Cardiac Free Fatty Acid Research Articles

Ginsenoside Rb1 ameliorates lipotoxicity-induced myocardial injury in diabetes mellitus by regulating Mfn2

PurposeDiabetic cardiomyopathy is a prevalent cardiovascular complication of diabetes mellitus. This study aimed to investigate the effects of ginsenoside Rb1 (GRb1) on the diabetic myocardium. MethodsLeptin receptor-deficient db/db mice and palmitic acid (PA)-treated cardiomyocyte models were utilized. Cardiac systolic and diastolic function, mitochondrial morphology, and respiratory chain function were determined. The expression of mitochondrial dynamics proteins was measured. Mitofusin 2 (Mfn2) overexpression and inhibition were achieved by lentiviral infection and small interfering RNA (siRNA) transfection. ResultsIn comparison to non-diabetic mice, db/db mice exhibited significant increases in body weight, blood glucose, blood lipids, and cardiac free fatty acid levels. This was accompanied by myocardial hypertrophy and left ventricular diastolic dysfunction, which were significantly ameliorated by GRb1 intervention. Stimulation with PA increased oxidative stress and apoptosis, and decreased viability in H9c2 cardiomyocytes. PA also reduced sarcomere contractility and relaxation in adult mice ventricular myocytes. PA-induced cellular and mitochondrial damage were reversed with GRb1 treatment. The cardiac tissue of db/db mice and PA-treated cardiomyocytes exhibited a decrease in Mfn2 expression, which was markedly improved by GRb1. Mfn2 overexpression reversed PA-induced mitochondrial fragmentation and functional damage in cardiomyocytes, while inhibition of Mfn2 expression by siRNA transfection blocked the protective effects of GRb1. ConclusionGRb1 alleviated myocardial lipid accumulation and mitochondrial injury, and attenuated ventricular diastolic dysfunction in diabetic mice. The regulation of Mfn2 was involved in the protective effects of GRb1 against lipotoxic myocardial injury.

The G-Protein-Coupled Estrogen Receptor Agonist Prevents Cardiac Lipid Accumulation by Stimulating Cardiac Peroxisome Proliferator-Activated Receptor α: A Preclinical Study in Ovariectomized-Diabetic Rat Model.

Type 2 diabetes mellitus (T2DM) is associated with cardiometabolic changes, and menopause exacerbates these conditions, leading to a greater risk of cardiovascular diseases (CVDs). The G protein-coupled estrogen receptor (GPER), which mediates the rapid effects of estrogen, has beneficial cardiac effects in both T2DM and menopause, but its mechanism of action is not well understood. This study aimed to determine whether G1 as a selective GPER-agonist has beneficial effects on cardiac lipid metabolism in ovariectomized rats with T2DM. Female Wistar rats were divided into 5 groups (n = 7 in each group): Sham-control (Sh-Ctl), T2DM, ovariectomized-T2DM (OVX-T2DM), OVX-T2DM-G1 (GPER-agonist), and OVX-T2DM-vehicle (OVX-T2DM-Veh). After stabilization of T2DM, G1 (200 μg/Kg) was administrated for 6 weeks. Then, the levels of free fatty acids (FFAs), CD36, peroxisome proliferator-activated receptor α (PPARα), and lipid accumulation in the cardiac tissue were determined. Compared with the Sh-Ctl group, cardiac FFAs (P < 0.001), CD36 (P < 0.05), and lipid accumulation (P < 0.001) increased, and cardiac PPARα (P < 0.01) decreased in T2DM animals; ovariectomy intensified these changes. Also, cardiac FFAs, PPARα, and lipid accumulation (P < 0.05) significantly decreased in the OVX-T2DM-G1 group compared to the OVX-T2DM-Veh group. However, cardiac CD36 levels did not change. G1 as a selective GPER-agonist affects lipid metabolism in T2DM animals. It also plays a vital role in improving cardiac metabolism during postmenopausal diabetic conditions.

Inhibition of dipeptidyl peptidase-4 averts free fatty acids deposition in the hearts of oral estrogen-progestin contraceptive-induced hyperinsulinemic female rats.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen-progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen-progestin-treated female rats. From our data, estrogen-progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen-progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen-progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

SODIUM ACETATE ATTENUATES MYOCARDIAL TRIGLYCERIDE ACCUMULATION IN COMBINED ORAL CONTRACEPTIVE-TREATED RATS BY SUPPRESSING ADENOSINE DEAMINASE/XANTHINE OXIDASE-DEPENDENT PATHWAY

Objective: Myocardial triglyceride accumulation characterizes many cardiovascular disorders. Cardiovascular disorders are the leading cause of mortality and morbidity worldwide. Continuous usage of Combined Oral Contraceptive (COC) has been associated with disrupted lipid metabolism, however, the exact mechanism is not clear. Adenosine Deaminase (ADA) and Xanthine Oxidase (XO) are reportedly involved in cardiometabolic derangement, particularly lipid dysmetabolism. We, therefore hypothesized that increased ADA and XO activities and elevated uric acid level are involved in COC-induced myocardial triglyceride accumulation. This study also aimed at investigating the ameliorative effects of sodium acetate on COC-induced myocardial lipid accumulation in female Wistar rats. Design and method: Female Wistar rats received vehicle per ostium (p.o.) and COC (1.0 microgram of ethinylestradiol plus 5.0 microgram of levonorgestrel; p.o.) with or without sodium acetate (ACE; 200 miligram/kilogram; p.o.) for 8 weeks (n = 6/group). Insulin resistance was estimated by homeostatic model of assessment whereas glucose tolerance was determined by oral glucose tolerance test. Other biochemical variables were evaluated using standard methods. Data were analysed using one-way analysis of variance followed by Bonferroni's post hoc test. Significant differences were accepted at p &lt; 0.05. Results: Treatment with COC led to increased 1-h postload glucose response, plasma insulin, triglyceride-glucose index, insulin resistance and impaired glucose tolerance. COC treatment also resulted in increased plasma and cardiac free fatty acid, triglyceride, triglyceride/high density lipoprotein-cholesterol ratio, malondialdehyde, uric acid, ADA and XO activities. On the other hand, COC led to reduction in nitric oxide level. However, sodium acetate significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment. Conclusions: Therefore, sodium acetate would impact positively on myocardial lipid accumulation-related cardiovascular disorders, at least in part, by suppression of adenosine deaminase/xanthine oxidase/uric acid-dependent pathway.

Dexamethasone causes defective glucose-6-phosphate dehydrogenase dependent antioxidant barrier through endoglin in pregnant and nonpregnant rats

Glucocorticoid therapy has been associated with adverse cardiometabolic effects during pregnancy. Inflammation-mediated cardiac dysfunction, an independent risk factor for morbidity and mortality, has been linked to defective glucose-6-phosphate dehydrogenase (G6PD) dependent antioxidant defenses and increased endoglin expression. We therefore sought to investigate the effects of dexamethasone (DEX) on cardiac endoglin and G6PD-dependent antioxidant defense. Twenty-four rats were randomly assigned to nonpregnant (PRE(-)), DEX-exposed nonpregnant (PRE(-) + DEX), pregnant (PRE(+)), and DEX-exposed pregnant (PRE(+) + DEX) rats, respectively (n = 6 per group). PRE(-) and PRE(+) rats received vehicle (per oral (po)), while PRE(-) + DEX and PRE(+) + DEX groups were administered DEX (0.2 mg/kg po) between gestational days 14 and 19, respectively. Results showed that DEX caused increased cardiac pro-inflammatory markers (adenosine deaminase (ADA) activity, endoglin, vascular cell adhesion molecule-1 (VCAM-1), tissue injury markers (LDH, GGT, AST, ALT, and ALP), metabolic disturbances (elevated fasting plasma glucose, free fatty acid (FFA), lactate, cardiac FFA, and lactate) and depressed G6PD-dependent antioxidant defenses (G6PD activity, reduced glutathione/oxidized glutathione ratio, and nitric oxide) in pregnant and nonpregnant rats. The present study demonstrates that DEX led to increased cardiac endoglin and VCAM-1 that is accompanied by defective G6PD-dependent antioxidant defenses but not cardiac lipid accumulation in both pregnant and nonpregnant rats.

Effect and mechanism of cardiac adipose triglyceride lipase overexpression on burn-induced cardiac injury

Objective: To explore the effect and potential mechanism of cardiac adipose triglyceride lipase (ATGL) overexpression on burn-induced cardiac injury. Methods: Eight-week-old C57BL/6J mice with cardiac ATGL overexpression driven by the myosin heavy chain (MHC) promoter (MHC-ATGL burn group) and wild-type (wild-type burn group) mice were randomly chose to the following experiments with burn injury after 24 h (n=8/group), MHC-ATGL mice and wild-type mice with corresponded age and sex were included as control. Cardiac ATGL protein expression, serum levels of cardiac troponin T and cardiac kinase-MB (CK-MB), cardiac free fatty acid and reactive oxygen species were detected. The wild-type and MHC-ATGL burn groups were not only compared with their corresponded control groups, but also compared between each other. Results: The hair color and development were shown little difference between each group. ATGL protein expression is elevated in wild-type burn group (1.00±0.68 vs 3.09±0.93, P=0.023) and decreased in MHC-ATGL burn group (17.84±2.41 vs 10.36±2.22, P<0.001), while ATGL protein expression is still increased in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Serum levels of cardiac troponin T and CK-MB were both elevated in wild-type burn group and MHC-ATGL burn group [(0.456±0.131) vs (0.076±0.019) μg/L and (0.219±0.089) vs (0.060±0.019) μg/L, (1 421±162) vs (221±67) U/L and (761±142) vs (221±41) U/L] (all P<0.001), while serum levels of cardiac troponin T and CK-MB was still decreased in MHC-ATGL burn group compared with wild-type burn group (P<0.001). In addition, cardiac free fatty acid was increased in wild-type burn group and little difference was found in MHC-ATGL burn group [(2.54±0.51) vs (0.46±0.27) mmol/L, P<0.001, and (0.81±0.38) vs (0.59±0.25) mmol/L, P=0.251], while cardiac free fatty acid was significant reduction in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Levels of cardiac reactive oxygen species was both elevated in wild-type burn group and MHC-ATGL burn group [(1.89±0.23) vs (1.00±0.18) and (1.38±0.17) vs (0.95±0.13)] (both P<0.001), while levels of cardiac reactive oxygen was reduction in MHC-ATGL burn group compared with wild-type burn group (P<0.001). Conclusion: Cardiac ATGL overexpression may protect against burn-induced cardiac injury through reducing free fatty acid and reactive oxygen species production.

P.768 Does the Camellia sinensis plant have an therapeutic effect on cognitive deficits in diabetes-induced Alzheimer?

The aim of this study was to investigate the in vivo effects of 17β-estradiol (E2) on myocardial metabolism and inducible nitric oxide synthase (iNOS) expression/activity in obese rats. Male Wistar rats were fed with a normal or a high fat (HF) diet (42% fat) for 10 weeks. Half of the HF fed rats were treated with a single dose of E2 while the other half were placebo-treated. 24 h after treatment animals were sacrificed. E2 reduced cardiac free fatty acid (FFA) (p < 0.05), L-arginine (p < 0.01), iNOS mRNA (p < 0.01), and protein (p < 0.05) levels and translocation of the FFA transporter (CD36) (p < 0.01) to the plasma membrane (PM) in HF fed rats. In contrast, Akt phosphorylation at Thr308 (p < 0.05) and translocation of the glucose transporter GLUT4 (p < 0.05) to the PM increased after E2 treatment in HF rats. Our results indicate that E2 acts via the PI3K/Akt signalling pathway to partially protect myocardial metabolism by attenuating the detrimental effects of increased iNOS expression/activity in HF fed rats.

Acute and Chronic Increases of Circulating FSTL1 Normalize Energy Substrate Metabolism in Pacing-Induced Heart Failure.

FSTL1 (follistatin-like protein 1) is an emerging cardiokine/myokine that is upregulated in heart failure (HF) and is found to be cardioprotective in animal models of cardiac injury. We tested the hypothesis that circulating FSTL1 can affect cardiac function and metabolism under baseline physiological conditions and in HF. FSTL1 was acutely (10 minutes) or chronically (2 weeks) infused to attain clinically relevant blood levels in conscious dogs with cardiac tachypacing-induced HF. Dogs with no cardiac pacing and FSTL1 infusion served as control. 3H-oleate and 14C-glucose were infused to track the metabolic fate of free fatty acids and glucose. Cardiac uptake of lactate and ketone bodies and systemic respiratory quotient were also measured. HF caused a shift from prevalent cardiac and systemic fat to carbohydrate oxidation. Although acute FSTL1 administration caused minimal hemodynamic changes at baseline, in HF dogs it enhanced cardiac oxygen consumption and transiently reversed the changes in free fatty acid and glucose oxidation and systemic respiratory quotient. In HF, chronic FSTL1 infusion stably normalized cardiac free fatty acid, glucose, ketone body consumption, and systemic respiratory quotient, while moderately improving diastolic and contractile function. Consistently, FSTL1 prevented the downregulation of medium-chain acyl-CoA dehydrogenase-a representative enzyme of the free fatty acid oxidation pathway. Complementary in vitro experiments in primary cardiac and skeletal muscle myocytes showed that FSTL1 stimulated oxygen consumption through AMPK (AMP-activated kinase) activation. These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo.

P4-3 - Cardiac Dysfunction Due to CD36 Deficiency Was Improved by Administration of Β-Blocker and Angiotensin-Converting Enzyme Inhibitor

CD36 is a multifunctional membrane-type receptor glycoprotein and transporter for long chain free fatty acids. CD36 deficiency is concerned to be caused an abnormality of cardiac free fatty acid metabolism. We reports two cases with heart failure due to CD36 deficiency. Case 1: A 36 year-old male patient was admitted with palpitation and dyspnea during exercise. Echocardiography showed significant expansion of left ventricle and ejection fraction (EF) was 31%. 123I-BMIPP myocardial perfusion scintigraphy showed absence of uptake in myocardium. In blood test, expressions of CD36 was low (granulocyte 3.3%, monocyte 3%, platelet 0.47%). Therefore, we diagnosed with heart failure due to type 1 of CD36 deficiency. His cardiac function was improved after treatment (EF = 54% after 2.5 years). Case 2: A 50 year-old female patient was admitted with weight gain and dyspnea on effort. She was pointed out low cardiac function (EF 20%) by echocardiography. She underwent 123I-BMIPP myocardial perfusion scintigraphy which showed absence of uptake in myocardium. In blood test, expressions of CD36 was low (granulocyte 2.0%, monocyte 4.5%, platelet 0.32%). Therefore, we diagnosed with heart failure due to type 1 of CD36 deficiency. Her cardiac function was improved after treatment (EF 36% after 6 months). Conclusion: Cardiac dysfunction due to CD36 deficiency was improved by administration of Angiotensin-converting enzyme inhibitor and β-blocker.

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

The aim of this study was to investigate the in vivo effects of 17β-estradiol (E2) on myocardial metabolism and inducible nitric oxide synthase (iNOS) expression/activity in obese rats. Male Wistar rats were fed with a normal or a high fat (HF) diet (42% fat) for 10 weeks. Half of the HF fed rats were treated with a single dose of E2 while the other half were placebo-treated. 24 h after treatment animals were sacrificed. E2 reduced cardiac free fatty acid (FFA) (p < 0.05), L-arginine (p < 0.01), iNOS mRNA (p < 0.01), and protein (p < 0.05) levels and translocation of the FFA transporter (CD36) (p < 0.01) to the plasma membrane (PM) in HF fed rats. In contrast, Akt phosphorylation at Thr308 (p < 0.05) and translocation of the glucose transporter GLUT4 (p < 0.05) to the PM increased after E2 treatment in HF rats. Our results indicate that E2 acts via the PI3K/Akt signalling pathway to partially protect myocardial metabolism by attenuating the detrimental effects of increased iNOS expression/activity in HF fed rats.

Phenylpyruvic Acid-2-O-β-D-Glucoside Attenuates High Glucose-Induced Apoptosis in H9c2 Cardiomyocytes.

Chronic hyperglycemia is closely associated with impaired substrate metabolism, dysregulated mitochondrial membrane potential, and apoptosis in the diabetic heart. As adult cardiomyocytes display a limited capacity to regenerate following an insult, it is essential to protect the myocardium against the detrimental effects of chronic hyperglycemia. This study therefore investigated whether phenylpyruvic acid-2-O-β-D-glucoside, present in Aspalathus linearis (rooibos), is able to attenuate hyperglycemia-induced damage in H9c2 cardiomyocytes. H9c2 cardiomyocytes were exposed to a high glucose concentration (33 mM) prior to treatment with phenylpyruvic acid-2-O-β-D-glucoside (1 µM), metformin (1 µM), or a combination of phenylpyruvic acid-2-O-β-D-glucoside and metformin (both at 1 µM). Our data revealed that high glucose exposure increased cardiac free fatty acid uptake and oxidation, mitochondrial membrane potential, and apoptosis (caspase 3/7 activity and TUNEL), and decreased the Bcl2/Bax protein expression ratio. Phenylpyruvic acid-2-O-β-D-glucoside treatment, alone or in combination with metformin, attenuated these glucose-induced perturbations, confirming its protective effect in H9c2 cardiomyocytes exposed to chronic hyperglycemia.

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.

The gut hormone ghrelin partially reverses energy substrate metabolic alterations in the failing heart.

The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects; hence, it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. Human des-acyl ghrelin [1.2 nmol/kg per hour] was infused intravenously for 15 minutes, followed by washout (rebaseline) and infusion of acyl ghrelin at the same dose. (3)H-oleate and (14)C-glucose were coinfused and arterial and coronary sinus blood sampled to measure cardiac free fatty acid and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF because baseline oxidation levels of free fatty acids and glucose were, respectively, >70% lower and >160% higher compared with control. Neither des-acyl ghrelin nor acyl ghrelin significantly affected function and metabolism in normal hearts. However, in HF, des-acyl and acyl ghrelin enhanced myocardial oxygen consumption by 10.2±3.5% and 9.9±3.7%, respectively (P<0.05), and cardiac mechanical efficiency was not significantly altered. This was associated, respectively, with a 41.3±6.7% and 32.5±10.9% increase in free fatty acid oxidation and a 31.3±9.2% and 41.4±8.9% decrease in glucose oxidation (all P<0.05). Acute increases in des-acyl or acyl ghrelin do not interfere with cardiac metabolism in normal dogs, whereas they enhance free fatty acid oxidation and reduce glucose oxidation in HF dogs, thus partially correcting metabolic alterations in HF. This novel mechanism might contribute to the cardioprotective effects of ghrelin in HF.

Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure

When recovering from heart failure (HF), the myocardium displays a marked plasticity and can regain normal gene expression and function; however, recovery of substrate oxidation capacity has not been explored. We tested whether cardiac functional recovery is matched by normalization of energy substrate utilization during post-HF recovery. HF was induced in dogs by pacing the left ventricle (LV) at 210-240 beats/min for 4 wk. Tachycardia was discontinued, and the heart was allowed to recover. An additional group was studied in HF, and healthy dogs served as controls (n = 8/group). Cardiac free fatty acids (FFAs) and glucose oxidation were measured with [3H]oleate and [14C]glucose. At 10 days of recovery, hemodynamic parameters returned to control values; however, the contractile response to dobutamine remained depressed, LV end-diastolic volume was 28% higher than control, and the heart mass-to-body mass ratio was increased (9.8 +/- 0.4 vs. 7.5 +/- 0.2 g/kg, P < 0.05). HF increased glucose oxidation (76.8 +/- 19.7 nmol.min(-1).g(-1)) and decreased FFA oxidation (20.7 +/- 6.4 nmol.min(-1).g(-1)), compared with normal dogs (24.5 +/- 6.3 and 51.7 +/- 9.6 nmol.min(-1).g(-1), respectively), and reversed to normal values at 10 days of recovery (25.4 +/- 6.0 and 46.6 +/- 6.7 nmol.min(-1).g(-1), respectively). However, similar to HF, the recovered dogs failed to increase glucose and fatty acid uptake in response to pacing stress. The activity of myocardial citrate synthase and aconitase was significantly decreased during recovery compared with that in control dogs (58 and 27% lower, respectively, P < 0.05), indicating a persistent reduction in mitochondrial oxidative capacity. In conclusion, cardiac energy substrate utilization is normalized in the early stage of post-HF recovery at baseline, but not under stress conditions.

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.

Normalization of the myocardial metabolic phenotype precedes the cardiac contractile recovery and morphological reverse remodeling during post‐heart failure recompensation in chronic dogs

We tested the hypothesis that full functional recovery requires the normalization of the myocardial metabolic phenotype in post‐heart failure recompensation. In 6 chronically instrumented dogs, heart failure (HF) was induced by pacing the left ventricle (LV) at high frequency for 4 weeks. When LV end‐diastolic pressure reached 23±1 mmHg, the pacemaker was turned off to allow 10 days for recompensation. The comparisons were made with 5 dogs in HF and 5 control dogs. Cardiac free fatty acids and glucose oxidation were measured by infusing 3H‐oleate and 14C‐glucose intravenously. After recompensation, hemodynamic parameters returned to control values, however dP/dtmax and LV ejection fraction remained, respectively, 15.8±5.3 and 14.6±2.4% lower than control (both P&lt;0.05) and the heart weight to bodyweight ratio was increased (9.9±0.5 vs 8.0±0.1 g/kg, P&lt;0.05). Despite this incomplete functional and morphological recovery, fatty acid and glucose oxidation returned to control values and therefore they were, compared to HF, respectively higher (45.1±7.1 vs 20.4±7.7 nmol/min/g, P&lt;0.05) and lower (28.9±7.8 vs 61.6±15.9 nmol/min/g, P&lt;0.05). No significant differences in cardiac oxygen consumption were found among groups. In conclusion, in post‐HF recompensation, the normalization of cardiac substrate utilization is dissociated from complete functional recovery and reverse morphological remodeling. Supported by P01‐HL‐74237.

The Role of Cardiac Free Fatty Acid Metabolism in Verapamil Toxicity Treated with Intravenous Fat Emulsions

The Role of Cardiac Free Fatty Acid Metabolism in Verapamil Toxicity Treated with Intravenous Fat Emulsions

PPARγ agonist induced cardiac enlargement is associated with reduced fatty acid and increased glucose utilization in myocardium of Wistar rats

In toxicological studies, high doses of peroxisome proliferator-activated receptor-gamma (PPARγ) agonists cause cardiac enlargement. To investigate whether this could be explained by a large shift from free fatty acid to glucose utilization by the heart, Wistar rats were treated for 2–3 weeks with a potent, selective PPARγ agonist (X334, 3 μmol/kg/d), or vehicle. X334 treatment increased body-weight gain and ventricular mass. Treatment lowered plasma triglycerides by 61%, free fatty acid levels by 72%, insulin levels by 45%, and reduced total plasma protein concentration by 7% (indicating plasma volume expansion) compared to vehicle animals. Fasting plasma glucose levels were unaltered. To assess cardiac free fatty acid and glucose utilization in vivo we used simultaneous infusions of non-β-oxidizable free fatty acid analogue, [9,10- 3H]( R)-2-bromopalmitate and [U- 14C]2-deoxy- d-glucose tracers, which yield indices of local free fatty acid and glucose utilization. In anesthetized, 7 h fasted animals, left ventricular glucose utilization was increased to 182% while free fatty acid utilization was reduced by 28% ( P < 0.05) compared to vehicle. In separate studies we attempted to prevent the X334-induced hypolipidemia. Various dietary fat supplements were unsuccessful. By contrast, restricting the time during which the treated animals had access to food (promoting endogenous lipolysis), restored plasma free fatty acid from 27% to 72% of vehicle control levels and prevented the cardiac enlargement. Body-weight gain in these treated-food restricted rats was not different from vehicle controls. In conclusion, the cardiac enlargement caused by intense PPARγ activation in normal animals is associated with marked changes in free fatty acid/glucose utilization and the enlargement can be prevented by restoring free fatty acid availability.

Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs

Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1) po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [(3)H]oleate, [(14)C]glucose, and [(13)C]lactate, respectively. After 10 days of L-NAME administration, despite no differences in left ventricular afterload, cardiac O(2) consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 +/- 2.0 vs. 1.7 +/- 0.5 micromol.min(-1).100 g(-1), P < 0.05 vs. control) and lactate (21.6 +/- 5.6 vs. 11.8 +/- 2.6 micromol.min(-1).100 g(-1), P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 micromol.kg(-1).min(-1) iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the L-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.

Takotsubo-shaped cardiomyopathy with type I CD36 deficiency

A transient left ventricular apical ballooning (so-called "ampulla" or "Takotsubo-shaped" cardiomyopathy) with type I CD36 deficiency is described in a 71-year-old woman. The patient was referred because of chest pain and worsening of dyspnea. Electrocardiogram showed T-wave inversions on the precordal leads, and acute coronary syndrome was suspected. Left ventricular apical ballooning was observed by echocardiogram and left ventriculography, and coronary arteriography did not reveal any significant stenosis. Left ventricular motion normalized at the follow-up period and there were no increases in specific markers for myocardial damage, such as myocardial band fraction of creatine kinase and troponin T, through out the admission. 123I-metaiodobengylguanidine myocardial single photon emission computed tomography (SPECT) revealed decreased accumulation areas at the apex, while 201Tl SPECT showed normal accumulation. An abnormal metabolism of cardiac free fatty acid was suggested by lack of accumulation of 123I beta-methyliodophenyl pentadecanoic acid (BMIPP) SPECT. No CD36 expression in either platelets or monocytes/macrophages was shown using flow cytometer analysis and type I CD36 deficiency was diagnosed. DNA sequencing showed that the patient had compound heterozygosity of the CD36 gene (a nucleotide change in C478T and an adenine insertion at nucleotide 1159 in exon 10). Although CD36 deficiency is thought to be involved with many cardiovascular disease and metabolic abnormalities, Takotsubo-shaped cardiomyopathy with CD36 deficiency had not been reported. Further studies of Takotsubo-shaped cardiomyopathy and CD36 deficiency may reveal an association between this cardiomyopathy and specific genetic profiles.