contractile cells, cardiomyocytes, or myoblasts is presently
being explored by a number of groups. The article by Menasché
et al reports one of the first clinical cases in which myoblasts,
or satellite cells, harvested from skeletal muscle of the patient
have been transferred to an infarcted area during coronary bypass
surgery. Five months after surgery, PET following intravenous
injection of 18F-fluorodeoxyglucose documented tracer uptake in
the previously infarcted region, which was attributed to the transplanted
cells. This case report highlights the interest of using PET with
metabolic tracers to document the viability of transplanted cells
in future studies.
R. Lerch
Beneficial haemodynamic effects of insulin
in chronic heart failure
Parsonage WA, Hetmanski D, Cowley AJ. Heart.
2001;85:508–513.
A single-blind, placebo-controlled study was carried out at a
university teaching hospital to characterize the central and regional
hemodynamic effects of insulin in 10 patients with stable chronic
heart failure. A hyperinsulinemic-euglycemic clamp was performed
and noninvasive hemodynamic measurements carried out to evaluate
change in resting heart rate, blood pressure, cardiac output,
and regional splanchnic and skeletal muscle blood flow. Insulin
infusion led to a dose-dependent increase in skeletal muscle blood
flow of 0.36 (0.13) and 0.73 (0.14) mL/dL per min during low-
and high-dose insulin infusions (P < 0.05 and P < 0.005
vs. placebo, respectively). Low- and high-dose insulin infusions
led to a fall in heart rate of 4.6 (1.4) and 5.1 (1.3) beats/min
(P < 0.05 and P < 0.005 vs. placebo, respectively) and a
modest increase in cardiac output. There were no significant changes
in superior mesenteric artery blood flow. The authors concluded
that in patients with chronic heart failure, insulin is a selective
skeletal muscle vasodilator that leads to increased muscle perfusion
primarily through redistribution of regional blood flow rather
than by increased cardiac output. These results provide a rational
hemodynamic explanation for the apparent beneficial effects of
insulin infusion in the setting of heart failure.
Commentary
The use of glucose-insulin-potassium (GIK) infusion has been studied
in patients since 1962. So far, clinical studies have concentrated
on acute myocardial infarction and patients undergoing cardiac
surgery. In the present study Parsonage et al studied patients
with chronic heart failure caused by ischemic and idiopathic cardiomyopathy
and found a decrease in forearm vascular resistance and an increase
in cardiac output by GIK infusion. Although many questions remain
unanswered (see also the editorial in the same issue of Heart),
this study is the first to demonstrate a possible beneficial effect
in patients with chronic heart failure and this hopefully will
lead to many other studies on the same subject
F. Visser
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