Adropin在慢性心力衰竭中的作用机制研究
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摘要
目前心力衰竭的治疗方案包括拮抗神经内分泌系统的激活,比如β受体阻滞剂、血管紧张素转换酶抑制、血管紧张素受体拮抗剂、醛固酮拮抗剂等药物,对症治疗,比如利尿剂、强心甙等药物,以及机械辅助治疗。虽然心力衰竭的治疗措施已经取得了长足发展,但心力衰竭的患病率和死亡率仍居高不下,晚期心力衰竭患者人数在逐年增多,这些患者需要新的治疗策略来改善他们的预后。
正常心脏依靠线粒体氧化磷酸化生成的大量ATP来维持自身舒缩功能,其中约60-90%的ATP来自脂肪酸氧化,10-40%的ATP来自乳酸盐和葡萄糖。既往动物和临床研究证实心力衰竭时心肌能量代谢出现异常,转变心肌底物代谢模式能改善心室功能,减缓心力衰竭患者左心室功能障碍的发生。心肌能量代谢调节有望成为一种新型的心力衰竭治疗手段。
Adropin是2008年由Kumar等在研究下丘脑性肥胖小鼠肝脏基因表达时发现的一种由76个氨基酸构成的分泌性蛋白,它由能量动态平衡相关基因(Enho)编码,后者在肝脏、脑部、脐静脉和冠状动脉内皮细胞都有表达。肝脏Enho表达受机体能量代谢状态和摄取食物中的营养成分组成调节,在肥胖状态下发生改变。转基因过表达或重组adropin治疗能改善进食诱导的肥胖模型胰岛素抵抗和葡萄糖耐量受损。Adropin能减弱与肥胖相关的代谢紊乱,而肥胖易与高血压病、胰岛素抵抗、血脂异常等集结出现,是心力衰竭的独立危险因素,据此,我们推测adropin可能参与了心力衰竭的病理生理过程。本研究主要探讨adropin与心力衰竭的关系及其对心肌细胞的作用,希望找到一个以adropin作为靶点的新的心力衰竭能量代谢治疗方法。
第一部分:慢性心力衰竭患者外周血adropin水平的变化及意义
目的:探讨慢性心力衰竭患者外周血adropin水平的变化及其临床意义。
方法:根据最新ACC/AHA慢性心力衰竭诊断和治疗指南,入选56例慢性心力衰竭患者和20例健康对照者;用ELISA法测adropin、TNF-α、IL-6水平;同时采用RIA法检测BNP水平;用全自动生化分析仪测血糖、血脂、肝肾功能;测量患者身高、体重,计算体重指数;超声检测心脏功能。
结果:心力衰竭组LVEF随着NYHA心功能分级的加重而降低,BNP浓度随着NYHA心功能分级的加重而明显增高,BNP与LVEF负相关(r=-0.889,p<0.001)。在NYHAⅣ级的心力衰竭组,IL-6和Cr比对照组明显增高(p<0.05,p<0.05),而TC和LDL-C比对照组降低(p<0.01,p<0.05)。以NYHA心功能分级的3组心力衰竭组及正常对照组间adropin水平差异显著(p<0.001):血浆adropin水平随着心功能的恶化而升高,对照组:6.0±0.3 ng/mL;NYHAⅡ:7.6±0.4 ng/mL;NYHAⅢ:9.8±0.5 ng/mL; NYHAⅣ:12.4±0.6 ng/mL。慢性心力衰竭患者adropin水平与血浆BNP水平成正比(r=0.723,p<0.001),与血浆IL-6水平成正比(r=0.326,p<0.01),与血浆Cr水平成正比(r=0.238,p<0.05),与BMI成正比(r=0.295,p<0.05)。血浆adropin水平与LVEF负相关(r=-0.710,p<0.001)。多元线性回归分析表明,血浆BNP和BMI是心力衰竭患者血浆adropin水平的主要影响因素。
结论:慢性心力衰竭患者血浆adropin水平随着心功能的恶化而增高。多元线性回归分析证实BNP和BMI是血浆adropin水平的主要影响因素。这些发现表明慢性心力衰竭患者释放到血液中的adropin增多可能参与了心力衰竭发展的病理生理过程,但是具体的机制需要进一步的研究。
第二部分:重组adropin对缺血性心力衰竭大鼠模型心功能的影响
目的:检测缺血性心力衰竭大鼠模型外周血adropin水平的变化;观察重组adropin注射2周后对缺血性心力衰竭大鼠模型心功能的影响。
方法:采用50只SD大鼠分为实验组(n=40)和假手术组(n=10),实验组大鼠通过前降支结扎至心肌梗死的方法构建心力衰竭模型,并经超声证实,术后2周分为早期干预组和晚期干预组,每组再分为生理盐水治疗组(n=6)和adropin治疗组(n=6),adropin治疗组腹腔注射adropin 100ug/kg/d,生理盐水治疗组腹腔注射同等量生理盐水,治疗2周后进行各项检测。检测早期干预组的生理盐水治疗组和假手术组大鼠术前及术后24h、3d、2w、4w的adropin水平;早期干预组大鼠治疗2周后处死,进行心肌病理组织学检测,用TUNEL试剂盒进行细胞凋亡检测;晚期干预组大鼠治疗2周后进行超声检测大鼠心脏左室舒张末直径(LVEDD)、左室收缩末直径(LVESD)、左室舒张末容积(LVEDV)、左室收缩末容积(LVESV)和左室射血分数(LVEF)。
结果:早期干预组与假手术组相比,术后24小时adropin水平显著下降(3.22±0.24ng/mL vs 5.60±0.16ng/mL, p<0.01),术后3日adropin水平较假手术组升高,但是不明显,直到术后4周较假手术组明显增加(8.06±0.15ng/mL vs 5.96±0.15ng/mL, p<0.01);在早期干预组中，生理盐水治疗组心肌变性坏死明显，而adropin治疗组虽有心肌变性坏死,但程度明显降低;③在早期干预组中,生理盐水治疗组TUNEL阳性细胞率明显高于adropin治疗组(39.8±8.2% vs 4.67±2.2%, p<0.01, n=6);③在晚期干预组中,adropin治疗组与生理盐治疗组相比,大鼠心脏LVEF明显改善(48.72±6.58% vs 35.52±2.05, p<0.01, n=6)。
结论:心梗后大鼠血清adropin水平早期即出现波动,有短期内先下降而后持续上升特点,进入心力衰竭期后水平进一步升高。重组adropin治疗2周后明显减轻心梗后心肌变性坏死和细胞凋亡,改善缺血性心力衰竭大鼠的心功能。
第三部分:Adropin对心肌细胞肥大、凋亡的作用及其机制
目的:观察:①adropin对缺氧诱导心肌细胞肥大和凋亡的影响;②adropin对乳鼠原代心肌细胞AMPK信号通路活化的作用。
方法:MTT法检测不同浓度adropin的干预对乳鼠原代心肌细胞在缺氧条件下细胞存活率的影响;Bradford法检测不同浓度adropin的干预对心肌细胞蛋白含量和合成速度的影响;Westernblot检测缺氧条件下adropin干预对乳鼠原代心肌细胞0～4小时p-AMPK水平变化的影响;Annexin V-FITC检测adropin对缺氧条件下乳鼠心肌细胞凋亡的影响。
结果:与对照组相比,10~(-8)~10~(-6)mol/L的adropin干预后可显著提高心肌细胞在低氧条件下的存活率(p<0.01),并呈浓度依赖性;与对照组相比，10~(-6)mol/L adropin干预可明显抑制低氧诱导的心肌细胞总蛋白含量和合成速度增高(p<0.01);与无血清组相比,adropin组细胞凋亡率无明显改变(p=0.12),但是adropin+缺氧组凋亡率较缺氧组显著降低(p<0.01),加入p-AMPK抑制物compound c后adropin+缺氧组凋亡增加,与缺氧组相比无显著差异;④10~(-6)mol/L的adropin干预可使体外培养的乳鼠心肌细胞p-AMPK水平较对照组增高(p<0.01)。
结论:Adropin可增加缺氧条件下心肌细胞的活性,抑制细胞肥大,提高心肌细胞的p-AMPK水平,并通过AMPK通路抑制心肌细胞凋亡。
Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensinreceptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies.
Normal cardiac function is dependent on a constant resynthesis of ATP by oxidative phosphorylation in the mitochondria. The healthy heart gets 60–90% of its energy for oxidative phosphorylation from fatty acid oxidation, with the balance from lactate and glucose. The failing heart has been shown to be metabolically abnormal, in both animal models and in patients, and chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction in heart failure patients. Thus, regulation of cardiac energy metabolism is expected to be a new therapeutic strategy for heart failure.
Adropin was initially discovered by Kumar et al. in 2008 during microarray analysis of liver gene expression in mouse models of obesity. Adropin is encoded by Energy Homeostasis Associated gene (Enho) that is expressed in the liver, brain, human umbilical vein and coronary artery endothelial cells. Liver Enho expression is regulated by energy status and dietary nutrient content, and is altered with obesity. Transgenic overexpression or systemic adropin treatment improves diet-induced obesity, insulin resistance, and glucose tolerance. Elevated BMI and obesity have been associated with the cardiovascular disease risk factors of hypertension, insulin resistance and dyslipidemia. Obesity has been linked to the development of HF. Thus, we hypothesized that adropin may also be related to the failing heart. In the present study, we are intent to investigate the relationship between adropin and HF, and to explore the effects of adropin on proliferation, apoptosis and energy metabolism in cardiocytes.
PartⅠChanges of circulating adropin and its significance in CHF patients
Objective: Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis. we investigated plasma adropin levels in patients with CHF and evaluated the relationship between those and the severity of CHF.
Methods: According to the present guidelinges for the diagnosis and management of chronic heart failure of the ACC/AHA, 56 patients with CHF and 20 healthy subjects were enrolled in this study. Plasma levels of adropin, TNF-α, IL-6 were measured using a commercial ELISA kit, and plasma BNP levels were measured with a commercial RIA kit. The plasma glucose levels were measured by an automated glucose oxidase method, serum levels of total TC, TG, HDL-C, LDL-C were measured by enzymatic methods using the autoanalyzer. The height and weight of subjects were measured to calculate the BMI. Ultrasonic was used to measure the heart function.
Results: The LVEF gradually decreased and, inversely, plasma levels of BNP were exponentially elevated according to NYHA class in the CHF patients. Plasma BNP had a negative correlation with LVEF (r =-0.889, p<0.001,). Plasma levels of IL–6 and Cr were significantly higher in the classⅣpatients than those in the control group (p<0.05, p<0.05, respectively). Lipid analysis showed that plasma levels of TC and LDL-C were lower in the classⅣthan those in the control group (p<0.01, p<0.05, respectively). The plasma level of adropin increased with the deterioration of cardiac function ( control: 6.0±0.3 ng/mL; NYHAⅡ: 7.6±0.4 ng/mL; NYHAⅢ: 9.8±0.5 ng/mL; NYHAⅣ: 12.4±0.6 ng/mL, respectively, p<0.001). Plasma adropin level had a positive correlation with plasma BNP levels (r=0.723, p<0.001), plasma IL-6 levels (r=0.326, p<0.05),plasma Cr (r=0.238, p<0.05) and BMI (r=0.295, p<0.05). Plasma adropin levels negatively correlated with LVEF (r =-0.710, p<0.001,). In the multiple regression analysis, plasma BNP and BMI had independent impact on plasma adropin level in patients with CHF.
Conclusion: Plasma adropin levels were significantly increased according to the severity of CHF. Multiple regression analysis showed BNP and BMI had independent impact on plasma adropin level. These findings suggest that the augmented release of adropin may be involved in the pathogenesis of CHF, but further study is necessary to explain the exact role of adropin in CHF.
PartⅡEffect of synthetic adropin on cardiac function of HF rat
Objective: To investigate the changes of circulating adropin levels in ischemic heart failure model of rats and the effects of treatment with adropin for 2 weeks on cardiac function.
Methods: The SD rats were divided into experimental group (n = 40) and sham operation group (n=10), and model of heart failure induced by myocardial infarction was set up by ligating left descending anterior branch. The 40 rat models of heart failure were divided into early intervention group and late intervention group, each group was further divided into saline treatment group (n=6) and adropin treatment group (n=6). In adropin treatment group, rats were treated with 100ug/kg/d of adropin by intraperitoneal injection, and in saline treatment group, rats were treated with same doses of physiological saline. In early intervention saline treatment group and sham operation group, adropin was measured in five points of time, such as preoperative, postoperative 24h, 3d, 2wks, 4wks. In early intervention group, the histopathology of rat heart was observed by Gonori chromotropic acid staining and TUNEL kit after 2 weeks of treatment. In late intervention group, echocardiography was examined after 2 weeks of treatment.
Results: Compared with sham operation group, adropin levels of rat in early intervention group were drop significantly in postoperative 24 hour (3.22±0.24ng/mL vs 5.60±0.16ng/mL, p<0.01), and began to increase in postoperative 3 days, but there was not statistically significant. The adropin levels were significantly increased in postoperative 4 weeks compared with sham operation group (8.06±0.15ng/mL vs 5.96±0.15ng/mL, p<0.01). In early intervention group, the degeneration and necrosis of rat myocardium in saline treatment group were much more serious than that in adropin treatment group. In early intervention group, TUNEL positive cells rate of rats in saline treatment group was significantly higher than that in adropin treatment group (39.8±8.2% vs 4.67±2.2%, p<0.01). In the late intervention group, LVEF of rat heart in adropin treatment group was significantly higher than that in saline treatment group (48.72±6.58% vs 35.52±2.05, p<0.01).
Conclusion: After myocardial infarction, adropin levels of rat were transiently drop and then continued to rise. Treatment with adropin attenuated myocardial necrosis and apoptosis, and improved heart function of heart failure rat.
PartⅢEffects of adropin on proliferation and apoptosis of cardiomyocyte
Objective: Obeserve effects of adropin on AMPK pathways activating, and apoptosis induced by hypoxia in rat neonatal cardiomyocytes.
Methods: MTT method was used to detect cell livability; Bradford method was used to measure cell protein level and synthetic speed of protein; Westernblot was used to detect cell p-AMPK levels; Annexin V-FITC was used to detect cell apoptosis in rat neonatal cardiomyocytes.
Results: Compared with the control group, adropin significantly increased cell livability in hypoxic conditions (p<0.01), and reduced the total protein and the protein synthesis speed with a dose-response trend (p<0.01). Compared with serum-free group, there was no significant changes in cell apoptosis rate in adropin group cell (p=0.12), but apoptosis rate of adropin+hypoxia group cell was significantly reduced compared with hypoxia group (p < 0.01),this effect can be reversed by compound c,which is an inhibitor of p-AMPK. Treating with adropin (10~(-6) mol/L), the p-AMPK level in adropin+hypoxia group transiently increased in 15min to 30min compared with hypoxia group (p < 0.01).
Conclusion: Adropin increased livability of cell, inhibited cell hypertrophy, elevated p-AMPK level in rat neonatal cardiomyocytes, and it had anti-apoptotic effects through AMPK activities under the condition of hypoxia.
正常心脏依靠线粒体氧化磷酸化生成的大量ATP来维持自身舒缩功能,其中约60-90%的ATP来自脂肪酸氧化,10-40%的ATP来自乳酸盐和葡萄糖。既往动物和临床研究证实心力衰竭时心肌能量代谢出现异常,转变心肌底物代谢模式能改善心室功能,减缓心力衰竭患者左心室功能障碍的发生。心肌能量代谢调节有望成为一种新型的心力衰竭治疗手段。
Adropin是2008年由Kumar等在研究下丘脑性肥胖小鼠肝脏基因表达时发现的一种由76个氨基酸构成的分泌性蛋白,它由能量动态平衡相关基因(Enho)编码,后者在肝脏、脑部、脐静脉和冠状动脉内皮细胞都有表达。肝脏Enho表达受机体能量代谢状态和摄取食物中的营养成分组成调节,在肥胖状态下发生改变。转基因过表达或重组adropin治疗能改善进食诱导的肥胖模型胰岛素抵抗和葡萄糖耐量受损。Adropin能减弱与肥胖相关的代谢紊乱,而肥胖易与高血压病、胰岛素抵抗、血脂异常等集结出现,是心力衰竭的独立危险因素,据此,我们推测adropin可能参与了心力衰竭的病理生理过程。本研究主要探讨adropin与心力衰竭的关系及其对心肌细胞的作用,希望找到一个以adropin作为靶点的新的心力衰竭能量代谢治疗方法。
第一部分:慢性心力衰竭患者外周血adropin水平的变化及意义
目的:探讨慢性心力衰竭患者外周血adropin水平的变化及其临床意义。
方法:根据最新ACC/AHA慢性心力衰竭诊断和治疗指南,入选56例慢性心力衰竭患者和20例健康对照者;用ELISA法测adropin、TNF-α、IL-6水平;同时采用RIA法检测BNP水平;用全自动生化分析仪测血糖、血脂、肝肾功能;测量患者身高、体重,计算体重指数;超声检测心脏功能。
结果:心力衰竭组LVEF随着NYHA心功能分级的加重而降低,BNP浓度随着NYHA心功能分级的加重而明显增高,BNP与LVEF负相关(r=-0.889,p<0.001)。在NYHAⅣ级的心力衰竭组,IL-6和Cr比对照组明显增高(p<0.05,p<0.05),而TC和LDL-C比对照组降低(p<0.01,p<0.05)。以NYHA心功能分级的3组心力衰竭组及正常对照组间adropin水平差异显著(p<0.001):血浆adropin水平随着心功能的恶化而升高,对照组:6.0±0.3 ng/mL;NYHAⅡ:7.6±0.4 ng/mL;NYHAⅢ:9.8±0.5 ng/mL; NYHAⅣ:12.4±0.6 ng/mL。慢性心力衰竭患者adropin水平与血浆BNP水平成正比(r=0.723,p<0.001),与血浆IL-6水平成正比(r=0.326,p<0.01),与血浆Cr水平成正比(r=0.238,p<0.05),与BMI成正比(r=0.295,p<0.05)。血浆adropin水平与LVEF负相关(r=-0.710,p<0.001)。多元线性回归分析表明,血浆BNP和BMI是心力衰竭患者血浆adropin水平的主要影响因素。
结论:慢性心力衰竭患者血浆adropin水平随着心功能的恶化而增高。多元线性回归分析证实BNP和BMI是血浆adropin水平的主要影响因素。这些发现表明慢性心力衰竭患者释放到血液中的adropin增多可能参与了心力衰竭发展的病理生理过程,但是具体的机制需要进一步的研究。
第二部分:重组adropin对缺血性心力衰竭大鼠模型心功能的影响
目的:检测缺血性心力衰竭大鼠模型外周血adropin水平的变化;观察重组adropin注射2周后对缺血性心力衰竭大鼠模型心功能的影响。
方法:采用50只SD大鼠分为实验组(n=40)和假手术组(n=10),实验组大鼠通过前降支结扎至心肌梗死的方法构建心力衰竭模型,并经超声证实,术后2周分为早期干预组和晚期干预组,每组再分为生理盐水治疗组(n=6)和adropin治疗组(n=6),adropin治疗组腹腔注射adropin 100ug/kg/d,生理盐水治疗组腹腔注射同等量生理盐水,治疗2周后进行各项检测。检测早期干预组的生理盐水治疗组和假手术组大鼠术前及术后24h、3d、2w、4w的adropin水平;早期干预组大鼠治疗2周后处死,进行心肌病理组织学检测,用TUNEL试剂盒进行细胞凋亡检测;晚期干预组大鼠治疗2周后进行超声检测大鼠心脏左室舒张末直径(LVEDD)、左室收缩末直径(LVESD)、左室舒张末容积(LVEDV)、左室收缩末容积(LVESV)和左室射血分数(LVEF)。
结果:早期干预组与假手术组相比,术后24小时adropin水平显著下降(3.22±0.24ng/mL vs 5.60±0.16ng/mL, p<0.01),术后3日adropin水平较假手术组升高,但是不明显,直到术后4周较假手术组明显增加(8.06±0.15ng/mL vs 5.96±0.15ng/mL, p<0.01);在早期干预组中，生理盐水治疗组心肌变性坏死明显，而adropin治疗组虽有心肌变性坏死,但程度明显降低;③在早期干预组中,生理盐水治疗组TUNEL阳性细胞率明显高于adropin治疗组(39.8±8.2% vs 4.67±2.2%, p<0.01, n=6);③在晚期干预组中,adropin治疗组与生理盐治疗组相比,大鼠心脏LVEF明显改善(48.72±6.58% vs 35.52±2.05, p<0.01, n=6)。
结论:心梗后大鼠血清adropin水平早期即出现波动,有短期内先下降而后持续上升特点,进入心力衰竭期后水平进一步升高。重组adropin治疗2周后明显减轻心梗后心肌变性坏死和细胞凋亡,改善缺血性心力衰竭大鼠的心功能。
第三部分:Adropin对心肌细胞肥大、凋亡的作用及其机制
目的:观察:①adropin对缺氧诱导心肌细胞肥大和凋亡的影响;②adropin对乳鼠原代心肌细胞AMPK信号通路活化的作用。
方法:MTT法检测不同浓度adropin的干预对乳鼠原代心肌细胞在缺氧条件下细胞存活率的影响;Bradford法检测不同浓度adropin的干预对心肌细胞蛋白含量和合成速度的影响;Westernblot检测缺氧条件下adropin干预对乳鼠原代心肌细胞0～4小时p-AMPK水平变化的影响;Annexin V-FITC检测adropin对缺氧条件下乳鼠心肌细胞凋亡的影响。
结果:与对照组相比,10~(-8)~10~(-6)mol/L的adropin干预后可显著提高心肌细胞在低氧条件下的存活率(p<0.01),并呈浓度依赖性;与对照组相比，10~(-6)mol/L adropin干预可明显抑制低氧诱导的心肌细胞总蛋白含量和合成速度增高(p<0.01);与无血清组相比,adropin组细胞凋亡率无明显改变(p=0.12),但是adropin+缺氧组凋亡率较缺氧组显著降低(p<0.01),加入p-AMPK抑制物compound c后adropin+缺氧组凋亡增加,与缺氧组相比无显著差异;④10~(-6)mol/L的adropin干预可使体外培养的乳鼠心肌细胞p-AMPK水平较对照组增高(p<0.01)。
结论:Adropin可增加缺氧条件下心肌细胞的活性,抑制细胞肥大,提高心肌细胞的p-AMPK水平,并通过AMPK通路抑制心肌细胞凋亡。
Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensinreceptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies.
Normal cardiac function is dependent on a constant resynthesis of ATP by oxidative phosphorylation in the mitochondria. The healthy heart gets 60–90% of its energy for oxidative phosphorylation from fatty acid oxidation, with the balance from lactate and glucose. The failing heart has been shown to be metabolically abnormal, in both animal models and in patients, and chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction in heart failure patients. Thus, regulation of cardiac energy metabolism is expected to be a new therapeutic strategy for heart failure.
Adropin was initially discovered by Kumar et al. in 2008 during microarray analysis of liver gene expression in mouse models of obesity. Adropin is encoded by Energy Homeostasis Associated gene (Enho) that is expressed in the liver, brain, human umbilical vein and coronary artery endothelial cells. Liver Enho expression is regulated by energy status and dietary nutrient content, and is altered with obesity. Transgenic overexpression or systemic adropin treatment improves diet-induced obesity, insulin resistance, and glucose tolerance. Elevated BMI and obesity have been associated with the cardiovascular disease risk factors of hypertension, insulin resistance and dyslipidemia. Obesity has been linked to the development of HF. Thus, we hypothesized that adropin may also be related to the failing heart. In the present study, we are intent to investigate the relationship between adropin and HF, and to explore the effects of adropin on proliferation, apoptosis and energy metabolism in cardiocytes.
PartⅠChanges of circulating adropin and its significance in CHF patients
Objective: Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis. we investigated plasma adropin levels in patients with CHF and evaluated the relationship between those and the severity of CHF.
Methods: According to the present guidelinges for the diagnosis and management of chronic heart failure of the ACC/AHA, 56 patients with CHF and 20 healthy subjects were enrolled in this study. Plasma levels of adropin, TNF-α, IL-6 were measured using a commercial ELISA kit, and plasma BNP levels were measured with a commercial RIA kit. The plasma glucose levels were measured by an automated glucose oxidase method, serum levels of total TC, TG, HDL-C, LDL-C were measured by enzymatic methods using the autoanalyzer. The height and weight of subjects were measured to calculate the BMI. Ultrasonic was used to measure the heart function.
Results: The LVEF gradually decreased and, inversely, plasma levels of BNP were exponentially elevated according to NYHA class in the CHF patients. Plasma BNP had a negative correlation with LVEF (r =-0.889, p<0.001,). Plasma levels of IL–6 and Cr were significantly higher in the classⅣpatients than those in the control group (p<0.05, p<0.05, respectively). Lipid analysis showed that plasma levels of TC and LDL-C were lower in the classⅣthan those in the control group (p<0.01, p<0.05, respectively). The plasma level of adropin increased with the deterioration of cardiac function ( control: 6.0±0.3 ng/mL; NYHAⅡ: 7.6±0.4 ng/mL; NYHAⅢ: 9.8±0.5 ng/mL; NYHAⅣ: 12.4±0.6 ng/mL, respectively, p<0.001). Plasma adropin level had a positive correlation with plasma BNP levels (r=0.723, p<0.001), plasma IL-6 levels (r=0.326, p<0.05),plasma Cr (r=0.238, p<0.05) and BMI (r=0.295, p<0.05). Plasma adropin levels negatively correlated with LVEF (r =-0.710, p<0.001,). In the multiple regression analysis, plasma BNP and BMI had independent impact on plasma adropin level in patients with CHF.
Conclusion: Plasma adropin levels were significantly increased according to the severity of CHF. Multiple regression analysis showed BNP and BMI had independent impact on plasma adropin level. These findings suggest that the augmented release of adropin may be involved in the pathogenesis of CHF, but further study is necessary to explain the exact role of adropin in CHF.
PartⅡEffect of synthetic adropin on cardiac function of HF rat
Objective: To investigate the changes of circulating adropin levels in ischemic heart failure model of rats and the effects of treatment with adropin for 2 weeks on cardiac function.
Methods: The SD rats were divided into experimental group (n = 40) and sham operation group (n=10), and model of heart failure induced by myocardial infarction was set up by ligating left descending anterior branch. The 40 rat models of heart failure were divided into early intervention group and late intervention group, each group was further divided into saline treatment group (n=6) and adropin treatment group (n=6). In adropin treatment group, rats were treated with 100ug/kg/d of adropin by intraperitoneal injection, and in saline treatment group, rats were treated with same doses of physiological saline. In early intervention saline treatment group and sham operation group, adropin was measured in five points of time, such as preoperative, postoperative 24h, 3d, 2wks, 4wks. In early intervention group, the histopathology of rat heart was observed by Gonori chromotropic acid staining and TUNEL kit after 2 weeks of treatment. In late intervention group, echocardiography was examined after 2 weeks of treatment.
Results: Compared with sham operation group, adropin levels of rat in early intervention group were drop significantly in postoperative 24 hour (3.22±0.24ng/mL vs 5.60±0.16ng/mL, p<0.01), and began to increase in postoperative 3 days, but there was not statistically significant. The adropin levels were significantly increased in postoperative 4 weeks compared with sham operation group (8.06±0.15ng/mL vs 5.96±0.15ng/mL, p<0.01). In early intervention group, the degeneration and necrosis of rat myocardium in saline treatment group were much more serious than that in adropin treatment group. In early intervention group, TUNEL positive cells rate of rats in saline treatment group was significantly higher than that in adropin treatment group (39.8±8.2% vs 4.67±2.2%, p<0.01). In the late intervention group, LVEF of rat heart in adropin treatment group was significantly higher than that in saline treatment group (48.72±6.58% vs 35.52±2.05, p<0.01).
Conclusion: After myocardial infarction, adropin levels of rat were transiently drop and then continued to rise. Treatment with adropin attenuated myocardial necrosis and apoptosis, and improved heart function of heart failure rat.
PartⅢEffects of adropin on proliferation and apoptosis of cardiomyocyte
Objective: Obeserve effects of adropin on AMPK pathways activating, and apoptosis induced by hypoxia in rat neonatal cardiomyocytes.
Methods: MTT method was used to detect cell livability; Bradford method was used to measure cell protein level and synthetic speed of protein; Westernblot was used to detect cell p-AMPK levels; Annexin V-FITC was used to detect cell apoptosis in rat neonatal cardiomyocytes.
Results: Compared with the control group, adropin significantly increased cell livability in hypoxic conditions (p<0.01), and reduced the total protein and the protein synthesis speed with a dose-response trend (p<0.01). Compared with serum-free group, there was no significant changes in cell apoptosis rate in adropin group cell (p=0.12), but apoptosis rate of adropin+hypoxia group cell was significantly reduced compared with hypoxia group (p < 0.01),this effect can be reversed by compound c,which is an inhibitor of p-AMPK. Treating with adropin (10~(-6) mol/L), the p-AMPK level in adropin+hypoxia group transiently increased in 15min to 30min compared with hypoxia group (p < 0.01).
Conclusion: Adropin increased livability of cell, inhibited cell hypertrophy, elevated p-AMPK level in rat neonatal cardiomyocytes, and it had anti-apoptotic effects through AMPK activities under the condition of hypoxia.
引文
1. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans dual carbonlabeled carbohydrate isotope experiments. J Clin Invest. 1988; 82: 2017–25.
2. Young LH, Coven DL, Russell RR, 3rd. Cellular and molecular regulation of cardiac glucose transport. J Nucl Cardiol. 2000; 7: 267–76.
3. Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ . Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo. Circulation. 1997; 95: 415–22.
4. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, Goodyear LJ, Tian R. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMPactivated protein kinase. J Biol Chem. 2003; 278: 28372–7.
5. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMPactivated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004; 114: 495–503.
6. Depre C, Rider MH, Hue L. Mechanisms of control of heart glycolysis. Eur J Biochem. 1998; 258: 277–90.
7. Kaijser L, Berglund B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol Scand. 1992; 144: 39–45.
8. Stanley WC. Myocardial lactate metabolism during exercise. Med Sci Sports Exerc. 1991; 23: 920–4.
9. Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart II studies on fat, ketone and amino acid metabolism. Am J Med. 1954; 16: 504–15.
10. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994; 1213: 263–76.
11. Augustus AS, Kako Y, Yagyu H, Goldberg IJ. Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA. Am J Physiol Endocrinol Metab. 2003; 284: E331–9.
12. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002; 43: 1997–2006.
13. van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res. 2000; 45: 279–93.
14. Schaffer JE. Fatty acid transport: the roads taken. Am J Physiol Endocrinol Metab. 2002; 282: E239–46.
15. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002; 53: 409–35.
16. Huang B, Wu P, Bowker-Kinley MM, Harris RA. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes. 2002; 51: 276–83.
17. Gilde AJ, Van Der Lee KA, Willemsen PH, Chinetti G, Van Der Leij FR, Van Der Vusse GJ, Staels B, Van Bilsen M. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003; 92: 518–24.
18. Harris RA, Huang B, Wu P. Control of pyruvate dehydrogenase kinase gene expression. Adv Enzyme Regul. 2001; 41: 269–88.
19. Goodwin GW, Taegtmeyer H. Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation. Am J Physiol. 1999; 277: E772–7.
20. Saddik M, Gamble J, Witters LA, Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem. 1993; 268: 25836–45.
21. Neubauer S. The failing heart– an engine out of fuel. N Engl J Med. 2007; 356: 1140–51.
22. Bessman SP, Geiger PJ. Transport of energy in muscle: the phosphorylcreatine shuttle. Science. 1981; 211: 448–52.
23. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005; 85: 1093–129.
24. Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Physiol. 1980; 238: H399–405.
25. Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5’-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res. 1997; 80: 482–9.
26. Itoi T, Lopaschuk GD. The contribution of glycolysis, glucose oxidation, lactate oxidation, and fatty acid oxidation to ATP production in isolated biventricular working hearts from 2-week-old rabbits. Pediatr Res. 1993; 34: 735–41.
27. Kantor PF, Robertson MA, Coe JY, Lopaschuk GD. Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J Am Coll Cardiol. 1999; 33: 1724–34.
28. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Morris DL, Craig JC. Metabolic fate of extracted glucose in normal human myocardium. J Clin Invest. 1985; 76: 1819–27.
29. Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids Studieswith 14C-labeled substrates in humans. J Clin Invest. 1987; 79: 359–66.
30. Sultan AM. Effects of diabetes and insulin on ketone bodies metabolism in heart. Mol Cell Biochem. 1992; 110: 17–23.
31. Chandler MP, Kerner J, Huang H, Vasquez E, Reszko A, Martini WZ, Hoppel Cl, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004; 287: H1538–43.
32. Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res. 1998; 83: 969–79.
33. Chandler MP, Stanley WC, Morita H, Suzuki G, Roth BA, Blackburn B, Wolff A, Sabbah HN. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res. 2002; 91: 278–80.
34. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002; 51: 2005–11.
35. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004; 25: 543–67.
36. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006; 98: 596–605.
37. Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, Paisey RB, Carey C, Macdermott S, Russel-Eggitt I, Shea SE, Davis J, Beck S, Shatirishvili G, Mihai CM, Hoeltzenbein M, Pozzan GB, Hopkinson I, Sicolo N, Naggert JK, Nishina PM. New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med. 2005; 165: 675–83.
38. Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen YT, Shannon RP. The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res. 2004; 61: 297–306.
39. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006; 12: 694–9.
40. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006; 97: 1759–64.
41. Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ, Francis GS, Gheorghiade M, Allman RM, Meleth S, Bourge RC. Heart failure, chronic diuretic use, and increase in mortality andhospitalization: an observational study using propensity score methods. Eur Heart J. 2006; 27: 1431–9.
42. Borst P, Loos JA, Christ EJ, Slater EC. Uncoupling activity of long-chain fatty acids. Biochim Biophys Acta. 1962; 62: 509–18.
43. Opie LH. The metabolic vicious cycle in heart failure. Lancet. 2004; 364: 1733–4.
44. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992; 24: 1333–47.
45. Casademont J, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev. 2002; 7: 131–9.
46. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation. 1991; 83: 504–14.
47. Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Prondzinski R, Gellerich FN, Silber RE, Holtz J . Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol. 2002; 40: 2174–81.
48. Marin-Garcia J, Goldenthal MJ, Moe GW. Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc Res. 2001; 52: 103–10.
49. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res. 1999; 85: 357–63.
50. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol. 2000; 278: H1345–51.
51. Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol. 2004; 555: 1–13.
52. Miyamoto T, Takeishi Y, Tazawa S, Inoue M, Aoyama T, Takahashi H, Arimoto T, Shishido T, Tomoike H, Kubota I. Fatty acid metabolism assessed by 125 I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded hearts. Eur J Clin Invest. 2004; 34: 176–81.
53. Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, and Yamaguchi I. Aging-induced decrease in PPAR level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol. 2002; 283: H1750–60.
54. Karbowska J, Kochan Z, Smolenski RT. Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol Biol Lett. 2003; 8: 49–53.
55. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of PPAR during cardiac hypertrophic growth. J Clin Invest. 2000; 105: 1723–30.
56. Stavinoha MA, RaySpellicy JW, Essop MF, Graveleau C, Abbel ED, Hart-Sailors ML, Mersmann HJ, Bray MS, Young ME. Evidence for mitochondrial thioesterase 1 as peroxisome proliferator-activated receptor-alpha regulated gene in cardiac and skeletal muscle. Am J Physiol Endocrinol Metab. 2004; 287: E888–95.
57. Young ME, Patil S, Ying J, Depre C, Ahuja HS, Shipley GL, Stepkowski SM, Davies PJ, Taegtmeyer H. Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J. 2001; 15: 833–45.
58. Garlid KD, Jaburek M, Jezek P, Varecha M. How do uncoupling proteins uncouple? Biochim Biophys Acta. 2000; 1459: 383–9.
59. Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P. On the mechanismof fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem. 1996; 271: 2615–20.
60. Starling RC HD, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Molec Cell Biochem. 1998; 150: 170–7.
61. Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S, Takahashi M, Morikawa S, Inubushi T, Nakamura Y, Kinoshita M, Horie M. Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J Am Coll Cardiol. 2003; 42: 1587–93.
62. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
63. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
64. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004 Jan 23;116(2):337-50.
65. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006 Jun;55(6):1537-45.
66. Heilbronn LK, Gregersen S, Shirkhedkar D, Hu D, Campbell LV. Impaired fat oxidation after asingle high-fat meal in insulin-sensitive nondiabetic individuals with a family history of type 2 diabetes. Diabetes. 2007 Aug;56(8):2046-53.
67. Butler AA. The melanocortin system and energy balance. Peptides. 2006 Feb;27(2):281-90.
68. Nogueiras R, Wiedmer P, Perez-Tilve D. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 2007 Nov;117(11):3475-88.
69. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr. 2005;25:317-40.
70. Kalaany NY, Mangelsdorf DJ. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol. 2006;68:159-91.
71. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006 Aug;4(2):107-10.
1. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–313.
2. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003;91:891–894.
3. Horwich TB, Fonarow GC. The impact of obesity on survival in patients with heart failure. Heart Fail Monit. 2002;3:8–14.
4. Mehra MR, Uber PA, Park MH, Scott RL, Ventura HO, Harris BC, Frohlich ED. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol. 2004;43:1590–1595.
5. Davos CH, Doehner W, Rauchhaus M, Cicoira M, Francis DP, Coats AJ, Clark AL, Anker SD. Body mass and survival in patients with chronic heart failure without cachexia: the importance of obesity. J Card Fail. 2003;91:29–35.
6. Poehlman ET, Scheffers J, Gottlieb SS, Fisher ML, Vaitekevicius P. Increased resting metabolic rate in patients with congestive heart failure. Ann Intern Med. 1994;121:860–862.
7. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
8. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation. 1997 Jul 15;96(2):509-16.
9. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004 Feb 10;109(5):594-600.
10. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 1991 Apr;87(4):1402-12.
11. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11Suppl):S185-92.
12. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991 Oct;84(4):1589-96.
13. Kasprzak JD, K?osińska M, Drozdz J. Clinical aspects of assessment of endothelial function. Pharmacol Rep. 2006;58 Suppl:33-40.
14. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995 Mar 1;91(5):1314-9.
15. Lafontan M, Berlan M, Stich V, Crampes F, Rivière D, De Glisezinski I, Sengenes C, Galitzky J. Recent data on the regulation of lipolysis by catecholamines and natriuretic peptides. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):86-90.
16. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ. Wasting as independent risk factor for mortality in chronic heart failure. Lancet. 1997 Apr 12;349(9058):1050-3.
1. Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 1997, 80: 15-25.
2. Piero A, Bernardo NG. Myocyte renewal and ventricular remodeling. Nature. 2002, 415: 240-243.
3. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
4. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
5. Hardie, D. G. The AMP-activated protein kinase cascade, the key sensor of cellular energy status. Endocrinology, 2003, 144:5179–5183.
6. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation, 2004, 109(18): 2221-2226.
7. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005; 85: 1093–129.
8. Sultan AM. Effects of diabetes and insulin on ketone bodies metabolism in heart. Mol Cell Biochem. 1992; 110: 17–23.
9. Chandler MP, Kerner J, Huang H, Vasquez E, Reszko A, Martini WZ, Hoppel Cl, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004; 287: H1538–43.
10. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002; 51: 2005–11.
11. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006; 12: 694–9.
12. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006; 97: 1759–64.
13. Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ, Francis GS, Gheorghiade M, AllmanRM, Meleth S, Bourge RC. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J. 2006; 27: 1431–9.
14. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992; 24: 1333–47.
15. Casademont J, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev. 2002; 7: 131–9.
16. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol. 2000; 278: H1345–51.
17. Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol. 2004; 555: 1–13.
1. Ingwall JS. ATP and the heart. MA, USA: Kluwer Academic Publishers, 2002: 197-216.
2. Nascimben L, Ingwall JS, Lorell BH, Pinz I, Schultz V, Tornheim K, Tian R. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension. 2004 Nov;44(5):662-7. Epub 2004 Oct 4.
3. Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure. J Nucl Med. 2001 Jan;42(1):55-62.
4. Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):808-13. Epub 2005 Jan 12.
5. Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007 Mar 15;356(11):1140-51.
6. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
7. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
8. Kuhn M. Molecular physiology of natriuretic peptide signaling. Basic Res Cardiol, 2004, 99:76-82.
9. Ito H, Adachi S, Tamamori M, Fujisaki H, Tanaka M, Lin M, Akimoto H, Marumo F, Hiroe M. Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible endogenous endothelin-1-mediated mechanism. J Mol Cell Cardiol. 1996 Jun;28(6):1271-7.
10. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85.
11. Hue L, Beauloye C, Bertrand L, Horman S, Krause U, Marsin AS, Meisse D, Vertommen D, Rider MH. New targets of AMP-activated protein kinase. Biochem Soc Trans. 2003 Feb;31(Pt 1):213-5.
12. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006 Jul;116(7):1776-83.
13. Winder WW, Thomson DM. Cellular energy sensing and signaling by AMP-activated protein kinase. Cell Biochem Biophys. 2007;47(3):332-47.
14. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
15. Wang XF, Zhang JY, Li L, Zhao XY, Tao HL, Zhang L. Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol. 2011 Feb;38(2):94-101.
16. Mokni W, Keravis T, Etienne-Selloum N, Walter A, Kane MO, Schini-Kerth VB, Lugnier C. Concerted regulation of cGMP and cAMP phosphodiesterases in early cardiac hypertrophy induced by angiotensin II. PLoS One. 2010 Dec 3;5(12):e14227.
17. Hardie DG.et al. AMPK: a key regulator of energy balance in the single cell and the whole organism.Int J Obes (Lond). 2008;32 Suppl 4:S7-12.
18. Kewalramani G, Puthanveetil P, Wang F, Kim MS, Deppe S, Abrahani A, Luciani DS,Johnson JD, Rodrigues B.AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death. Cardiovasc Res. 2009 Oct 1;84(1):42-53.
19. Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, Ogai A, Asakura M, Kim J, Minamino T, Takashima S, Sanada S, Sugimachi M, Komamura K, Mochizuki N,Kitakaze M. Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation. 2009 May 19;119(19):2568-77.
20. Kong HL, Wang JP, Li ZQ, Zhao SM, Dong J, Zhang WW. Anti-hypoxic effect of ginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation of glucose transporter-4 ex vivo. Acta Pharmacol Sin. 2009 Apr;30(4):396-403.
21. Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano T, Sadoshima J. AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy. 2007 Jul-Aug;3(4):405-7.
22. An D, Kewalramani G, Chan JK, Qi D, Ghosh S, Pulinilkunnil T, Abrahani A, Innis SM, Rodrigues B. Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3. Diabetologia. 2006;49(9):2174-84.
23. Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, Kawase I, Hirota H. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol. 2005;25(21):9554-75.
24. Hattori Y, Akimoto K, Nishikimi T, Matsuoka H, Kasai K. Activation of AMP-activated protein kinase enhances angiotensin ii-induced proliferation in cardiac fibroblasts. Hypertension. 2006;47(2):265-70.
25. Du J, Guan T, Zhang H, Xia Y, Liu F, Zhang Y. Inhibitory crosstalk between ERK and AMPK in the growth and proliferation of cardiac fibroblasts. Biochem Biophys Res Commun. 2008 Apr 4;368(2):402-7.
26. Kim MJ, Park IJ, Yun H, Kang I, Choe W, Kim SS, Ha J. AMP-activated protein kinase antagonizes pro-apoptotic extracellular signal-regulated kinase activation by inducing dual-specificity protein phosphatases in response to glucose deprivation in HCT116 carcinoma. J Biol Chem. 2010 Mar 10. [Epub ahead of print]
27. Hwang JT, Kim YM, Surh YJ, Baik HW, Lee SK, Ha J, Park OJ. Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells. Cancer Res. 2006 Oct 15;66(20):10057-63.
28. Kim JE, Ahn MW, Baek SH, Lee IK, Kim YW, Kim JY, Dan JM, Park SY. AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone. 2008;43(2):394-404.
1. Beer M, Seyfarth T, Sandstede J, Landschütz W, Lipke C, K?stler H, von Kienlin M, Harre K, Hahn D, Neubauer S. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol. 2002 Oct 2;40(7):1267-74.
2. Starling RC, Hammer DF, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem 1998; 180:171–177.
3. Hardy CJ, Weiss RG, Bottomley PA, Gerstenblith G. Altered myocardial highenergy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 1991; 122:795–801.
4. Neubauer S, Krahe T, Schindler R, Horn M, Hillenbrand H, Entzeroth C, Mader H, Kromer EP, Riegger GA, Lackner K,Ertl G. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992; 86:1810–1818.
5. Nascimben L, Ingwall JS, Pauletto P, Friedrich J, Gwathmey JK, Saks V, Pessina AC, Allen PD. Creatine kinase system in failing and nonfailing human myocardium. Circulation 1996; 94:1894–1901.
6. Ingwall JS. Transgenesis and cardiac energetics: new insights into cardiac metabolism. J Mol Cell Cardiol 2004; 37:613–623.
7. Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 2001; 88:529–535.
8. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999; 85:357–363.
9. Kalsi KK, Smolenski RT, Pritchard RD, Khaghani A, Seymour AM, Yacoub MH. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy. Eur J Clin Invest 1999; 29:469–477.
10. Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Prondzinsky R, Gellerich FN, Silber RE, Holtz J.Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol 2002; 40:2174–2181.
11. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996; 94:2837–2842.
12. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation 2001; 104:2923–2931.
13. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 2005; 115:547–555.
14. Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 2002; 277:40265–40274.
15. Sladek R, Bader JA, Giguere V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 1997; 17:5400–5409.
16. Wittels B, Spann JF Jr. Defective lipid metabolism in the failing heart. J Clin Invest 1968; 47:1787–1794.
17. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA.Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacinginduced heart failure. Circulation 2002; 106:606–612.
18. Recchia FA, Osorio JC, Chandler MP, Xu X, Panchal AR, Lopaschuk GD, Hintze TH, Stanley WC. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 2002; 282:E197–206.
19. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ.Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002; 40:271–277.
20. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, Gastaldelli A, Ciociaro D, Pellegrini P, Testa R, Menichetti L, L'Abbate A, Stanley WC, Recchia FA. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2007; 293:H3270–H3278.
21. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 2007; 12:331–343.
22. van Bilsen M, van Nieuwenhoven FA, van der Vusse GJ. Metabolic remodeling of the failing heart: beneficial or detrimental? Cardiovasc Res 2009; 81:420–428.
23. Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994; 43:174–179.
24. Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F] FDG in patients with congestive heart failure. J Nucl Med 2001; 42:55–62.
25. Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001; 103:2441–2446.
26. Andersson B, Blomstrom-Lundqvist C, Hedner T, Waagstein F. Exercise hemodynamics and myocardial metabolism during long-term betaadrenergic blockade in severe heart failure. J Am Coll Cardiol 1991; 18:1059–1066.
27. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy CR. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1994; 24:1310–1320.
28. Panchal AR, Stanley WC, Kerner J, Sabbah HN. Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Card Fail 1998; 4:121–126.
29. Stolen KQ, Kemppainen J, Kalliokoski KK, H?llsten K, Luotolahti M, Karanko H, Lehikoinen P, Viljanen T, Salo T, Airaksinen KE, Nuutila P, Knuuti J. Myocardial perfusion reserve and oxidative metabolism contribute to exercise capacity in patients with dilated cardiomyopathy. J Card Fail 2004; 10:132–140.
30. Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, Karpe F. Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS One 2009; 4:e7533.
31. Turer AT, Stevens RD, Bain JR, Muehlbauer MJ, van der Westhuizen J, Mathew JP, Schwinn DA, Glower DD, Newgard CB, Podgoreanu MV. Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion. Circulation 2009; 119:1736–1746.
32. Opie LH. The metabolic vicious cycle in heart failure. Lancet 2004; 364: 1733–1734.
33. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in human heart. Lancet 2004; 364:1786–1788.
34. Paolisso G, Tagliamonte MR, Rizzo MR, Gambardella A, Gualdiero P, Lama D, Varricchio G, Gentile S, Varricchio M. Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease. Am J Cardiol 1999;83:1338–1344.
35. Dutka DP, Pitt M, Pagano D, Mongillo M, Gathercole D, Bonser RS, Camici PG. Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease. J Am Coll Cardiol 2006; 48:2225–2231.
36. Schwarzer M, Schrepper A, Bugger H, Pytel G, Mohr fw, Doenst T. The development of heart failure in rats is associated with impaired insulin response and mitochondrial dysfunction. Circulation 2008; 118:S_540.
37. Amorim P, Nguyen TD, Schrepper A, Mohr FW, Doenst T. Postinfarct remodeling causes insulin resistance and defects in substrate oxidation. Thorac Cardiovasc Surg 2009; 56:76.
38. Boudina S, Bugger H, Sena S, O'Neill BT, Zaha VG, Ilkun O, Wright JJ, Mazumder PK, Palfreyman E, Tidwell TJ, Theobald H, Khalimonchuk O, Wayment B, Sheng X, Rodnick KJ, Centini R, Chen D, Litwin SE, Weimer BE, Abel ED. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 2009; 119:1272–1283.
39. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006; 12:694–699.
40. Tuunanen H, Engblom E, Naum A, Scheinin M, N?gren K, Airaksinen J, Nuutila P, Iozzo P, Ukkonen H, Knuuti J.Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction. J Card Fail 2006; 12:644–652.
41. Al-Hesayen A, Azevedo ER, Floras JS, Hollingshead S, Lopaschuk GD, Parker JD.Selective versus nonselective beta-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization. Eur J Heart Fail 2005; 7:618–623.
42. von Lewinski D, Rainer PP, Gasser R, Huber MS, Khafaga M, Wilhelm B, Haas T, M?chler H, R?ssl U, Pieske B. Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. Metabolism 2009.
43. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucosetransporter that is perturbed in disease states. Cardiovasc Res 2009; 84:111–118.
44. von Lewinski D, Gasser R, Rainer PP, Huber MS, Wilhelm B, Roessl U, Haas T, Wasler A, Grimm M, Bisping E, Pieske B. Functional effects of glucose transporters in human ventricular myocardium. Eur J Heart Fail 2010;12:106–113.
45. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 1995; 377:151–155.
46. Stenbit AE, Katz EB, Chatham JC, Geenen DL, Factor SM, Weiss RG, Tsao TS, Malhotra A, Chacko VP, Ocampo C, Jelicks LA, Charron MJ. Preservation of glucose metabolism in hypertrophic GLUT4-null hearts. Am J Physiol Heart Circ Physiol 2000; 279:H313–H318.
47. Liao R, Jain M, Cui L, D'Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation 2002; 106:2125–2131.
48. Yan J, Young ME, Cui L, Lopaschuk GD, Liao R, Tian R. Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation 2009; 119:2818–2828.
49. Tuunanen H, Engblom E, Naum A, N?gren K, Hesse B, Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 2006; 114:2130–2137.
50. Eshaghian S, Horwich TB, Fonarow GC. An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure. Am Heart J 2006; 151:91.
51. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol 2009; 54:422–428.
52. Issa VS, Amaral AF, Cruz FD, Ayub-Ferreira SM, Guimar?es GV, Chizzola PR, Souza GE, Bocchi EA. Glycemia and prognosis of patients with chronic heart failure: subanalysis of the Long-term Prospective Randomized Controlled Study Using Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients (REMADHE) trial.Am Heart J 2010; 159:90–97.
53. Taegtmeyer H, Ballal K. No low-fat diet for the failing heart? Circulation 2006; 114:2092–2093.
54. Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 2004; 287:H1538–H1543.
55. de Brouwer KF, Degens H, Aartsen WM, Lindhout M, Bitsch NJ, Gilde AJ, Willemsen PH, Janssen BJ, van der Vusse GJ, van Bilsen M. Specific and sustained downregulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice. J Mol Cell Cardiol 2006; 40:838–845.
56. Qanud K, Mamdani M, Pepe M, Khairallah RJ, Gravel J, Lei B, Gupte SA, Sharov VG, Sabbah HN, Stanley WC, Recchia FA. Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure. Am J Physiol Heart Circ Physiol 2008; 295:H2098–H2105.
57. Doenst T, Pytel G, Schrepper A, Amorim P, F?rber G, Shingu Y, Mohr FW, Schwarzer M. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 2010.
58. Bugger H, Pytel G, Schwarzer M, Schrepper A, Mohr FW, Doenst T. Mitochondrial dysfunction outweighs beneficial effects of altered substrate selection in heart failure. Thorac Cardiovasc Surg 2009; 56.
59. DepréC, Vanoverschelde JL, Melin JA, Borgers M, Bol A, Ausma J, Dion R, Wijns W. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol 1995; 268:H1265–H1275.
60. Vanoverschelde JL, Wijns W, DepréC, Essamri B, Heyndrickx GR, Borgers M, Bol A, Melin JA. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 1993; 87:1513–1523.
61. Garnier A, Zoll J, Fortin D, N'Guessan B, Lefebvre F, Geny B, Mettauer B, Veksler V, Ventura-Clapier R. Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II. Circ Heart Fail 2009; 2:342–350.
62. Zhao G, Jeoung NH, Burgess SC, Rosaaen-Stowe KA, Inagaki T, Latif S, Shelton JM, McAnally J, Bassel-Duby R, Harris RA, Richardson JA, Kliewer SA. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 2008; 294:H936–H943.
63. ten Hove M, Lygate CA, Fischer A, Schneider JE, Sang AE, Hulbert K, Sebag Montefiore L, Watkins H, Clarke K, Isbrandt D, Wallis J, Neubauer S. Reduced inotropic reserve and increased susceptibility to cardiac ischemia-reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice.Circulation 2005; 111:2477–2485.
2. Young LH, Coven DL, Russell RR, 3rd. Cellular and molecular regulation of cardiac glucose transport. J Nucl Cardiol. 2000; 7: 267–76.
3. Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ . Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo. Circulation. 1997; 95: 415–22.
4. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, Goodyear LJ, Tian R. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMPactivated protein kinase. J Biol Chem. 2003; 278: 28372–7.
5. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMPactivated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004; 114: 495–503.
6. Depre C, Rider MH, Hue L. Mechanisms of control of heart glycolysis. Eur J Biochem. 1998; 258: 277–90.
7. Kaijser L, Berglund B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol Scand. 1992; 144: 39–45.
8. Stanley WC. Myocardial lactate metabolism during exercise. Med Sci Sports Exerc. 1991; 23: 920–4.
9. Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart II studies on fat, ketone and amino acid metabolism. Am J Med. 1954; 16: 504–15.
10. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994; 1213: 263–76.
11. Augustus AS, Kako Y, Yagyu H, Goldberg IJ. Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA. Am J Physiol Endocrinol Metab. 2003; 284: E331–9.
12. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002; 43: 1997–2006.
13. van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res. 2000; 45: 279–93.
14. Schaffer JE. Fatty acid transport: the roads taken. Am J Physiol Endocrinol Metab. 2002; 282: E239–46.
15. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002; 53: 409–35.
16. Huang B, Wu P, Bowker-Kinley MM, Harris RA. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes. 2002; 51: 276–83.
17. Gilde AJ, Van Der Lee KA, Willemsen PH, Chinetti G, Van Der Leij FR, Van Der Vusse GJ, Staels B, Van Bilsen M. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003; 92: 518–24.
18. Harris RA, Huang B, Wu P. Control of pyruvate dehydrogenase kinase gene expression. Adv Enzyme Regul. 2001; 41: 269–88.
19. Goodwin GW, Taegtmeyer H. Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation. Am J Physiol. 1999; 277: E772–7.
20. Saddik M, Gamble J, Witters LA, Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem. 1993; 268: 25836–45.
21. Neubauer S. The failing heart– an engine out of fuel. N Engl J Med. 2007; 356: 1140–51.
22. Bessman SP, Geiger PJ. Transport of energy in muscle: the phosphorylcreatine shuttle. Science. 1981; 211: 448–52.
23. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005; 85: 1093–129.
24. Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Physiol. 1980; 238: H399–405.
25. Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5’-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res. 1997; 80: 482–9.
26. Itoi T, Lopaschuk GD. The contribution of glycolysis, glucose oxidation, lactate oxidation, and fatty acid oxidation to ATP production in isolated biventricular working hearts from 2-week-old rabbits. Pediatr Res. 1993; 34: 735–41.
27. Kantor PF, Robertson MA, Coe JY, Lopaschuk GD. Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J Am Coll Cardiol. 1999; 33: 1724–34.
28. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Morris DL, Craig JC. Metabolic fate of extracted glucose in normal human myocardium. J Clin Invest. 1985; 76: 1819–27.
29. Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids Studieswith 14C-labeled substrates in humans. J Clin Invest. 1987; 79: 359–66.
30. Sultan AM. Effects of diabetes and insulin on ketone bodies metabolism in heart. Mol Cell Biochem. 1992; 110: 17–23.
31. Chandler MP, Kerner J, Huang H, Vasquez E, Reszko A, Martini WZ, Hoppel Cl, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004; 287: H1538–43.
32. Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res. 1998; 83: 969–79.
33. Chandler MP, Stanley WC, Morita H, Suzuki G, Roth BA, Blackburn B, Wolff A, Sabbah HN. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res. 2002; 91: 278–80.
34. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002; 51: 2005–11.
35. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004; 25: 543–67.
36. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006; 98: 596–605.
37. Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, Paisey RB, Carey C, Macdermott S, Russel-Eggitt I, Shea SE, Davis J, Beck S, Shatirishvili G, Mihai CM, Hoeltzenbein M, Pozzan GB, Hopkinson I, Sicolo N, Naggert JK, Nishina PM. New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med. 2005; 165: 675–83.
38. Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen YT, Shannon RP. The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res. 2004; 61: 297–306.
39. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006; 12: 694–9.
40. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006; 97: 1759–64.
41. Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ, Francis GS, Gheorghiade M, Allman RM, Meleth S, Bourge RC. Heart failure, chronic diuretic use, and increase in mortality andhospitalization: an observational study using propensity score methods. Eur Heart J. 2006; 27: 1431–9.
42. Borst P, Loos JA, Christ EJ, Slater EC. Uncoupling activity of long-chain fatty acids. Biochim Biophys Acta. 1962; 62: 509–18.
43. Opie LH. The metabolic vicious cycle in heart failure. Lancet. 2004; 364: 1733–4.
44. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992; 24: 1333–47.
45. Casademont J, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev. 2002; 7: 131–9.
46. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation. 1991; 83: 504–14.
47. Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Prondzinski R, Gellerich FN, Silber RE, Holtz J . Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol. 2002; 40: 2174–81.
48. Marin-Garcia J, Goldenthal MJ, Moe GW. Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc Res. 2001; 52: 103–10.
49. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res. 1999; 85: 357–63.
50. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol. 2000; 278: H1345–51.
51. Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol. 2004; 555: 1–13.
52. Miyamoto T, Takeishi Y, Tazawa S, Inoue M, Aoyama T, Takahashi H, Arimoto T, Shishido T, Tomoike H, Kubota I. Fatty acid metabolism assessed by 125 I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded hearts. Eur J Clin Invest. 2004; 34: 176–81.
53. Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, and Yamaguchi I. Aging-induced decrease in PPAR level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol. 2002; 283: H1750–60.
54. Karbowska J, Kochan Z, Smolenski RT. Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol Biol Lett. 2003; 8: 49–53.
55. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of PPAR during cardiac hypertrophic growth. J Clin Invest. 2000; 105: 1723–30.
56. Stavinoha MA, RaySpellicy JW, Essop MF, Graveleau C, Abbel ED, Hart-Sailors ML, Mersmann HJ, Bray MS, Young ME. Evidence for mitochondrial thioesterase 1 as peroxisome proliferator-activated receptor-alpha regulated gene in cardiac and skeletal muscle. Am J Physiol Endocrinol Metab. 2004; 287: E888–95.
57. Young ME, Patil S, Ying J, Depre C, Ahuja HS, Shipley GL, Stepkowski SM, Davies PJ, Taegtmeyer H. Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J. 2001; 15: 833–45.
58. Garlid KD, Jaburek M, Jezek P, Varecha M. How do uncoupling proteins uncouple? Biochim Biophys Acta. 2000; 1459: 383–9.
59. Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P. On the mechanismof fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem. 1996; 271: 2615–20.
60. Starling RC HD, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Molec Cell Biochem. 1998; 150: 170–7.
61. Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S, Takahashi M, Morikawa S, Inubushi T, Nakamura Y, Kinoshita M, Horie M. Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J Am Coll Cardiol. 2003; 42: 1587–93.
62. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
63. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
64. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004 Jan 23;116(2):337-50.
65. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006 Jun;55(6):1537-45.
66. Heilbronn LK, Gregersen S, Shirkhedkar D, Hu D, Campbell LV. Impaired fat oxidation after asingle high-fat meal in insulin-sensitive nondiabetic individuals with a family history of type 2 diabetes. Diabetes. 2007 Aug;56(8):2046-53.
67. Butler AA. The melanocortin system and energy balance. Peptides. 2006 Feb;27(2):281-90.
68. Nogueiras R, Wiedmer P, Perez-Tilve D. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 2007 Nov;117(11):3475-88.
69. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr. 2005;25:317-40.
70. Kalaany NY, Mangelsdorf DJ. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol. 2006;68:159-91.
71. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006 Aug;4(2):107-10.
1. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–313.
2. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003;91:891–894.
3. Horwich TB, Fonarow GC. The impact of obesity on survival in patients with heart failure. Heart Fail Monit. 2002;3:8–14.
4. Mehra MR, Uber PA, Park MH, Scott RL, Ventura HO, Harris BC, Frohlich ED. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol. 2004;43:1590–1595.
5. Davos CH, Doehner W, Rauchhaus M, Cicoira M, Francis DP, Coats AJ, Clark AL, Anker SD. Body mass and survival in patients with chronic heart failure without cachexia: the importance of obesity. J Card Fail. 2003;91:29–35.
6. Poehlman ET, Scheffers J, Gottlieb SS, Fisher ML, Vaitekevicius P. Increased resting metabolic rate in patients with congestive heart failure. Ann Intern Med. 1994;121:860–862.
7. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
8. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation. 1997 Jul 15;96(2):509-16.
9. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004 Feb 10;109(5):594-600.
10. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 1991 Apr;87(4):1402-12.
11. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11Suppl):S185-92.
12. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991 Oct;84(4):1589-96.
13. Kasprzak JD, K?osińska M, Drozdz J. Clinical aspects of assessment of endothelial function. Pharmacol Rep. 2006;58 Suppl:33-40.
14. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995 Mar 1;91(5):1314-9.
15. Lafontan M, Berlan M, Stich V, Crampes F, Rivière D, De Glisezinski I, Sengenes C, Galitzky J. Recent data on the regulation of lipolysis by catecholamines and natriuretic peptides. Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):86-90.
16. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ. Wasting as independent risk factor for mortality in chronic heart failure. Lancet. 1997 Apr 12;349(9058):1050-3.
1. Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 1997, 80: 15-25.
2. Piero A, Bernardo NG. Myocyte renewal and ventricular remodeling. Nature. 2002, 415: 240-243.
3. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
4. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
5. Hardie, D. G. The AMP-activated protein kinase cascade, the key sensor of cellular energy status. Endocrinology, 2003, 144:5179–5183.
6. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation, 2004, 109(18): 2221-2226.
7. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005; 85: 1093–129.
8. Sultan AM. Effects of diabetes and insulin on ketone bodies metabolism in heart. Mol Cell Biochem. 1992; 110: 17–23.
9. Chandler MP, Kerner J, Huang H, Vasquez E, Reszko A, Martini WZ, Hoppel Cl, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004; 287: H1538–43.
10. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002; 51: 2005–11.
11. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006; 12: 694–9.
12. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006; 97: 1759–64.
13. Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ, Francis GS, Gheorghiade M, AllmanRM, Meleth S, Bourge RC. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J. 2006; 27: 1431–9.
14. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992; 24: 1333–47.
15. Casademont J, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev. 2002; 7: 131–9.
16. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol. 2000; 278: H1345–51.
17. Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol. 2004; 555: 1–13.
1. Ingwall JS. ATP and the heart. MA, USA: Kluwer Academic Publishers, 2002: 197-216.
2. Nascimben L, Ingwall JS, Lorell BH, Pinz I, Schultz V, Tornheim K, Tian R. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension. 2004 Nov;44(5):662-7. Epub 2004 Oct 4.
3. Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure. J Nucl Med. 2001 Jan;42(1):55-62.
4. Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):808-13. Epub 2005 Jan 12.
5. Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007 Mar 15;356(11):1140-51.
6. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW Jr, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA. Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 2008 Dec;8(6):468-81.
7. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S. Adropin is a novel regulator of endothelial function. Circulation. 2010 Sep 14;122(11 Suppl):S185-92.
8. Kuhn M. Molecular physiology of natriuretic peptide signaling. Basic Res Cardiol, 2004, 99:76-82.
9. Ito H, Adachi S, Tamamori M, Fujisaki H, Tanaka M, Lin M, Akimoto H, Marumo F, Hiroe M. Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible endogenous endothelin-1-mediated mechanism. J Mol Cell Cardiol. 1996 Jun;28(6):1271-7.
10. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85.
11. Hue L, Beauloye C, Bertrand L, Horman S, Krause U, Marsin AS, Meisse D, Vertommen D, Rider MH. New targets of AMP-activated protein kinase. Biochem Soc Trans. 2003 Feb;31(Pt 1):213-5.
12. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006 Jul;116(7):1776-83.
13. Winder WW, Thomson DM. Cellular energy sensing and signaling by AMP-activated protein kinase. Cell Biochem Biophys. 2007;47(3):332-47.
14. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
15. Wang XF, Zhang JY, Li L, Zhao XY, Tao HL, Zhang L. Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol. 2011 Feb;38(2):94-101.
16. Mokni W, Keravis T, Etienne-Selloum N, Walter A, Kane MO, Schini-Kerth VB, Lugnier C. Concerted regulation of cGMP and cAMP phosphodiesterases in early cardiac hypertrophy induced by angiotensin II. PLoS One. 2010 Dec 3;5(12):e14227.
17. Hardie DG.et al. AMPK: a key regulator of energy balance in the single cell and the whole organism.Int J Obes (Lond). 2008;32 Suppl 4:S7-12.
18. Kewalramani G, Puthanveetil P, Wang F, Kim MS, Deppe S, Abrahani A, Luciani DS,Johnson JD, Rodrigues B.AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death. Cardiovasc Res. 2009 Oct 1;84(1):42-53.
19. Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, Ogai A, Asakura M, Kim J, Minamino T, Takashima S, Sanada S, Sugimachi M, Komamura K, Mochizuki N,Kitakaze M. Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation. 2009 May 19;119(19):2568-77.
20. Kong HL, Wang JP, Li ZQ, Zhao SM, Dong J, Zhang WW. Anti-hypoxic effect of ginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation of glucose transporter-4 ex vivo. Acta Pharmacol Sin. 2009 Apr;30(4):396-403.
21. Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano T, Sadoshima J. AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy. 2007 Jul-Aug;3(4):405-7.
22. An D, Kewalramani G, Chan JK, Qi D, Ghosh S, Pulinilkunnil T, Abrahani A, Innis SM, Rodrigues B. Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3. Diabetologia. 2006;49(9):2174-84.
23. Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, Kawase I, Hirota H. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol. 2005;25(21):9554-75.
24. Hattori Y, Akimoto K, Nishikimi T, Matsuoka H, Kasai K. Activation of AMP-activated protein kinase enhances angiotensin ii-induced proliferation in cardiac fibroblasts. Hypertension. 2006;47(2):265-70.
25. Du J, Guan T, Zhang H, Xia Y, Liu F, Zhang Y. Inhibitory crosstalk between ERK and AMPK in the growth and proliferation of cardiac fibroblasts. Biochem Biophys Res Commun. 2008 Apr 4;368(2):402-7.
26. Kim MJ, Park IJ, Yun H, Kang I, Choe W, Kim SS, Ha J. AMP-activated protein kinase antagonizes pro-apoptotic extracellular signal-regulated kinase activation by inducing dual-specificity protein phosphatases in response to glucose deprivation in HCT116 carcinoma. J Biol Chem. 2010 Mar 10. [Epub ahead of print]
27. Hwang JT, Kim YM, Surh YJ, Baik HW, Lee SK, Ha J, Park OJ. Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells. Cancer Res. 2006 Oct 15;66(20):10057-63.
28. Kim JE, Ahn MW, Baek SH, Lee IK, Kim YW, Kim JY, Dan JM, Park SY. AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone. 2008;43(2):394-404.
1. Beer M, Seyfarth T, Sandstede J, Landschütz W, Lipke C, K?stler H, von Kienlin M, Harre K, Hahn D, Neubauer S. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol. 2002 Oct 2;40(7):1267-74.
2. Starling RC, Hammer DF, Altschuld RA. Human myocardial ATP content and in vivo contractile function. Mol Cell Biochem 1998; 180:171–177.
3. Hardy CJ, Weiss RG, Bottomley PA, Gerstenblith G. Altered myocardial highenergy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 1991; 122:795–801.
4. Neubauer S, Krahe T, Schindler R, Horn M, Hillenbrand H, Entzeroth C, Mader H, Kromer EP, Riegger GA, Lackner K,Ertl G. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992; 86:1810–1818.
5. Nascimben L, Ingwall JS, Pauletto P, Friedrich J, Gwathmey JK, Saks V, Pessina AC, Allen PD. Creatine kinase system in failing and nonfailing human myocardium. Circulation 1996; 94:1894–1901.
6. Ingwall JS. Transgenesis and cardiac energetics: new insights into cardiac metabolism. J Mol Cell Cardiol 2004; 37:613–623.
7. Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 2001; 88:529–535.
8. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999; 85:357–363.
9. Kalsi KK, Smolenski RT, Pritchard RD, Khaghani A, Seymour AM, Yacoub MH. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy. Eur J Clin Invest 1999; 29:469–477.
10. Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Prondzinsky R, Gellerich FN, Silber RE, Holtz J.Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol 2002; 40:2174–2181.
11. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996; 94:2837–2842.
12. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation 2001; 104:2923–2931.
13. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 2005; 115:547–555.
14. Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 2002; 277:40265–40274.
15. Sladek R, Bader JA, Giguere V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 1997; 17:5400–5409.
16. Wittels B, Spann JF Jr. Defective lipid metabolism in the failing heart. J Clin Invest 1968; 47:1787–1794.
17. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA.Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacinginduced heart failure. Circulation 2002; 106:606–612.
18. Recchia FA, Osorio JC, Chandler MP, Xu X, Panchal AR, Lopaschuk GD, Hintze TH, Stanley WC. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 2002; 282:E197–206.
19. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ.Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002; 40:271–277.
20. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, Gastaldelli A, Ciociaro D, Pellegrini P, Testa R, Menichetti L, L'Abbate A, Stanley WC, Recchia FA. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2007; 293:H3270–H3278.
21. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 2007; 12:331–343.
22. van Bilsen M, van Nieuwenhoven FA, van der Vusse GJ. Metabolic remodeling of the failing heart: beneficial or detrimental? Cardiovasc Res 2009; 81:420–428.
23. Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994; 43:174–179.
24. Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F] FDG in patients with congestive heart failure. J Nucl Med 2001; 42:55–62.
25. Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001; 103:2441–2446.
26. Andersson B, Blomstrom-Lundqvist C, Hedner T, Waagstein F. Exercise hemodynamics and myocardial metabolism during long-term betaadrenergic blockade in severe heart failure. J Am Coll Cardiol 1991; 18:1059–1066.
27. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy CR. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1994; 24:1310–1320.
28. Panchal AR, Stanley WC, Kerner J, Sabbah HN. Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Card Fail 1998; 4:121–126.
29. Stolen KQ, Kemppainen J, Kalliokoski KK, H?llsten K, Luotolahti M, Karanko H, Lehikoinen P, Viljanen T, Salo T, Airaksinen KE, Nuutila P, Knuuti J. Myocardial perfusion reserve and oxidative metabolism contribute to exercise capacity in patients with dilated cardiomyopathy. J Card Fail 2004; 10:132–140.
30. Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, Karpe F. Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS One 2009; 4:e7533.
31. Turer AT, Stevens RD, Bain JR, Muehlbauer MJ, van der Westhuizen J, Mathew JP, Schwinn DA, Glower DD, Newgard CB, Podgoreanu MV. Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion. Circulation 2009; 119:1736–1746.
32. Opie LH. The metabolic vicious cycle in heart failure. Lancet 2004; 364: 1733–1734.
33. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in human heart. Lancet 2004; 364:1786–1788.
34. Paolisso G, Tagliamonte MR, Rizzo MR, Gambardella A, Gualdiero P, Lama D, Varricchio G, Gentile S, Varricchio M. Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease. Am J Cardiol 1999;83:1338–1344.
35. Dutka DP, Pitt M, Pagano D, Mongillo M, Gathercole D, Bonser RS, Camici PG. Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease. J Am Coll Cardiol 2006; 48:2225–2231.
36. Schwarzer M, Schrepper A, Bugger H, Pytel G, Mohr fw, Doenst T. The development of heart failure in rats is associated with impaired insulin response and mitochondrial dysfunction. Circulation 2008; 118:S_540.
37. Amorim P, Nguyen TD, Schrepper A, Mohr FW, Doenst T. Postinfarct remodeling causes insulin resistance and defects in substrate oxidation. Thorac Cardiovasc Surg 2009; 56:76.
38. Boudina S, Bugger H, Sena S, O'Neill BT, Zaha VG, Ilkun O, Wright JJ, Mazumder PK, Palfreyman E, Tidwell TJ, Theobald H, Khalimonchuk O, Wayment B, Sheng X, Rodnick KJ, Centini R, Chen D, Litwin SE, Weimer BE, Abel ED. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 2009; 119:1272–1283.
39. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006; 12:694–699.
40. Tuunanen H, Engblom E, Naum A, Scheinin M, N?gren K, Airaksinen J, Nuutila P, Iozzo P, Ukkonen H, Knuuti J.Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction. J Card Fail 2006; 12:644–652.
41. Al-Hesayen A, Azevedo ER, Floras JS, Hollingshead S, Lopaschuk GD, Parker JD.Selective versus nonselective beta-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization. Eur J Heart Fail 2005; 7:618–623.
42. von Lewinski D, Rainer PP, Gasser R, Huber MS, Khafaga M, Wilhelm B, Haas T, M?chler H, R?ssl U, Pieske B. Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. Metabolism 2009.
43. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucosetransporter that is perturbed in disease states. Cardiovasc Res 2009; 84:111–118.
44. von Lewinski D, Gasser R, Rainer PP, Huber MS, Wilhelm B, Roessl U, Haas T, Wasler A, Grimm M, Bisping E, Pieske B. Functional effects of glucose transporters in human ventricular myocardium. Eur J Heart Fail 2010;12:106–113.
45. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 1995; 377:151–155.
46. Stenbit AE, Katz EB, Chatham JC, Geenen DL, Factor SM, Weiss RG, Tsao TS, Malhotra A, Chacko VP, Ocampo C, Jelicks LA, Charron MJ. Preservation of glucose metabolism in hypertrophic GLUT4-null hearts. Am J Physiol Heart Circ Physiol 2000; 279:H313–H318.
47. Liao R, Jain M, Cui L, D'Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation 2002; 106:2125–2131.
48. Yan J, Young ME, Cui L, Lopaschuk GD, Liao R, Tian R. Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation 2009; 119:2818–2828.
49. Tuunanen H, Engblom E, Naum A, N?gren K, Hesse B, Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 2006; 114:2130–2137.
50. Eshaghian S, Horwich TB, Fonarow GC. An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure. Am Heart J 2006; 151:91.
51. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol 2009; 54:422–428.
52. Issa VS, Amaral AF, Cruz FD, Ayub-Ferreira SM, Guimar?es GV, Chizzola PR, Souza GE, Bocchi EA. Glycemia and prognosis of patients with chronic heart failure: subanalysis of the Long-term Prospective Randomized Controlled Study Using Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients (REMADHE) trial.Am Heart J 2010; 159:90–97.
53. Taegtmeyer H, Ballal K. No low-fat diet for the failing heart? Circulation 2006; 114:2092–2093.
54. Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 2004; 287:H1538–H1543.
55. de Brouwer KF, Degens H, Aartsen WM, Lindhout M, Bitsch NJ, Gilde AJ, Willemsen PH, Janssen BJ, van der Vusse GJ, van Bilsen M. Specific and sustained downregulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice. J Mol Cell Cardiol 2006; 40:838–845.
56. Qanud K, Mamdani M, Pepe M, Khairallah RJ, Gravel J, Lei B, Gupte SA, Sharov VG, Sabbah HN, Stanley WC, Recchia FA. Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure. Am J Physiol Heart Circ Physiol 2008; 295:H2098–H2105.
57. Doenst T, Pytel G, Schrepper A, Amorim P, F?rber G, Shingu Y, Mohr FW, Schwarzer M. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 2010.
58. Bugger H, Pytel G, Schwarzer M, Schrepper A, Mohr FW, Doenst T. Mitochondrial dysfunction outweighs beneficial effects of altered substrate selection in heart failure. Thorac Cardiovasc Surg 2009; 56.
59. DepréC, Vanoverschelde JL, Melin JA, Borgers M, Bol A, Ausma J, Dion R, Wijns W. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol 1995; 268:H1265–H1275.
60. Vanoverschelde JL, Wijns W, DepréC, Essamri B, Heyndrickx GR, Borgers M, Bol A, Melin JA. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 1993; 87:1513–1523.
61. Garnier A, Zoll J, Fortin D, N'Guessan B, Lefebvre F, Geny B, Mettauer B, Veksler V, Ventura-Clapier R. Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II. Circ Heart Fail 2009; 2:342–350.
62. Zhao G, Jeoung NH, Burgess SC, Rosaaen-Stowe KA, Inagaki T, Latif S, Shelton JM, McAnally J, Bassel-Duby R, Harris RA, Richardson JA, Kliewer SA. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 2008; 294:H936–H943.
63. ten Hove M, Lygate CA, Fischer A, Schneider JE, Sang AE, Hulbert K, Sebag Montefiore L, Watkins H, Clarke K, Isbrandt D, Wallis J, Neubauer S. Reduced inotropic reserve and increased susceptibility to cardiac ischemia-reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice.Circulation 2005; 111:2477–2485.