Myocardial
metabolism and function in diabetes
Gary D. Lopaschuk
Cardiovascular Research Group, Faculty of Medicine,
University of Alberta, Edmonton, Alberta, Canada
Correspondence: Professor Gary D. Lopaschuk, Cardiovascular
Research Group,
Faculty of Medicine and Oral Health Sciences, University of
Alberta, 423 Heritage Medical Research Centre, Edmonton, Alberta,
Canada.
Tel: +1 780 492 2170, fax: +1 780 492 9753, e-mail
gary.lopaschuk@ualberta.ca
Introduction
Alterations in energy metabolism in the diabetic can have profound
effects on cardiac function, both in the presence and absence
of coronary artery disease. It has been well documented that abnormalities
in cardiac function (termed ‘diabetic cardiomyopathies’) can occur
in the diabetic in the absence of ischemic heart disease.[1–5]
Diabetes-induced alterations in myocardial fatty acid and glucose
metabolism are an important contributing factor to these cardiomyopathies.[6]
These changes in energy metabolism can also contribute to the
complications and severity of ischemic heart disease in the diabetic.
Diabetics have a significantly greater incidence and severity
of angina, acute myocardial infarctions, congestive heart failure,
and other manifestations of atherosclerosis than do nondiabetics.[1,7–9]
While an increased incidence and severity of coronary artery disease
are major contributors to the high prevalence of heart disease
in the diabetic compared with the nondiabetic population, it is
also clear that changes within the myocytes themselves contribute
to the severity of ischemic injury.
One of the prominent cellular changes that occurs in the heart
of a diabetic is an alteration in the control of energy metabolism.
In particular, glucose uptake and oxidation decrease, while fatty
acid oxidation increases.[6] These high fatty
acid oxidation rates and low glucose metabolism rates can decrease
contractile function and cardiac efficiency in the heart.[10]
The inability to use glucose also contributes to the severity
of an ischemic insult, and can impair functional recovery during
and following ischemia.[10] Both heart failure
following an acute myocardial infarction and diabetic cardiomyopathies
have been correlated with the acute metabolic status of the patient.[9,11–14]
Furthermore, cardiomyopathies in the absence of ischemic heart
disease can be improved by correction of hyperglycemia.[11]
As a result, diabetes-induced changes in energy metabolism have
the potential to significantly impact cardiac function both in
the presence and absence of ischemia.
Control of energy metabolism in the normal
and diabetic heart
Glucose is the principal carbohydrate metabolized by the heart.
Glucose is taken up by the cardiomyocytes in an insulin-dependent
manner, and is then predominantly metabolized through glycolysis
to form pyruvate.[15] Pyruvate generated from
glycolysis, and to a lesser extent from lactate, is further metabolized
within the mitochondria to produce the majority of carbohydrate-derived
ATP (Figure 1).
Figure 1. Effect of diabetes on energy metabolism in the
heart.
The conversion of pyruvate in the mitochondria
to acetyl-CoA is catalyzed by pyruvate dehydrogenase (PDH). This
acetyl-CoA undergoes further mitochondrial metabolism, culminating
in the synthesis of ATP by the process of oxidative phosphorylation.
Fatty acids are the other major source of acetyl-CoA for the TCA
cycle, and the oxidative production of myocardial ATP. Fatty acids
seem to be the ‘preferred’ substrate of the myocardium, contributing
approximately 60–70% of the heart’s energy requirements when supplied
at physiologic levels.[15] However, fatty acids
are not as efficient as glucose as a source of energy (with respect
to oxygen consumption), and require approximately 10% more oxygen
to produce the equivalent amount of ATP.
Diabetes-induced alterations
in glucose metabolism
Myocardial glucose transport, glycolysis, and glucose oxidation
are all decreased in diabetes (Figure 1). Accompanying the decrease
in glucose transport is a decrease in the rate of glycolysis in
the diabetic heart.[6] The rate of glucose
oxidation is also significantly reduced in the diabetic heart.[16,17]
This is due to a marked decrease in PDH activity, the rate-limiting
enzyme for glucose oxidation. High circulating free fatty acid
levels and myocardial fatty acid oxidation are the key factors
responsible for the decreased myocardial PDH activity in diabetes.
Numerous studies have now demonstrated that low PDH activity (and
therefore low glucose oxidation rates) are detrimental to heart
function in both the presence and absence of ischemia (see references
[6, 10] and
[18] for reviews). In support of this, therapeutic strategies
that increase PDH and glucose oxidation have been to improve cardiac
function in the diabetic heart, both in the absence and presence
of ischemia.[6,10,18]
This can be achieved by either directly stimulating PDH, or by
directly inhibiting fatty acid oxidation.
Diabetes-induced alterations
in fatty acid metabolism
While fatty acid oxidation normally provides 60–70% of the energy
requirements of the heart, in uncontrolled diabetes fatty acid
oxidation can provide between 90 and 100% of the heart’s energy
requirements (Figure 2).[6,10]
 Figure
2. Contribution of fatty acid oxidation and glucose oxidation
to mitochondrial TCA cycle activity in the diabetic rat heart.
Isolated working hearts from control and 6-week streptozotocin
diabetic rats were perfused with 5 mM [U-14]glucose, 1.2 mM [9,10-3H]palmitate,
and 100 µU/ml insulin, palmitate and glucose oxidation measured,
and the contribution of palmitate and glucose to TCA cycle activity
determined, as described in reference 19.
While decreased glucose uptake due to insulin deficiency
can partly explain the decrease in glucose metabolism, high levels
of circulating fatty acids and alterations in the control of fatty
acid oxidation appear to be primarily responsible for this switch.
Plasma free fatty acid levels are elevated in patients with either
noninsulin-dependent or insulin-dependent diabetes. In diabetics,
in whom plasma levels of both free fatty acids and triacylglycerol-rich
lipoproteins are increased, fatty acid inhibition of both glycolysis
and glucose oxidation in the heart is especially prominent.
Although high levels of circulating fatty acids contribute to
low rates of glucose metabolism, alterations in the control of
fatty acid oxidation also occur within the myocardium of diabetics.
One site that appears to be particularly important is the control
of fatty acid uptake by the mitochondria.[6,18]
Energy metabolism during and following
cardiac ischemia in the
diabetic
During a mild ischemic episode, fatty acid oxidation and glucose
oxidation both decrease, with glycolysis becoming the dominant
source of energy production.[15] A large increase
in the amount of glycolysis relative to glucose oxidation occurs,
resulting in the anaerobic hydrolysis of ATP and the production
of excess cytosolic protons. This uncoupling of glycolysis from
glucose oxidation is a major source of proton production in the
myocardium during ischemia. Since coronary flow is diminished
at this time, excess protons accumulate, resulting in intracellular
acidosis. These protons exchange for other cations, and can lead
to an increase in intracellular calcium overload. The need to
use ATP to reestablish H+, Na+, and Ca2+ homeostasis can lead
to a decrease in cardiac efficiency. As a result, low glucose
oxidation rates contribute to a decrease in cardiac efficiency
during ischemia.[19]
During reperfusion following an episode of ischemia, a rapid recovery
of mitochondrial energy production must occur if contractile function
is to recover. During this period, fatty acid oxidation quickly
recovers and becomes the predominant source of myocardial ATP
production, providing 80–90% of the heart’s energy requirements.[19]
High rates of fatty acid oxidation during reperfusion of ischemic
hearts markedly decrease glucose oxidation rates, contributing
to contractile dysfunction during reperfusion.[19]
In the diabetic, the problems associated with low glucose oxidation
both during and following ischemia are exacerbated. While serum
fatty acid concentrations in normal individuals range from 0.2
to 0.5 mM, during an acute myocardial infarction serum fatty acids
can increase above 1 mM.[6] In diabetics, serum
fatty acids can be elevated even in the absence of an acute myocardial
infarction, and can rise during ischemia to very high levels.
A number of experimental studies have examined the involvement
of fatty acids during ischemia, and possible mechanisms by which
fatty acids contribute to injury (see references
6, 10 and 18 for
reviews). Fatty acid inhibition of glucose oxidation (via PDH
inhibition) appears to be one contributing factor to ischemic
injury. Fatty acids also promote and accelerate arrhythmias, decrease
mechanical function, and impair membrane integrity and suborganelle
performance.
Pharmacological modification of cardiac
energy metabolism in the diabetic
Interventions aimed at decreasing proton production by increasing
glucose oxidation have the potential to improve cardiac efficiency.[19]
Recent experimental and clinical studies have shown that stimulating
glucose oxidation can improve both cardiac function and cardiac
efficiency.[6,10] Experimental
studies have shown that direct stimulation of glucose oxidation
can improve cardiac function in hearts from diabetic animals,
and decrease the adverse effects of ischemia.[20]
Stimulation of glucose oxidation can either be by direct
stimulation of glucose oxidation, or indirectly by inhibiting
fatty acid oxidation. For instance, direct stimulation of glucose
oxidation with the PDH activator dichloroacetate improves cardiac
function in the nonischemic heart,[20] and
improves functional recovery and cardiac efficiency in the reperfused
ischemic heart.[19] Overcoming fatty acid inhibition
of PDH with L-carnitine is another effective approach to benefiting
cardiac function in the nonischemic and ischemic heart.[21]
Another effective approach to increasing glucose oxidation in
the heart is by inhibiting fatty acid oxidation. This can either
be achieved by inhibiting fatty acid uptake into the mitochondria,
or by inhibiting fatty acid b-oxidation within the mitochondria.
Agents that block mitochondrial fatty acid uptake (such as etomoxir,
methylpalmoxirate, and oxfenicine) have been shown in experimental
studies to improve heart function and decrease ischemic injury
in animal models of diabetes.[10] Direct inhibition
of fatty acid b-oxidation within the mitochondria can also benefit
the diabetic heart. Pharmacological agents that inhibit fatty
acid oxidation and stimulate glucose oxidation are now being used
clinically to treat ischemic heart disease. Trimetazidine, the
first 3-KAT inhibitor which stimulates glucose oxidation in the
heart secondary to an inhibition of fatty acid oxidation,[22]
is licensed worldwide for the treatment of ischemic heart disease.[23]
Whether a similar approach may be efficacious in diabetics with
ischemic heart disease is presently being evaluated. Clinical
studies in Poland coordinated by Dr Hanna Szwed have shown that
trimetazidine can reduce the symptoms, severity, and frequency
of angina attacks in diabetic patients with angina pectoris.[24]
Further studies are necessary to evaluate whether diabetic cardiomyopathic
changes can also be decreased with the use of this therapy.
Summary
Increased fatty acid oxidation and decreased glucose metabolism
contribute to the development of diabetic cardiomyopathies, and
can decrease the ability of the heart to withstand an ischemic
insult. Optimizing energy metabolism is now recognized as an effective
clinical approach to treating ischemic heart disease. This metabolic
approach may also have clinical potential in treating the diabetic
patient.
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in diabetic patients (31.2% of the diabetic patients compared
to 15.7%). The difference was most prominent in diabetic patients
who had sustained prior infarction (50% compared to 16%), but
was evident also in diabetic patients with initial infarction
(26% compared to 16%). The mortality rate was greater in diabetic
patients (p less than 0.04). When diabetic and nondiabetic patients
were stratified with respect to the presence or absence of CHF,
survival curves were comparable. The increased incidence of
CHF despite a smaller infarct size suggests that additional
factors must contribute to myocardial dysfunction and the resultant
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Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
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of the follow-up period survival status was known for all patients.
By the time of the MI the prevalence of diabetes was 5.6%. Patients
with and without diabetes were compared. There were no differences
in the estimated primary or secondary risk. The cumulative survival
rate 1, 2, and 5 yr after the MI was 82, 78, and 58% among the
diabetic subjects compared with 94, 92, and 82% among the nondiabetic
subjects (P less than 0.001). The difference remained even after
allowance for age and estimated secondary risk in a multivariate
regression analysis. There were no differences in mortality
rates among patients with type I diabetes compared with type
II diabetes, nor among patients treated with diet alone, sulfonylurea,
or insulin, but the numbers were small. The cumulative rate
of reinfarctions after 1, 2, and 5 yr was 18, 28, and 46% in
diabetic subjects and 12, 17, and 27% in nondiabetic subjects
(P = 0.004). A history of diabetes was an independent secondary
risk factor among male survivors of a first MI with respect
to deaths and reinfarctions.
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Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO.
Department of Pediatrics, Faculty of Medicine, University of
Alberta, Edmonton, Canada.
Publication Types:
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Review
|
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Hyperglycemia and prognosis of acute myocardial infarction
in patients without diabetes mellitus.
Bellodi G, Manicardi V, Malavasi V, Veneri L, Bernini G,
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II Medical Division, Hospital of Guastalla, Reggio Emilia, Italy.
The present study assessed the prognostic value of hyperglycemia--a
common feature in the early phase of acute myocardial infarction
(AMI)--in 330 nondiabetic patients. Seventy-nine known diabetics
and 10 (3%) unknown diabetics--diagnosed before discharge by
stable glycosylated hemoglobin greater than 6.9% and by oral
glucose tolerance testing--were excluded. Thirty-three (10%)
patients died. The mortality rate was higher in women, in patients
with anterior AMI, in older patients (greater than 65 years)
and in the presence of heart failure. It was highest in patients
with cardiogenic shock (24/36 vs 9/294; p less than 0.0001).
Admission plasma glucose was significantly higher in nonsurvivors
than in survivors (163 +/- 60 vs 114 +/- 36 mg/dl; p less than
0.0001). Mortality rate increased with increasing admission
plasma glucose: 3% in normoglycemic patients (less than or equal
to 120 mg/dl) versus 15% in patients with borderline plasma
glucose (121 to 180 mg/dl) versus 43% in hyperglycemic patients
(greater than 180 mg/dl) (p less than 0.0001). Multiple regression
(stepwise) analysis identified cardiogenic shock, infarct site
and age as the major determinants of mortality, while admission
plasma glucose failed to reach full statistical significance
(p = 0.067). Hyperglycemia was related to all 3 of these independent
prognostic factors; when age and infarct site were accounted
for, hyperglycemia was significantly associated with heart failure
only and this association was characterized by a remarkable
mortality rate. In nondiabetic patients with AMI, hyperglycemia
is a correlate of heart failure and, therefore, an important
factor of prognosis.
PMID: 2801556 [PubMed - indexed for MEDLINE]-
Prevalence and risks of hyperglycaemia and undiagnosed diabetes
in patients with acute myocardial infarction.
Oswald GA, Corcoran S, Yudkin JS.
Two studies were undertaken to assess the prevalence of undiagnosed
diabetes mellitus in patients admitted with acute myocardial
infarction (AMI), and the effect of diabetes mellitus and admission
hyperglycaemia on outcome. In the retrospective study, admission
levels of plasma glucose (APG) were higher (p less than 0.02)
in patients dying from cardiogenic shock than in survivors,
but they were not related to infarct size. In the prospective
study APG was related (p less than 0.01) to concurrent levels
of glycosylated haemoglobin (HbA1c), which were in turn related
to outcome--the mortality rate was 23% for those with normal
HbA1c (less than 7.5%), 33% for those with borderline abnormal
HbA1c (7.5-8.5%), and 63% for those with clearly abnormal HbA1c
(greater than 8.5%). Cardiogenic shock was commoner in the groups
with higher HbA1c levels. In addition, admission hyperglycaemia
was associated (p less than 0.01) with the incidence of cardiogenic
shock even after correcting for the effects of HbA1c. All of
the survivors from the clearly abnormal HbA1c group, but none
of those from other groups, were diabetic at follow up, suggesting
an overall prevalence of undiagnosed diabetes mellitus of 5.3%.
The contribution of undiagnosed diabetes mellitus to total mortality
following AMI seems at present to be underestimated.
PMID: 6144976 [PubMed - indexed for MEDLINE]-
Determinants and importance of stress hyperglycaemia in non-diabetic
patients with myocardial infarction.
Oswald GA, Smith CC, Betteridge DJ, Yudkin JS.
Determinants of plasma glucose concentrations were studied in
patients on admission to hospital with confirmed acute myocardial
infarction but without previous glucose intolerance as evidenced
by raised concentrations of glycosylated haemoglobin (HbAlc).
Mortality in hospital increased significantly with increasing
plasma concentrations of glucose in patients with both normal
(p less than 0.0001, n = 311) and borderline (p less than 0.02,
n = 70) concentrations of HbAlc. There was a weak relation between
plasma glucose concentrations and infarct size as estimated
by peak aspartate transaminase activity in both HbAlc groups
(rs = 0.26, n = 101 and rs = 0.41, n = 35 respectively). A correlation
was found between adrenaline and plasma glucose concentrations
(r = 0.47, n = 27) and cortisol and plasma glucose concentrations
(r = 0.75, n = 19), but the relation of plasma noradrenaline
and plasma glucose suggested a threshold effect. Concentrations
of adrenaline, but not those of noradrenaline or cortisol, correlated
with infarct size as measured both by peak aspartate transaminase
activity and cumulative release of creatine kinase MB isoenzyme.
Multiple regression analysis showed that concentrations of cortisol,
adrenaline, and noradrenaline (but not the concentration of
HbAlc, infarct size, or age) are the main determinants of plasma
glucose concentration measured in non-diabetic patients when
admitted to hospital after acute myocardial infarction.
PMID: 3094714 [PubMed - indexed for MEDLINE]-
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mortality and five-year survival.
Partamian JO, Bradley RF.
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Regulation of glucose uptake by muscles. 10. Effects of alloxan-diabetes,
starvation, hypophysectomy and adrenalectomy, and of fatty acids,
ketone bodies and pyruvate, on the glycerol output and concentrations
of free fatty acids, long-chain fatty acyl-coenzyme A, glycerol
phosphate and citrate-cycle intermediates in rat heart and diaphragm
muscles.
Garland PB, Randle PJ.
PMID: 5839199 [PubMed - indexed for MEDLINE]-
Glucose oxidation rates in fatty acid-perfused isolated working
hearts from diabetic rats.
Wall SR, Lopaschuk GD.
Department of Pediatrics, Faculty of Medicine, University of
Alberta, Edmonton, Canada.
The effect of fatty acids and the carnitine palmitoyltransferase
I (CPT I) inhibitor, Etomoxir, on myocardial glucose oxidation
in diabetes was studied. 14CO2 production from 11 mM [14C]glucose
was measured in control or 6-week streptozotocin-diabetic isolated
working rat hearts perfused with or without 1.2 mM palmitate
(bound to 3% albumin). In control hearts, addition of palmitate
to the buffer resulted in a marked reduction (13-fold) in glucose
oxidation rates. Glucose oxidation in diabetic rat hearts perfused
with palmitate was almost abolished. Even though glucose oxidation
rates were low, exogenous palmitate oxidation rates, measured
as 14CO2 production from [14C]palmitate, were not increased
in diabetic versus control hearts. Addition of the CPT 1 inhibitor,
Etomoxir (1.10(-6) M), resulted in a doubling of glucose oxidation
rates in both control and diabetic rat hearts, in the presence
or absence of palmitate. The effects of Etomoxir on glucose
oxidation could not be explained by reduced exogenous palmitate
oxidation or decreased levels of citrate. Cardiac function,
as measured by the heart rate x peak systolic pressure product,
was reduced in diabetic rat hearts. Etomoxir significantly increased
heart function in palmitate-perfused hearts from both control
and diabetic rats. These data suggest that fatty acids contribute
to decreased glucose oxidation and cardiac function in diabetic
rat hearts. These effects of fatty acids can be partially reversed
with the CPT 1 inhibitor, Etomoxir.
PMID: 2804076 [PubMed - indexed for MEDLINE]
18. Stanley WC, Lopaschuk GD,
Kivilo KM. Alterations
in myocardial energy metabolism in streptozotocin diabetes. In:
McNeill JH, ed. Experimental Models of Diabetes. Boca Raton, FL:
CRC Press; 1999:19–38.
-
Cardiac efficiency is improved after ischemia by altering
both the source and fate of protons.
Liu B, Clanachan AS, Schulz R, Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Cardiac efficiency is decreased in hearts after severe ischemia.
We determined whether reducing the production of H+ from glucose
metabolism or inhibiting the clearance of H+ via Na(+)-H+ exchange
could increase cardiac efficiency during reperfusion. This was
achieved using dichloroacetate (DCA) to stimulate glucose oxidation
and 5-(N,N-dimethyl)-amiloride (DMA) to inhibit Na(+)-H+ exchange,
respectively. Isolated working rat hearts were subjected to
30 minutes of global ischemia and 60 minutes of reperfusion.
Glycolysis and oxidation rates of glucose, lactate, and palmitate
were measured. Recovery of cardiac work, O2 consumption (MVO2),
and rates of acetyl-coenzyme A and ATP production during reperfusion
were determined. After ischemia, cardiac work recovered to 35
+/- 5% of preischemic values in control hearts (n = 23), although
MVO2, tricarboxylic acid (TCA) cycle activity, and ATP production
from glycolysis and oxidative metabolism rapidly recovered to
preischemic levels. This decrease in cardiac efficiency was
accompanied by a substantial production of H+ from glucose metabolism
DCA caused a 2.2-fold increase in glucose oxidation, a 46 +/-
17% decrease in H+ production, a 1.6-fold increase in cardiac
efficiency, and a 2.0-fold increase in cardiac work during reperfusion
(n = 17). Inhibition of Na(+)-H+ exchange with DMA did not alter
TCA cycle activity and ATP production rates but did result in
a 1.8-fold increase in cardiac efficiency and a 1.7-fold increase
in cardiac work (n = 12). These data show that cardiac efficiency
and the contractile function after ischemia can be improved
by either reducing the rate of H+ production from glucose metabolism
during reperfusion or inhibiting the clearance of H+ via Na(+)-H+
exchange. Our data suggest that an increased requirement for
ATP to restore ischemia-reperfusion-induced alterations in ion
homeostasis contributes to the decrease in cardiac efficiency
and contractile function after ischemia.
PMID: 8888686 [PubMed - indexed for MEDLINE]
-
Effects of free fatty acids and dichloroacetate on isolated
working diabetic rat heart.
Nicholl TA, Lopaschuk GD, McNeill JH.
Faculty of Pharmaceutical Sciences, University of British Columbia,
Vancouver, Canada.
It is well established that cardiac dysfunction independent
of atherosclerosis develops in both humans and animals with
diabetes mellitus. The etiology is complex, involving many different
processes, one of which may be increased fatty acid utilization
and/or a concomitant decrease in glucose utilization by the
diabetic heart. We compared control and 6-wk streptozotocin
(STZ)-induced diabetic isolated working rat hearts and were
able to demonstrate cardiac dysfunction in the diabetic as assessed
by depressed heart rate (HR), heart rate peak systolic pressure
product (HR.PSP), left ventricular developed pressure (LVDP),
and rate of pressure rise (+dP/dt). Paralleling depressed cardiac
function in the diabetic were hyperglycemia, hyperlipidemia,
and decreased body weight gain compared with age-matched controls.
The addition of free fatty acids, in the form of 1.2 mM palmitate,
to the isolated working heart perfusate had no effect on either
control or diabetic heart function, with the exception of a
depressive effect on +dP/dt of diabetic hearts. But diabetic
hearts perfused with palmitate-containing perfusate plus the
glucose oxidation stimulator dichloroacetate (DCA) showed a
marked improvement in function. HR and HR.PSP in spontaneously
beating hearts, as well as LVDP and +dP/dt in paced hearts were
all restored to control heart values in diabetic hearts perfused
in the presence of DCA. Creatine phosphate and ATP levels were
similar under all perfusion conditions, thus eliminating energy
stores as the limiting factor in heart function. Results indicate
that DCA will acutely reverse diabetic cardiac function depression.
Therefore glucose oxidation depression in the diabetic heart
may be a significant factor contributing to cardiac dysfunction.
PMID: 1928388 [PubMed - indexed for MEDLINE]
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L-carnitine increases glucose metabolism and mechanical function
following ischaemia in diabetic rat heart.
Broderick TL, Quinney HA, Lopaschuk GD.
Cardiovascular Disease Research Group, University of Alberta,
Edmonton, Canada.
OBJECTIVE: Stimulation of glucose oxidation by L-carnitine improves
mechanical recovery of ischaemic hearts from non-diabetic rats
perfused with high levels of fatty acids. The aim of this study
was to determine whether L-carnitine also increases glucose
oxidation and function in diabetic rat hearts, which have suppressed
glucose metabolism. METHODS: Isolated working hearts from six
week streptozotocin diabetic and control rats were perfused
with 11 mM (5-3H/U-14C)-glucose, 1.2 mM palmitate. Hearts were
paced at 260 beats.min-1 during 60 min of low flow ischaemia,
and were then subjected to 30 min of aerobic reperfusion. Total
myocardial carnitine content in these hearts was first increased
by a 60 min aerobic perfusion with 10 mM L-carnitine. RESULTS:
Steady state glucose oxidation rates (measured as 14CO2 production)
were depressed in diabetic rat hearts compared to control hearts
during the initial aerobic period. However, L-carnitine treatment
dramatically increased glucose oxidation rates in the diabetic
rat hearts, as well as in control hearts. Glycolysis was also
lower in diabetic rat hearts compared to control hearts, although
L-carnitine treatment significantly increased glycolysis only
in the diabetic animals. During reperfusion, steady state rates
of glucose oxidation and glycolysis returned to preischaemic
values in both the control and diabetic groups. L-carnitine
treatment stimulated glucose oxidation during reperfusion in
control and diabetic rat hearts. Mechanical function of control
hearts returned to 38(SEM 9)% of preischaemic values, whereas
in L-carnitine treated hearts function returned to 90(7)% of
preischaemic values. Recovery of function was 80(15)% of preischaemic
in the diabetic rat hearts, and was increased to 100% of preischaemic
function with L-carnitine. CONCLUSIONS: Carnitine improves recovery
of function of ischaemic non-diabetic rats by stimulating glucose
oxidation during reperfusion, whereas it may be beneficial in
diabetic rat hearts by stimulating both glycolysis during ischaemia
and glucose oxidation during reperfusion.
PMID: 7781011 [PubMed - indexed for MEDLINE]
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Comment in:
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Circ Res. 2000 Mar 17;86(5):487-9 |
The antianginal drug trimetazidine shifts cardiac energy
metabolism from fatty acid oxidation to glucose oxidation by
inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD.
Cardiovascular Research Group and the Division of Pediatric
Cardiology, University of Alberta, Edmonton, Canada.
Trimetazidine is a clinically effective antianginal agent that
has no negative inotropic or vasodilator properties. Although
it is thought to have direct cytoprotective actions on the myocardium,
the mechanism(s) by which this occurs is as yet undefined. In
this study, we determined what effects trimetazidine has on
both fatty acid and glucose metabolism in isolated working rat
hearts and on the activities of various enzymes involved in
fatty acid oxidation. Hearts were perfused with Krebs-Henseleit
solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L
glucose, and fatty acids of different chain lengths. Both glucose
and fatty acids were appropriately radiolabeled with either
(3)H or (14)C for measurement of glycolysis, glucose oxidation,
and fatty acid oxidation. Trimetazidine had no effect on myocardial
oxygen consumption or cardiac work under any aerobic perfusion
condition used. In hearts perfused with 5 mmol/L glucose and
0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate
oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1)
x minute(-1) (P<0.05), whereas it increased rates of glucose
oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1)
x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia,
trimetazidine resulted in a 210% increase in glucose oxidation
rates. In both aerobic and ischemic hearts, glycolytic rates
were unaltered by trimetazidine. The effects of trimetazidine
on glucose oxidation were accompanied by a 37% increase in the
active form of pyruvate dehydrogenase, the rate-limiting enzyme
for glucose oxidation. No effect of trimetazidine was observed
on glycolysis, glucose oxidation, fatty acid oxidation, or active
pyruvate dehydrogenase when palmitate was substituted with 0.8
mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine
directly inhibits long-chain fatty acid oxidation. This reduction
in fatty acid oxidation was accompanied by a significant decrease
in the activity of the long-chain isoform of the last enzyme
involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A
(CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast,
concentrations of trimetazidine in excess of 10 and 100 micromol/L
were needed to inhibit the medium- and short-chain forms of
3-ketoacyl CoA thiolase, respectively. Previous studies have
shown that inhibition of fatty acid oxidation and stimulation
of glucose oxidation can protect the ischemic heart. Therefore,
our data suggest that the antianginal effects of trimetazidine
may occur because of an inhibition of long-chain 3-ketoacyl
CoA thiolase activity, which results in a reduction in fatty
acid oxidation and a stimulation of glucose oxidation.
PMID: 10720420 [PubMed - indexed for MEDLINE]
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Trimetazidine. A review of its use in stable angina pectoris
and other coronary conditions.
McClellan KJ, Plosker GL.
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
The orally administered antianginal agent trimetazidine increases
cell tolerance to ischaemia by maintaining cellular homeostasis.
In theory, this cytoprotective activity should limit myocyte
loss during ischaemia in patients with angina pectoris. Data
from studies in patients with coronary artery disease indicate
that, unlike the effects of other antianginals, the anti-ischaemic
effects of trimetazidine 20 mg are not associated with alterations
in haemodynamic determinants of myocardial oxygen consumption
such as heart rate, systolic blood pressure and the rate-pressure
product. Furthermore, limited evidence suggests trimetazidine
may improve left ventricular function in patients with chronic
coronary artery disease or ischaemic cardiomyopathy and in patients
experiencing acute periods of ischaemia when undergoing percutaneous
transluminal coronary angioplasty. Clinical studies have shown
that oral trimetazidine 20 mg 3 times daily reduces the frequency
of anginal attacks and nitroglycerin use and increases exercise
capacity when used as monotherapy in patients with angina pectoris.
Its clinical effects are broadly similar to those of nifedipine
40 mg/day and propranolol 120 to 160 mg/day but, unlike these
agents, trimetazidine does not affect the rate-pressure product
during peak exercise or at rest. Adjunctive trimetazidine 60
mg/day reduces the frequency of anginal attacks and nitroglycerin
use and improves exercise capacity in patients with angina pectoris
not sufficiently controlled by conventional antianginal agents.
Furthermore, the drug appears to be more effective than isosorbide
dinitrate 30 mg/day when used adjunctively in patients with
angina pectoris poorly controlled by propranolol 120 mg/day.
The tolerability profile of trimetazidine 60 mg/day was similar
to that of placebo when used as add-on therapy in patients with
angina pectoris insufficiently controlled by other antianginal
agents and was superior to that of either nifedipine 40 mg/day
or propranolol 120 to 160 mg/day when used as monotherapy. The
most frequently reported adverse events in trimetazidine recipients
were gastrointestinal disorders, although the incidence of these
events was low. CONCLUSIONS: Trimetazidine is an effective and
well tolerated anti-ischaemic agent which, in addition to providing
symptom relief and functional improvement in patients with angina
pectoris, has a cytoprotective action during ischaemia. The
drug is suitable for initial use as monotherapy in patients
with angina pectoris and, because of its different mechanism
of action, as adjunctive therapy in those with symptoms not
sufficiently controlled by nitrates, beta-blockers or calcium
antagonists. The role of trimetazidine in other coronary conditions
has yet to be clearly established.
Publication Types:
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Review
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Review, tutorial |
PMID: 10439934 [PubMed - indexed for MEDLINE]
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The antiischemic effects and tolerability of trimetazidine
in coronary diabetic patients. A substudy from TRIMPOL-1.
Szwed H, Sadowski Z, Pachocki R, Domzal-Bochenska M, Szymczak
K, Szydlowski Z, Paradowski A, Gajos G, Kaluza G, Kulon I, Wator-Brzezinska
A, Elikowski W, Kuzniak M.
National Institute of Cardiology, Warsaw, Poland.
Diabetes mellitus, a disease with a wide prevalence, has major
cardiovascular effects, being a risk factor for the development
of ischemic heart disease and congestive heart failure. The
aim of this open, multicenter study was to assess the antiischemic
efficacy and tolerability of trimetazidine, a metabolic agent
acting at the myocardial mitochondrial level, in diabetic patients
with stable effort angina treated previously with a single conventional
antianginal drug. Fifty diabetic patients (mean age 58 years)
with proven coronary artery disease, stable effort angina for
at least 3 months, and positive, comparable results of two initial
treadmill exercise tests separated by a 1-week interval were
included in the study. They continued their conventional antianginal
monotherapy with a long-acting nitrate, beta-blocker, or calcium
channel blocker. After stabilization, 4-week therapy with trimetazidine,
three times daily, 20 mg was initiated in combination with previous
treatment. The results showed a significant improvement in exercise
tolerance (440.2 vs. 383.2 s; P < 0.01), time to 1-mm ST-segment
depression (358.3 vs. 301.6 s; P < 0.01), time to onset of
anginal pain (400.0 vs. 238.3 s; P < 0.01), and total work
(9.39 vs. 8.67 metabolic equivalents, P < 0.01). Maximal
ST-segment depression was attenuated compared with baseline
(1.82 vs. 1.91 mm). Other findings included a significant decrease
in the mean frequency of anginal episodes (3.06 vs. 4.79 per
week; P < 0.01) and in mean nitrate consumption (2.29 vs.
4.2 doses/week). These results suggest that trimetazidine may
be effective and is well tolerated as combination therapy for
diabetic coronary artery disease patients uncontrolled with
a single hemodynamic agent.
Publication Types:
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Clinical trial
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Multicenter study |
PMID: 10439884 [PubMed - indexed for MEDLINE]
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