Energetic myocardial metabolism and oxidative stress: Let's make them our friends in the fight against heart failure

Heart failure (HF) is a syndrome causing a huge burden in morbidity and mortality worldwide. Current medical therapies for HF are aimed at suppressing the neurohormonal activation. However, novel therapies are needed for HF, independent of the neurohormonal axis, that can improve cardiac performance and prevent the progression of heart dysfunction. The modulation of cardiac metabolism may represent a new approach to the treatment of HF. The healthy heart converts chemical energy stored in fatty acids (FA) and glucose. Utilization of FA costs more oxygen per unit of ATP generated than glucose, and the heart gets 60–90% of its energy for oxidative phosphorylation from FA oxidation. The failing heart has been demonstrated to be metabolically abnormal, in both animal models and in patients, showing a shift toward an increased glucose uptake and utilization. The manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less FA oxidation may improve ventricular performance and slow the progression of heart dysfunction. Impaired mitochondrial function and oxidative phosphorylation can reduce cardiac function by providing an insufficient supply of ATP to cardiomyocytes and by increasing myocardial oxidative stress. Although there are no effective stimulators of oxidative phosphorylation, several classes of drugs have been shown to open mitochondrial K_ATP channels and, indirectly, to improve cardiac protection against oxidative stress. This article focuses on the energetic myocardial metabolism and oxidative status in the normal and failing heart, and briefly, it overviews the therapeutic potential strategies to improve cardiac energy and oxidative status in HF patients.     

Metabolic intervention for the ischemic and post-ischemic heart.

There is increasing evidence that the availability of different metabolic substrates can influence post-ischemic functional recovery of the heart and the damage incurred during episodes of myocardial ischemia. Here we present the rationale for metabolic interventions, describe their mechanisms of action and suggest potential clinical applications. In cardiac surgery, basic research, studies of human myocardial metabolism after cardiac operations, and available experience with metabolic interventions provide a rationale for metabolic support with glutamate and/or high-dose glucose-insulin-potassium (GIK) in postoperative cardiac failure. In the treatment of acute myocardial infarction GIK deserves serious evaluation as recent randomized studies in diabetics with myocardial infarction and in patients undergoing reperfusion strategies demonstrate significant reductions in mortality. However, before large scale prospective randomized studies are undertaken, further studies of myocardial metabolism in acute myocardial infarction and the impact of different GIK regimes may be advisable in order to determine appropriate doses. A brief overview of metabolic modulation with pharmacological measures is given as it eventually may prove that we have to await the introduction of pharmacological agents which enhance full glucose oxidation at the expense of free fatty acids to create the commercial interest necessary to achieve widespread use of metabolic therapies.     

Defective lipid metabolism in the failing heart

The metabolism of long chain fatty acids was investigated in the failing heart of guinea pigs with chronic constriction of the ascending aorta. Homogenates prepared form failing hearts exhibited (a) a decreased capacity to oxidize palmitic acid (failure = 0.50 +/- 0.06 mumole/g of protein per 20 min; control = 1.09 +/- 0.10); (b) a reduced level of carnitine, a myocardial constituent which serves to control the oxidation rate of long chain fatty acids in the heart (failure = 0.91 +/- 0.10 mumole/g wet weight; control = 1.69 +/- 0.10); and (c) an increased rate of palmitate incorporation into triglycerides and lecithin. Exogenous carnitine effected a restoration of the defective palmitate metabolism of the homogenates towards normal. In contrast to long chain fatty acid oxidation, glucose oxidation by the failing heart was not impaired. As a consequence of this selective lesion in energy substrate utilization, the failing heart might be forced to rely on substrates other than long chain fatty acids for its major energy supply.     

Fatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded hearts

BACKGROUND: The peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily and regulates gene expression of fatty acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure-overload, myocardial energy utilization reverts to the fetal pattern, and metabolic substrate switches from fatty acid to glucose. However, myocardial metabolism in volume-overloaded hearts has not been rigorously studied. The aim of the present study was to examine fatty acid metabolism and protein expressions of PPARalpha and fatty acid oxidation enzymes in volume-overloaded rabbit hearts. METHODS: Volume-overload was induced by carotid-jugular shunt formation. Sham-operated rabbits were used as control. Chronic volume-overload increased left ventricular weight and ventricular cavity size, and relative wall thickness was decreased, indicating eccentric cardiac hypertrophy. (125)I-iodophenyl 9-methylpentadecanoic acid (9MPA) was intravenously administered, and animals were sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to iodophenyl-3-methylnonanoic acid (3MNA) by beta-oxidation. Lipid extraction from the myocardium was performed by the Folch method, and radioactivity distribution of metabolites was assayed by thin-layer chromatography. The protein was extracted from the left ventricular myocardium, and levels of PPARalpha and fatty acid oxidation enzymes were examined by Western blotting. RESULTS: Myocardial distribution of 9MPA tended to be more heterogeneous in shunt than in sham rabbits (P = 0.06). In volume-overloaded hearts by shunt, the conversion from 9MPA to 3MNA by beta-oxidation was faster than the sham-control hearts (P < 0.05). However, protein levels of PPARalpha and fatty acid utilization enzymes were unchanged in shunt rabbits compared with sham rabbits. CONCLUSIONS: These data suggest that myocardial fatty acid metabolism is enhanced in eccentric cardiac hypertrophy by volume-overload without changes in protein expressions of PPARalpha and fatty acid utilization enzymes. Our data may provide a novel insight into the subcellular mechanisms for the pathological process of cardiac remodelling in response to mechanical stimuli.     

Impaired energetics in heart failure - a new therapeutic target

Heart failure is a syndrome of huge and growing importance worldwide. It is widely accepted that the energy status of the myocardium in heart failure is impaired, irrespective of etiology. Agents which modify cardiac substrate utilisation have the potential to ameliorate this energy deficiency by increasing cardiac mechanical efficiency. This may represent a new therapeutic paradigm in heart failure. In this review we discuss existing and new agents that alter cardiac substrate use and summarise the data on clinical efficacy.     

Alterations in energy metabolism in cardiomyopathies

Despite the fact that the heart requires huge amounts of energy to sustain contractile function, it has limited energy reserves and must therefore continually produce large amounts of adenosine triphosphate (ATP) to sustain function. Fatty acids are the primary energy substrate of the adult heart, with more than 60% of the energy normally obtained from the oxidation of fatty acids, the remainder coming from the metabolism of carbohydrates. Alterations in both the rates of ATP production and the type of energy substrate used by the heart can have consequences on contractile function, as well as on its ability to respond to energetic stresses. Switches in myocardial substrate utilization and energy production rates have been shown to occur in various cardiomyopathies, as well as in any subsequent heart failure. Heart failure is characterized by an inefficient pumping of the heart, which fails to meet the energy requirements of the body. A number of cardiomyopathies can lead to heart failure. This paper will review the alterations in energy metabolism that occur in a number cardiomyopathies, including ischemic and diabetic cardiomyopathies, as well as hypertrophic cardiomyopathies resulting from mutations in enzymes involved in energy metabolism, such as 5′adenosine monophosphate‐activated protein kinase (AMPK).     

Alterations in energy metabolism in cardiomyopathies

Despite the fact that the heart requires huge amounts of energy to sustain contractile function, it has limited energy reserves and must therefore continually produce large amounts of adenosine triphosphate (ATP) to sustain function. Fatty acids are the primary energy substrate of the adult heart, with more than 60% of the energy normally obtained from the oxidation of fatty acids, the remainder coming from the metabolism of carbohydrates. Alterations in both the rates of ATP production and the type of energy substrate used by the heart can have consequences on contractile function, as well as on its ability to respond to energetic stresses. Switches in myocardial substrate utilization and energy production rates have been shown to occur in various cardiomyopathies, as well as in any subsequent heart failure. Heart failure is characterized by an inefficient pumping of the heart, which fails to meet the energy requirements of the body. A number of cardiomyopathies can lead to heart failure. This paper will review the alterations in energy metabolism that occur in a number cardiomyopathies, including ischemic and diabetic cardiomyopathies, as well as hypertrophic cardiomyopathies resulting from mutations in enzymes involved in energy metabolism, such as 5' adenosine monophosphate-activated protein kinase (AMPK).     

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg·kg(-1) of body weight·day(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial (14)C-glucose and (14)C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2±0.7 μg/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF.     

Myocardial metabolic imaging: Viability and beyond

Because of the high metabolic cost of maintaining an adequate cardiac output, the heart possesses the ability to utilize a wide variety of metabolic substrates, including fatty acids, glucose, lactate, amino acids, and ketone bodies. The relative contribution of each of these substrates is regulated by multiple factors, including substrate concentration, presence of adequate blood flow and oxygen, the action of a variety of hormones, and the influences of disease states that can alter the metabolic machinery of the heart. This review summarizes the biochemical and cellular basis of myocardial substrate selection, as well as the changes in the metabolic phenotype of the heart in response to cardiac diseases. Based on this background, this review also illustrates the nuclear-based imaging techniques that can be used to assess myocardial metabolism and their current and future applications to patient care.     

Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-alpha, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of high-frequency left ventricular pacing (HF + Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. [3H]Oleate and [14C]Glucose were infused intravenously to measure the rate of substrate oxidation. At 21 days of pacing, left ventricular end-diastolic pressure was significantly lower in HF + Feno (14.1 +/- 1.6 mm Hg) compared with HF (18.7 +/- 1.3 mm Hg), but it increased up to 25 +/- 2 mm Hg, indicating end-stage failure, in both groups after 29 +/- 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA beta-oxidation pathway, was reduced in HF versus control (1.46 +/- 0.25 versus 2.42 +/- 0.24 micromol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 +/- 0.18 micromol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.     

Myocardial metabolism in toxin-induced heart failure and therapeutic implications

BACKGROUND: Under normal conditions, myocardial metabolism is 60-80% reliant on the oxidation of fatty acids. This can be modified by conditions such as ischemia or poisoning with specific drugs, with the myocardium becoming more dependent on carbohydrate metabolism for energy. Acute poisoning with cardiotoxic drugs may be complicated by heart failure that is at present usually treated by inotropic drugs and vasopressors. However, changes in metabolic processes in poisoning may offer an opportunity for novel therapies. CURRENT EVIDENCE: The scientific evidence obtained from ischemia-reperfusion models and the preservation of myocardial metabolism when myocardial blood flow is restored after a brief coronary occlusion (a theory known as "myocardial stunning") support this concept. Generalized or localized myocardial stunning may develop in patients who do not present with acute myocardial ischemia secondary to coronary artery disease, a condition referred to as takotsubo cardiomyopathy. This is characterized by the preservation of myocardial blood flow, associated with a depressed myocardial contractility, lasting from hours to weeks. THERAPEUTIC IMPLICATIONS: Several factors have been associated with takotsubo cardiomyopathy:- excessive sympathetic stimulation, either from exogenous or endogenous origin; drug poisoning or drug withdrawal. The metabolism of both glucose and fatty acids appears to be reduced in the hypocontractile areas. One of the hypotheses is that the catecholamine-mediated myocardial insulin resistance may be responsible for reduced glucose uptake. Among the drugs taken in overdose, calcium channel blockers and beta-blockers have been shown to influence myocardial metabolism, with a shift from fatty acids to glucose utilization. This is the rationale for the administration of insulin in order to stimulate glucose myocardial uptake. In addition, insulin at high doses seems also to have inotropic effects, which are independent from its effects on myocardial substrate handling. CONCLUSION: Better understanding of the relationship between the receptor interactions of myocardial toxins and their effects on myocardial metabolism is likely to result in the development of new targeted therapies aimed specifically at optimising metabolic processes in poisoning.     

SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy

Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.     

Myocardial metabolism in toxin-induced heart failure and therapeutic implications

Background. Under normal conditions, myocardial metabolism is 60–80% reliant on the oxidation of fatty acids. This can be modified by conditions such as ischemia or poisoning with specific drugs, with the myocardium becoming more dependent on carbohydrate metabolism for energy. Acute poisoning with cardiotoxic drugs may be complicated by heart failure that is at present usually treated by inotropic drugs and vasopressors. However, changes in metabolic processes in poisoning may offer an opportunity for novel therapies. Current evidence. The scientific evidence obtained from ischemia-reperfusion models and the preservation of myocardial metabolism when myocardial blood flow is restored after a brief coronary occlusion (a theory known as “myocardial stunning”) support this concept.

Generalized or localized myocardial stunning may develop in patients who do not present with acute myocardial ischemia secondary to coronary artery disease, a condition referred to as takotsubo cardiomyopathy. This is characterized by the preservation of myocardial blood flow, associated with a depressed myocardial contractility, lasting from hours to weeks. Therapeutic implications. Several factors have been associated with takotsubo cardiomyopathy:- excessive sympathetic stimulation, either from exogenous or endogenous origin; drug poisoning or drug withdrawal. The metabolism of both glucose and fatty acids appears to be reduced in the hypocontractile areas. One of the hypotheses is that the catecholamine-mediated myocardial insulin resistance may be responsible for reduced glucose uptake. Among the drugs taken in overdose, calcium channel blockers and beta-blockers have been shown to influence myocardial metabolism, with a shift from fatty acids to glucose utilization. This is the rationale for the administration of insulin in order to stimulate glucose myocardial uptake. In addition, insulin at high doses seems also to have inotropic effects, which are independent from its effects on myocardial substrate handling.

Conclusion. Better understanding of the relationship between the receptor interactions of myocardial toxins and their effects on myocardial metabolism is likely to result in the development of new targeted therapies aimed specifically at optimising metabolic processes in poisoning.     

Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart

Summary. Background: Modulation of energy substrate metabolism may constitute a novel therapeutic intervention against ischemia/reperfusion (I/R) injury. AMP‐activated protein kinase (AMPK) has emerged as a key regulator of favorable metabolic signaling pathways in response to myocardial ischemia. Recently, we demonstrated that activated protein C (APC) is cardioprotective against ischemia/reperfusion (I/R) injury by augmenting AMPK signaling. Objectives:  The objective of this study was to determine whether the APC modulation of substrate metabolism contributes to its cardioprotective effect against I/R injury. Methods: An ex vivo working mouse heart perfusion system was used to characterize the effect of wild‐type APC and its signaling‐proficient mutant, APC‐2Cys (which has dramatically reduced anticoagulant activity), on glucose transport in the ischemic heart. Results: Both APC and APC‐2Cys (0.2 μg g^?1) augment the ischemic stress‐induced translocation of the glucose transporter (GLUT4) to the myocardial cell membrane, leading to increased glucose uptake and glucose oxidation in the ischemic heart (P < 0.05 vs. vehicle). Both APC derivatives increased the autophagic flux in the heart following I/R. The activity of APC‐2Cys in modulating these metabolic pathways was significantly higher than APC during I/R (P < 0.05). Intriguingly, APC‐2Cys, but not wild‐type APC, attenuated the I/R‐initiated fatty acid oxidation by 80% (P < 0.01 vs. vehicle). Conclusions: APC exerts a cardioprotective effect against I/R injury by preferentially enhancing the oxidation of glucose over fatty acids as energy substrates in the ischemic heart. Given its significantly higher beneficial metabolic modulatory effect, APC‐2Cys may be developed as a potential therapeutic drug for treating ischemic heart disease without risk of bleeding.     

Metabolic therapy for the treatment of ischemic heart disease: reality and expectations

Ischemic heart disease is a major cause of morbidity and mortality in the world. Most of the existing therapeutic strategies used to treat ischemic heart disease aim at either increasing the oxygen supply to the heart (thrombolysis, revascularization, angiotensin converting enzyme inhibition and antiplatelet therapy) or decreasing the oxygen demand of the heart (β-blockers and nitrates). Despite the fact that a compromised energy supply to the heart muscle is central to the pathology of ischemic heart disease, therapeutic approaches that focus on altering cardiac energy metabolism have not seen major clinical use. Therapeutic strategies in which the efficiency of oxygen utilization by the heart is enhanced could theoretically benefit the ischemic heart, and could have an additive benefit to existing therapeutic strategies. The energy supply for the heart (in the form of ATP) is normally provided by the balanced metabolism of both fatty acids (major part) and carbohydrates (minor part) oxidation. During reperfusion, this balance is broken by the dramatic enhancement of fatty acid oxidation and attenuation of carbohydrate oxidation, which results in intracellular H⁺ accumulation and Ca²⁺ overload. This article reviews the alterations in cardiac energy metabolism that occur in the ischemic heart, and discusses the existing and proposed pharmacologic therapies to optimize the balance of fatty acids and carbohydrate oxidation for the treatment of ischemic heart diseases.     

Metabolic therapy for the treatment of ischemic heart disease: reality and expectations

Ischemic heart disease is a major cause of morbidity and mortality in the world. Most of the existing therapeutic strategies used to treat ischemic heart disease aim at either increasing the oxygen supply to the heart (thrombolysis, revascularization, angiotensin converting enzyme inhibition and antiplatelet therapy) or decreasing the oxygen demand of the heart (beta-blockers and nitrates). Despite the fact that a compromised energy supply to the heart muscle is central to the pathology of ischemic heart disease, therapeutic approaches that focus on altering cardiac energy metabolism have not seen major clinical use. Therapeutic strategies in which the efficiency of oxygen utilization by the heart is enhanced could theoretically benefit the ischemic heart, and could have an additive benefit to existing therapeutic strategies. The energy supply for the heart (in the form of ATP) is normally provided by the balanced metabolism of both fatty acids (major part) and carbohydrates (minor part) oxidation. During reperfusion, this balance is broken by the dramatic enhancement of fatty acid oxidation and attenuation of carbohydrate oxidation, which results in intracellular H(+) accumulation and Ca(2+) overload. This article reviews the alterations in cardiac energy metabolism that occur in the ischemic heart, and discusses the existing and proposed pharmacologic therapies to optimize the balance of fatty acids and carbohydrate oxidation for the treatment of ischemic heart diseases.     

Energy-supplying metabolism of the volume overloaded and hypoxia stressed heart in children

This study summarizes results obtained with regard to atrial and ventricular enzymes of energy supplying metabolism in children with different types of congenital heart disease. In all groups of patients - normoxemic as well as hypoxemic - significant atrio - ventricular differences were observed: the right ventricle is amply equipped for utilization and oxidation of all major nutrients, while the right atrium utilizes glucose predominantly. Myocardial metabolism in children with congenital heart disease was significantly influenced by hypoxemia: the capacity of aerobic enzymes in cyanotic patients was significantly lower, both in atrial and ventricular tissue, whereby the atrial changes were even more striking. No marked differences were found between atrial and ventricular septal defects in normoxemic patients; the only difference was a lower capacity of fatty acid catabolism in children with atrial septal defect.     

Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage

AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the gamma2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant gamma2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of gamma2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the gamma2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.     

Diabetic heart muscle disease

Diabetic patients may have various abnormalities in left ventricular systolic and diastolic function not attributable to coronary heart disease, hypertension or other known cardiac disease. Although the exact causes of this diabetic heart muscle disease or "diabetic cardiomyopathy" are still incompletely understood, several mechanisms may contribute to it including disturbed myocardial energy metabolism, microvascular changes, structural changes in collagen, increased myocardial fibrosis, and cardiac autonomic neuropathy. Perhaps the most typical feature of diabetic heart muscle disease is an abnormal filling pattern of the left ventricle, suggesting reduced compliance or prolonged relaxation. Left ventricular systolic function is commonly normal at rest in asymptomatic diabetic patients, but it frequently becomes abnormal during exercise. The abnormalities in left ventricular systolic function may be partly reversible along with an improvement of metabolic control of diabetes. It is not known how frequently subclinical abnormalities in left ventricular function in diabetic patients result in clinically manifest heart failure.