Myocardial Free Fatty Acid Research Articles

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. MethodsNine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1–14C]VLDL-TG. ResultsIn the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml−1 min−1; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml−1 min−1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. ConclusionsUsing robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

Metabolic modulation as a common adaptive mechanism in patients with different subtypes of aortic valve stenosis

Abstract Background Aortic valve stenosis (AS) is a rapidly growing global health problem due to aging and population growth. If treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function and marked increase of mortality. In conditions of AS or heart failure a cardiac remodelling occurs including a change in cardiac substrate utilization. However, it is difficult to determine the stage of AS-induced cardiac remodelling and therefore the reversibility of this changes after AVR. As cardiac metabolism might be therapeutic target for patients not recovering after valve replacement a better understanding of the metabolic remodelling in different AS subtypes is necessary. Metabolomics constitute a potent screening tool for defining changes in global and cardiac-specific metabolism in cardiovascular disease. Methods/Results Serum metabolomic profiling for 1293 metabolites was performed in serum samples of 40 AS-patients and 10 healthy controls using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. AS-patients were divided in four groups (10 patients/group) with respect to ejection fraction (EF, normal/reduced) and aortic valve gradient (&amp;gt; or &amp;lt;40 mmHg). Principal component analysis revealed a clear difference of metabolic profiles in AS-patients vs controls. However, less separation between AS-subtypes could be detected. A Random Forest Analysis comparing all AS-patients to healthy controls resulted in a predictive accuracy of 94%. In AS-patients we observed an increase of acyl carnitines compared to control indicating an alteration of myocardial free fatty acid oxidation. Moreover, we detected a higher ketone body concentrations in AS-patients that could serve as an alternative fuel source for the heart. Interestingly, no differences between the AS subgroups could be detected indicating that changes occur independently from EF and AS-gradient. Additionally, several compounds involved in nitrogen balance were increased in AS-patients while numerous amino acids were decreased, possibly also due to alternative energy production. Increased circulating heme catabolites have been associated with heart failure. Here, we found increased heme catabolites only in patients with low EF and high-gradient with unclear significance. Conclusion In summary, our study indicates a shift of cardiac substrate utilization in patients with AS from free fatty acid oxidation to alternative substrates like ketone bodies and amino acids. As no differences between AS subtypes were observed, this metabolic remodelling may occur as an adaptive mechanism independent from EF and AS-gradient in patients with severe AS. Since our study was conducted by an unspecific approach with a small sample size, further investigation is necessary for a better understanding of the specific myocardial metabolic changes in AS patients. Funding Acknowledgement Type of funding sources: None.

CD36 inhibition partially attenuates myocardial injury in diabetic rats with ischemic postconditioning

IntroductionTo investigate the role of CD36 (fatty acid translocation enzyme) in the myocardial ischemia reperfusion (IR) injury in diabetes with ischemic postconditioning (IPostC).Research design and methodsAdult male Sprague-Dawley rats received...

Qiliqiangxin Improves Cardiac Function through Regulating Energy Metabolism via HIF-1α-Dependent and Independent Mechanisms in Heart Failure Rats after Acute Myocardial Infarction.

The present study is aimed at investigating whether Qiliqiangxin (QL) could regulate myocardial energy metabolism in heart failure rats after acute myocardial infarction (AMI) and further exploring the underlying mechanisms. AMI was established by ligating the left anterior descending coronary artery in adult male SD rats. AMI rats with ejection fraction (EF) < 50% at two weeks after the operation were chosen as heart failure rats for the main study. Rats were randomized into the sham, MI, MI+QL, and MI+QL+2-MeOE2 groups. The results showed that compared with the MI group, QL significantly improved cardiac function, reduced serum NT-proBNP level, and alleviated myocardial fibrosis. QL also increased myocardial capillary density by upregulated protein expressions of vascular endothelial growth factor (VEGF) and CD31 by regulating the HIF-1α/VEGF pathway. Moreover, QL promoted ATP production, glucose uptake, and glycolysis by upregulating HIF-1α and a series of glycolysis-relevant enzymes in a HIF-1α-dependent manner. QL also improved myocardial glucose oxidation enzyme expression and free fatty acid uptake by a HIF-1α-independent pathway. Our results indicate that QL treatment improves cardiac function through regulating glucose uptake, FFA uptake, and key enzymes of energy metabolism via HIF-1α-dependent and independent mechanisms.

Change of short-chain acyl-CoA dehydrogenase in heart failure after myocardial infarction in rats and the intervention of aerobic exercise

To Study the changes of short-chain acyl-CoA dehydrogenase (SCAD) in heart failure (HF) after myocardial infarction (MI), and the effect of aerobic exercise on SCAD. Healthy male Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), sham operation swimming group (Sham+swim group), HF model group (LAD group) and HF swimming group (LAD+swim group) by random number table method, with 9 rats in each group. The left anterior descending branch of coronary artery (LAD) was ligated to establish a rat model of HF after MI. In Sham group, only one loose knot was threaded under the left coronary artery, and the rest operations were the same as those in LAD group. Rats in Sham+swim group and LAD+swim group were given swimming test for 1 week after operation (from 15 minutes on the 1st day to 60 minutes on the 5th day). Then they were given swimming endurance training (from the 2nd week onwards, 60 minutes daily, 6 times weekly, 10 weeks in a row). Tail artery systolic pressure (SBP) was measured before swimming endurance training and every 2 weeks until the end of the 10th week. Ten weeks after swimming training, echocardiography was performed to measure cardiac output (CO), stroke volume (SV), left ventricular ejection fraction (LVEF), shortening fraction (FS), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV). Morphological changes of heart were observed by Masson staining. Apoptosis of myocardial cells was detected by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling stain (TUNEL) and apoptosis index (AI) was calculated. Reverse transcription-polymerase chain reaction (RT-PCR) and Western Blot were used to detect the mRNA and protein expression of myocardial SCAD respectively. In addition, the enzyme activity of SCAD, the content of adenosine triphosphate (ATP) and free fatty acid (FFA) in serum and myocardium were detected according to the kit instruction steps. Compared with Sham group, Sham+swim group showed SBP did not change significantly, with obvious eccentric hypertrophy and increased myocardial contractility, and LAD group showed persistent hypotension, obvious MI, thinning of left ventricle, and decreased myocardial systolic/diastolic function. Compared with LAD group, SBP, systolic/diastolic function and MI in LAD+swim group were significantly improved [SBP (mmHg, 1 mmHg = 0.133 kPa): 119.5±4.4 vs. 113.2±4.5 at 4 weeks, 120.3±4.0 vs. 106.5±3.7 at 6 weeks, 117.4±1.3 vs. 111.0±2.3 at 8 weeks, 126.1±1.6 vs. 119.4±1.9 at 10 weeks; CO (mL/min): 59.10±6.31 vs. 33.19±4.76, SV (μL): 139.42±17.32 vs. 84.02±14.26, LVEF: 0.523±0.039 vs. 0.309±0.011, FS: (28.17±2.57)% vs. (15.93±3.64)%, LVEDD (mm): 8.80±0.19 vs. 9.35±0.30, LVESD (mm): 5.90±0.77 vs. 7.97±0.60, LVEDV (μL): 426.57±20.84 vs. 476.24±25.18, LVESV (μL): 209.50±25.18 vs. 318.60±16.10; AI: (20.4±1.4)% vs. (31.2±4.6)%; all P < 0.05]. Compared with Sham group, the mRNA and protein expression of myocardium SCAD, the activity of SCAD in Sham+swim group were significantly increased, the content of ATP was slightly increased, the content of serum FFA was significantly decreased, and the content of myocardial FFA was slightly decreased; conversely, the mRNA and protein expression of myocardium SCAD, the activity of SCAD and the content of ATP in LAD group were significantly decreased, the content of serum and myocardial FFA were significantly increased. Compared with LAD group, the mRNA and protein expression of myocardium SCAD, the content of ATP were significantly increased in LAD+swim group [SCAD mRNA (2-ΔΔCt): 0.52±0.16 vs. 0.15±0.01, SCAD/GAPDH (fold increase from Sham group): 0.94±0.08 vs. 0.60±0.11, ATP content (μmol/g): 52.8±10.1 vs. 14.7±6.1, all P < 0.05], the content of serum and myocardial FFA were significantly decreased [serum FFA (nmol/L): 0.11±0.03 vs. 0.29±0.04, myocardial FFA (nmol/g): 32.7±8.2 vs. 59.7±10.7, both P < 0.05], and the activity of SCAD was slightly increased (kU/g: 12.3±4.3 vs. 8.9±5.8, P > 0.05). The expression of SCAD in HF was significantly down-regulated, and the expression was significantly up-regulated after aerobic exercise intervention, indicating that swimming may improve the severity of HF by up-regulating the expression of SCAD.

Metabolic Remodeling in Diabetic Cardiomyopathy.

Diabetes is a risk factor for heart failure and cardiovascular mortality with specific changes to myocardial metabolism, energetics, structure, and function. The gradual impairment of insulin production and signalling in diabetes is associated with elevated plasma fatty acids and increased myocardial free fatty acid uptake and activation of the transcription factor PPARα. The increased free fatty acid uptake results in accumulation of toxic metabolites, such as ceramide and diacylglycerol, activation of protein kinase C, and elevation of uncoupling protein-3. Insulin signalling and glucose uptake/oxidation become further impaired, and mitochondrial function and ATP production become compromised. Increased oxidative stress also impairs mitochondrial function and disrupts metabolic pathways. The diabetic heart relies on free fatty acids (FFA) as the major substrate for oxidative phosphorylation and is unable to increase glucose oxidation during ischaemia or hypoxia, thereby increasing myocardial injury, especially in ageing female diabetic animals. Pharmacological activation of PPARγ in adipose tissue may lower plasma FFA and improve recovery from myocardial ischaemic injury in diabetes. Not only is the diabetic heart energetically-impaired, it also has early diastolic dysfunction and concentric remodelling. The contractile function of the diabetic myocardium negatively correlates with epicardial adipose tissue, which secretes proinflammatory cytokines, resulting in interstitial fibrosis. Novel pharmacological strategies targeting oxidative stress seem promising in preventing progression of diabetic cardiomyopathy, although clinical evidence is lacking. Metabolic agents that lower plasma FFA or glucose, including PPARγ agonism and SGLT2 inhibition, may therefore be promising options.

Sex-related differences in the associations between plasma free fatty acid levels and clinical features in patients with hypertrophic cardiomyopathy.

BackgroundPrevious studies have indicated that inefficient energy utilization may play a pivotal role in hypertrophic cardiomyopathy (HCM). However, whether plasma free fatty acid (FFA), a main energy substrate of heart, has an effect on HCM remains unclear. Besides, several studies have suggested sex-related differences in HCM features and FFA metabolism. Here, we aimed to explore the association between plasma FFA levels and HCM and potential effects of sex on this relation.MethodsA total of 412 patients (age 47.8 ± 12.7 years, 243 males (59.0%)) with HCM were recruited. Complete medical history was collected. Echocardiography and cardiovascular magnetic resonance imaging (CMRI) were performed. Fasting plasma FFA was determined by clinical laboratory. Left ventricular mass (LVM), maximum wall thickness (MWT), and left atrium diameter (LAD) were assessed with CMRI.ResultsThe median FFA levels were 0.38 (interquartile range (IQR) 0.27–0.52) mmol/L in men and 0.40 (IQR 0.30–0.59) mmol/L in women. The FFA levels were significantly lower in men compared with those in women (p = 0.005). Compared with women, men had greater LVM index (LVMI) (96.8 ± 37.6 vs. 78.6 ± 31.5 g/m2, p < 0.001). FFA levels in male patients correlated positively with LVM, LVMI, LAD, cholesterol levels, high-density lipoprotein-cholesterol (HDL-C) levels, heart rate, and systolic blood pressure (SBP). However, none of these variables were significantly associated with sqrt (FFA) in female patients except a borderline correlation of LAD (p = 0.050). Multiple linear regression analysis was performed in male patients and revealed that HDL-C (β = 0.191, p = 0.002), heart rate (β = 0.182, p = 0.004), SBP (β = 0.167, p = 0.007), LVMI (β = 0.132, p = 0.032), and LAD (β = 0.165, p = 0.009) were independently associated with increasing FFA levels.ConclusionsIn patients with HCM, LVMI, LAD, HDL-C, SBP, and heart rate were independently associated with increasing plasma FFA levels in males, whereas not in females. These results suggest that sex may affect the pathogenesis of HCM through influencing FFA metabolism. And these sex-related differences should be taken into account in therapeutic approaches to influence myocardial FFA metabolism in HCM.

Left ventricular vascular and metabolic adaptations to high‐intensity interval and moderate intensity continuous training: a randomized trial in healthy middle‐aged men

High-intensity interval training (HIIT) has become popular, time-sparing alternative to moderate intensity continuous training (MICT), although the cardiac vascular and metabolic effects of HIIT are incompletely known. We compared the effects of 2-week interventions with HIIT and MICT on myocardial perfusion and free fatty acid and glucose uptake. Insulin-stimulated myocardial glucose uptake was decreased by training without any significantly different response between the groups, whereas free fatty acid uptake remained unchanged. Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P=0.03 for interaction) and was correlated with myocardial glucose uptake for the entire dataset and especially after HIIT training. HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT, and this should be considered when prescribing very intense HIIT for previously untrained subjects. High-intensity interval training (HIIT) is a time-efficient way of obtaining the health benefits of exercise, although the cardiac effects of this training mode are incompletely known. We compared the effects of short-term HIIT and moderate intensity continuous training (MICT) interventions on myocardial perfusion and metabolism and cardiac function in healthy, sedentary, middle-aged men. Twenty-eight healthy, middle-aged men were randomized to either HIIT or MICT groups (n=14 in both) and underwent six cycle ergometer training sessions within 2weeks (HIIT session: 4-6×30s all-out cycling/4min recovery, MICT session 40-60min at 60% V̇O2 peak ). Cardiac magnetic resonance imaging (CMRI) was performed to measure cardiac structure and function and positron emission tomography was used to measure myocardial perfusion at baseline and during adenosine stimulation, insulin-stimulated glucose uptake (MGU) and fasting free fatty acid uptake (MFFAU). End-diastolic and end-systolic volumes increased and ejection fraction slightly decreased with both training modes, although no other changes in CMRI were observed. MFFAU and basal myocardial perfusion remained unchanged. MGU was decreased by training (HIIT from 46.5 to 35.9; MICT from 47.4 to 44.4mmol100g-1 min-1 , P=0.007 for time, P=0.11 for group×time). Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P=0.03 for group×time interaction). HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT. This should be taken into account when prescribing very intense HIIT for previously untrained subjects.

Free Fatty Acid Uptake in Humans With CD36 Deficiency

Animal models have demonstrated that CD36 facilitates cell membrane free fatty acid (FFA) transport, but its role in human metabolism is not well understood. We measured heart, liver, adipose (three depots), and muscle (truncal postural and thigh locomotive) FFA uptake using [11C]palmitate positron emission tomography (PET) scans in a family of five carrying the Pro90Ser CD36 mutation (2 homozygotes had no CD36) and matched control volunteers. PET scans were done under conditions of suppressed and slightly increased palmitate concentrations. During suppressed palmitate conditions, muscle and adipose palmitate uptake were markedly reduced in homozygotes but not heterozygotes for the Pro90Ser CD36 mutation, whereas when palmitate concentration was slightly increased, uptake in muscle and adipose did not differ between control subjects and homozygous family members. Hepatic FFA uptake was similar in all participants regardless of palmitate concentrations, whereas myocardial FFA uptake was diminished in the Pro90Ser homozygotes during both suppressed and increased palmitate conditions. We conclude that CD36 1) facilitates FFA transport into muscle and adipose tissue in humans when extracellular concentrations are reduced but not when they are modestly elevated, 2) is not rate limiting for hepatic FFA uptake, and 3) is needed for normal cardiac FFA uptake over a range of FFA concentrations from low to slightly elevated.

Comment on Minamimoto: incidental focal FDG uptake in heart is a lighthouse for considering cardiac screening

Dear Sir,An interesting article has recently been published [1] on theclinical significance of focal cardiac FDG uptake inpatients with unknown cardiac disease studied for unre-lated purposes. The topic is of great interest because thepossibility to identify unexpected cardiac disease duringPET studies could allow an early diagnosis and reduceunfavorable events. The paper suggests a correlationbetween focal cardiac FDG uptake and the likelihood ofcoronary artery disease (CAD) in patients without cardiacsymptoms and unknown cardiac disease. Apart from theinteresting analysis and the effort to identify the clinicalsignificance of focal uptakes, we agree and highlight theremarks and concerns reported by the authors in the paper.The myocardium derives energy from many sources suchas free fatty acid (FFAs), glucose, pyruvate, ketone bodies,lactate, and amino acids [2–4]. In fasting and resting con-dition, heart metabolism is mainly based on FFAs oxida-tion, the myocardial FDG uptake should be negligible,glycolysis contributes only about 30 % of substrate butdietary and hormonal conditions can modify this situation[5]. In the fasting state, the rate of myocardial FFAs oxi-dation is high, inhibiting glycolysis and glucose oxidationwith consequently low levels of glucose and insulin, while,after glucose load or during hyperglycemic condition,plasma concentrations of glucose and insulin rise reducingperipheral lipolysis, lowering plasma concentrations ofFFAs and hence reducing their availability to the myo-cardium. Glucose then becomes the dominant substrate formyocardial energy production [5, 6]. However, the myo-cardial FDG uptake in the fasting healthy subjects variesunder the clinical fasting conditions [7, 8] and increasedFDG uptake in the myocardium does not significantlycorrelate with the blood glucose level, age, or duration offasting in non-diabetic patients [7, 9]. Only in the uncon-trolled diabetic patients with high levels of blood glucosethere is absent or faint myocardial FDG uptake. Myocardialischemia strikingly alters myocardial substrate metabolism[5]. As blood flow and oxygen supply decline, oxidativemetabolism decreases but still remains the dominant sourceof residual ATP production accounting for more than 90 %[10]. Ischemia is also associated with increased glycolysisbut becomes uncoupled from glucose oxidation with excessproduction of pyruvate and lactate which impair glycolysis[4, 11]. In the normal myocardium FDG distribution pat-terns could be classified into three types (absent to faintuptake; regional uptake; diffuse uptake), but they couldhave no specific meaning [7]. Moreover, even in the sameindividual and under similar fasting conditions, the myo-cardial FDG uptake is neither stable nor reproducible andthe transition from the intense FDG uptake of a dominantlyglycolytic myocardial metabolism to the absent FDGuptake of a dominantly FFAs metabolism is not entirelyuniform either temporally or regionally [6]. In daily clini-cal practise, despite adequate fasting period, the pattern ofmyocardial FDG heart uptake varies a lot, making difficultthe differential diagnosis between physiological and path-ological uptakes. For these reasons the results of

Total Depletion and Abnormal Composition of Myocardial Free Fatty Acid Stores in Patients With Advanced Heart Failure

Total Depletion and Abnormal Composition of Myocardial Free Fatty Acid Stores in Patients With Advanced Heart Failure

Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium.

The effects of timolol (2.5 mg i.v.) on coronary haemodynamics and myocardial metabolism were studied in 26 patients with angina pectoris. Cardiac venous flow (CVF) was measured by thermodilution technique. Blood was sampled for metabolic studies. Angina pectoris was induced by atrial pacing and the same heart rate was regained after timolol. Metabolic ischaemia was defined as reduction in myocardial lactate extraction ratio (MLE) by at least 50% and to a ratio below 0.15. The study was completed in 22 patients, 9 of whom fulfilled the metabolic criteria for ischaemia. This subgroup did not differ from the total group in any other respect than in lactate metabolism. Beta-adrenergic blockade reduced myocardial oxygen consumption (MVO2) and CVF significantly at rest, but MVO2, CVF, myocardial glucose uptake and MLE were unchanged during pacing despite a decrease in systolic aortic pressure, ejection time and reduced myocardial free fatty acid uptake. Conclusively, timolol did not reduce MVO2 and metabolic ischaemia during pacing-induced angina.

Effects of Metabolic Approach in Diabetic Patients with Coronary Artery Disease

The pivotal therapeutic role of myocardial metabolic modulation in ischemic heart disease (IHD) is increasingly recognized. Among the others, inhibitors of free fatty acids (FFA) oxidation have been consistently shown to play an important role in the therapeutic strategy of IHD patients. Additionally, abnormalities of glucose homeostasis are consistently present in patients with IHD, definitely contributing to the progression of the primary disease. If not adequately treated, in most patients glucose metabolism abnormalities will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. Apart from a meticulous metabolic control of frank diabetes, special attention should be also paid to insulin resistance, a condition that is generally underdiagnosed as a distinct clinical entity. An important metabolic alteration in diabetic patients is the increase in free fatty acid concentrations and the increased muscular and myocardial free fatty acid uptake and oxidation. The increased uptake and utilization of free fatty acid and the reduced utilization of glucose as source of energy during stress and ischemia are responsible for the increased susceptibility of the diabetic heart to myocardial ischemia and to a greater decrease of myocardial performance for a given amount of ischemia compared to non diabetic hearts. In order to shift cardiac metabolism from FFA to preferential glucose utilization, the use of FFA inhibitors has been advocated. Among FFA inhibitors etomoxir, perhexiline, oxfenicine and trimetazidine have been evaluated. Among them, trimetazidine, specifically a 3-ketoacyl coenzyme A thiolase inhibitor, has been shown to improve overall glucose metabolism in IHD patients with diabetes and left ventricular dysfunction. The observed combined beneficial effects of FFA inhibitors on myocardial ischemia, left ventricular function and glucose metabolism, represent an additional advantage of these drugs, especially when myocardial and glucose metabolism abnormalities coexist. In this paper, the recent literature on the beneficial therapeutic effects of FFA oxidation inhibitors on myocardial ischemia, left ventricular dysfunction and glucose metabolism in patients with ischemic heart disease and abnormalities of carbohydrate metabolism is reviewed and discussed.

Myocardial FFA metabolism during rest and atrial pacing in humans

There is limited in vivo data in humans evaluating myocardial fat utilization during increased heart work. This study was done to determine myocardial free fatty acid (FFA) metabolism during rest and atrial pacing, which increases cardiac work without changing arterial substrate concentration. We studied seven healthy men and women (age = 49.7 +/- 3.9 yr, BMI = 23.4 +/- 1.1 kg/m(2), Vo(2max) = 35.5 +/- 3.0 ml.kg(-1).min(-1), ejection fraction = 68 +/- 3%). After 3 days of dietary control, coronary sinus, femoral arterial and venous, and peripheral venous catheters were placed. Subjects received [(13)C]bicarbonate followed by a continuous infusion of [1-(13)C]palmitate through the end of the study. Arterial and coronary sinus blood sampling and measurements of resting coronary sinus blood flow were made during rest and atrial pacing to 120 beats/min. MVo(2) increased (P < 0.05) from rest to atrial pacing. Coronary sinus FFA concentration was significantly lower than arterial through rest and atrial pacing (P = 0.007). Isotopically measured myocardial palmitate uptake increased significantly from rest to atrial pacing (P = 0.03). Approximately one-third of palmitate delivery was extracted by the myocardium during rest and atrial pacing. Myocardial V(13)CO(2) production and palmitate oxidation increased significantly from rest (P < 0.01) to atrial pacing. Net glycerol balance was significantly greater than zero during rest (P = 0.04) but not different from zero during atrial pacing (P = 0.13). These data suggest that myocardial lipid uptake and oxidation increase with greater heart work during atrial pacing, with a similar relative proportion of fat oxidation to total myocardial energy expenditure.

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy. Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [(15)O]H(2)O, [(11)C]acetate, and [(11)C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9+/-8.5% to 34.8+/-12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and beta-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9+/-0.7 versus 5.5+/-0.6 mmol/L, P=0.047; insulin: 10+/-6.9 versus 7.6+/-3.6 mU/L, P=0.031; homeostasis model assessment index: 2.75+/-2.28 versus 1.89+/-1.06, P=0.027). The degree of beta-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001). In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater beta1-adrenoceptor occupancy, suggesting a synergistic mechanism.

Effect of Modified Glucose-Insulin-Potassium on Free Fatty Acids, Matrix Metalloproteinase, and Myoglobin in ST-Elevation Myocardial Infarction

Insulin has a free fatty acid (FFA)-suppressive effect, vascular endothelial growth factor (VEGF)- and matrix metalloproteinase (MMP)-lowering effect, and a potential myocardial-protective effect. Whether low-dose insulin exerts these effects in patients with acute myocardial infarction (MI) was investigated. Thirty-two patients administered thrombolytics and heparin were randomly assigned to a modified glucose-insulin-potassium (GIK) regimen (insulin 2.5 U/hour, dextrose and potassium titrated to prevent hyperglycemia) or normal saline solution and potassium (controls) for 48 hours. Plasma FFA, serum VEGF, pro-MMP-1, and myoglobin were measured at baseline and sequentially for 48 hours. FFA concentrations were increased at baseline; increased further in the first 4 hours in controls (p<or=0.008), but not in the GIK group, and were higher at 4 hours in controls compared with the GIK group (p=0.0009). VEGF decreased to 7% of baseline at 2 hours and remained suppressed in both groups (p=0.0008). Pro-MMP-1 decreased in both groups (p<0.005), but this decrease was seen earlier at 2 hours in the GIK group compared with 4 hours in controls. There was no significant increase in myoglobin at 2 hours in the GIK group, whereas there was a significant increase in controls. Mean blood glucose was 131 mg/dl in controls and 124 mg/dl in the GIK group (p=NS). In conclusion, this modified GIK regimen attenuated the increase in FFA, but did not suppress it to less than the threshold for myocardial FFA uptake. It suppressed pro-MMP-1 rapidly and decreased myoglobin, whereas heparin suppressed VEGF in patients with acute MI. This provided additional rationale for conducting a trial to assess the clinical benefits of this modified GIK regimen in patients with acute MI.

Metabolic agents in the management of diabetic coronary patients: A new era

Modulation of myocardial free fatty acid metabolism is the key target for metabolic interventions in patients with coronary artery disease (CAD) with diabetes mellitus (DM). Because of its beneficial effects on heart metabolism at rest and on myocardial ischemia and left ventricular function, trimetazidine should be always combined with classical anti-ischemic treatment in patients with DM with CAD. We believe that, the new metabolic agents including L-carnitine, dichloroacetate, perhexiline and etomoxir will be added into our arsenal for the battle against CAD especially in patients with DM in the near future.

Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene: A positron emission tomography study

The relationship between myocardial metabolic changes and the severity of left ventricular (LV) hypertrophy in patients with hypertrophic cardiomyopathy (HCM) is largely unknown. We characterized metabolic abnormalities in patients with a genetically identical cause for HCM but with variable LV hypertrophy. Eight patients with HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene underwent myocardial perfusion, oxidative, and free fatty acid (FFA) metabolism measurements via positron emission tomography and oxygen 15-labeled water, carbon 11 acetate, and fluorine 14(R,S)-[18F] Fluoro-6-thia-heptadecanoic acid (18 FTHA). LV mass, work, and efficiency were assessed by echocardiography. Thirty-six healthy volunteers served as control subjects. Compared with control subjects, HCM patients had increased myocardial oxidative metabolism and FFA uptake (P < .05). However, in patients, LV mass was inversely related to global myocardial perfusion, oxidative metabolism, and FFA uptake (all P < .03), and regional wall thickness was inversely related to regional perfusion (P < .01), oxidative metabolism (P < .001), and FFA uptake (P < .01). Therefore patients with mild (LV mass less than median of 177 g) but not advanced LV hypertrophy were characterized by increased perfusion, oxidative metabolism, and LV efficiency as compared with control subjects (P < .05). In HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, myocardial oxidative metabolism and FFA metabolism are increased and inversely related to LV hypertrophy at both the whole heart and regional level. Increased metabolism and efficiency characterize patients with mild myocardial hypertrophy. These hypermetabolic alterations regress with advanced hypertrophy.

Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure

Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM). Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8+/-8.0 years, ejection fraction 33+/-8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate-pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071+/-0.019 to 0.055+/-0.016 min(-1), P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4+/-12.6 to 31.6+/-13.3 mm Hg x L x g(-1), P<0.05). Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.

Decreased Myocardial Free Fatty Acid Uptake in Patients With Idiopathic Dilated Cardiomyopathy: Evidence of Relationship With Insulin Resistance and Left Ventricular Dysfunction

Background Results on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and β-blocker therapy. Methods and Results Nineteen patients with IDCM (age 58 ± 8 years, ejection fraction 33 ± 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [ 15O]H 2O, [ 11C]acetate and [ 11C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of β-blockade was estimated with a β-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 ± 2 versus 57 ± 12 mm Hg ·L ·g −1, P < .0001) and reduced myocardial FFA uptake (5.5 ± 2.0 versus 6.4 ± 1.2 μmol ·100 g −1 ·min −1, P < .05), but the FFA β-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction ( r = −0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA β-oxidation rate constant correlated positively with the HOMA index ( r = 0.53, P < .05). In patients on β-1 selective β-blockers, β-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective β-blocker. Conclusions Myocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.