Energy Metabolism in the Hypertrophied Heart

In response to a prolonged pressure- or volume-overload, alterations occur in myocardial fatty acid, glucose, and glycogen metabolism. Oxidation of long chain fatty acids has been found to be reduced in hypertrophied hearts compared to non-hypertrophied hearts. However, this observation depends upon the degree of cardiac hypertrophy, the severity of carnitine deficiency, the concentration of fatty acid in blood or perfusate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. Despite the acceleration of glycolysis, glucose oxidation is not correspondingly increased leading to lower coupling between glycolysis and glucose oxidation and greater H⁺ production than in non-hypertrophied hearts. Although glycogen metabolism does not differ in the absence of ischemia, synthesis and degradation of glycogen are accelerated in severely ischemic hypertrophied hearts. These alterations in carbohydrate metabolism may contribute to the increased susceptibility of hypertrophied hearts to injury during ischemia and reperfusion by causing disturbances in ion homeostasis that reduce contractile function and efficiency to a greater extent than normal. As in non-hypertrophied hearts, pharmacologic enhancement of coupling between glycolysis and glucose oxidation (e.g., by directly stimulating glucose oxidation) improves recovery of function of hypertrophied hearts after ischemia. This observation provides strong support for the concept that modulation of energy metabolism in the hypertrophied heart is a useful approach to improve function of the hypertrophied heart during ischemia and reperfusion. Future investigations are necessary to determine if alternative approaches, such as glucose-insulin-potassium infusion and inhibitors of fatty acid oxidation (e.g., ranolazine, trimetazidine), also produce beneficial effects in ischemic and reperfused hypertrophied hearts.     

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptin-mediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.     

心型脂肪酸结合蛋白与急性脑梗死

脂肪酸结合蛋白（FABP）是一种小分子胞内脂肪酸结合蛋白，与细胞生长、基因表达、离子通道的功能有关。细胞缺血损伤时，可发生胞内FABP渗漏。业已证实，脑梗死超早期可出现血清FABP水平增高。文章综述了FABP的生物学功能和在缺血性脑损伤中的表达机制。     

Exercise training restores abnormal myocardial glucose utilization and cardiac function in diabetes

BACKGROUND: Clinical and experimental studies have shown that a reduction in myocardial glucose utilization is a factor contributing to diabetic cardiomyopathy. This study determined whether exercise training could prevent the depression in glucose utilization observed in the diabetic rat heart. METHODS: Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). After 10 weeks of treadmill running, exogenous myocardial glucose utilization and cardiac function were determined in isolated working hearts perfused under aerobic conditions and then subjected to a 60-min period of low-flow ischemia followed by reperfusion. RESULTS: Compared to aerobically perfused sedentary control hearts, rates of myocardial glucose oxidation and glycolysis were lower in diabetic hearts. Diabetes was also characterized by a pronounced decrease in cardiac function. Following exercise training, rates of myocardial glucose oxidation and glycolysis were restored and cardiac performance was improved compared to sedentary diabetic hearts. During low-flow ischemia, the decrease in glycolysis observed in hearts of sedentary diabetic rats was attenuated following exercise training. Following ischemia, glucose oxidation and glycolysis returned to preischemic levels in all groups. However, hearts from trained diabetic animals had higher rates of glucose oxidation compared to their respective sedentary group. This was accompanied by an enhanced recovery of heart function following ischemia. CONCLUSIONS: Our results indicate that exercise training is effective in preventing the depression in myocardial glucose metabolism observed in the diabetic rat. This may explain the benefits of exercise in preventing cardiac dysfunction in diabetes.     

干细胞治疗缺血性心力衰竭研究进展

干细胞移植已经被用于治疗如急性心肌梗死、心力衰竭等心脏疾病,其可以提高心功能、促进新生血管的形成和对心脏生理间接影响。被研究的干细胞包括胚胎干细胞、胎儿心肌细胞、骨骼肌肌原细胞、骨髓干细胞、外周血CD34 细胞、内皮祖细胞、心肌祖细胞和成纤维细胞。虽然干细胞治疗心力衰竭是一项革命性进展,但还有许多问题期待解决,比如说何种人群适合做干细胞治疗、移植细胞种类、移植方式、移植细胞数目和疗效的评估等都还没有明确。现从干细胞类型,移植后的效果及移植的方法等方面做一综述。     

心肌代谢药物治疗缺血性心脏病的研究进展

近年来通过改变心肌代谢发挥抗心绞痛作用的一类药物受到关注。这类代谢药物主要通过诱导游离脂肪酸代谢向葡萄糖代谢的转换,从而增加单位氧耗生成三磷酸腺苷供能物质的量而发挥抗心绞痛作用。适用于冠心病、肥厚型心肌病、非手术主动脉狭窄和慢性心力衰竭心肌缺血的治疗。代谢药物有可能成为缺血性心脏病患者药物治疗新的选择。现对4种心肌代谢药物进行综述。     

促红细胞生成素在慢性心力衰竭的临床应用及机制研究进展

促红细胞生成素是特异性作用于红系祖细胞的造血生长因子,但新近有证据表明,促红细胞生成素具有重要的心脏保护功能。动物实验显示：促红细胞生成素能改善左心室功能,促红细胞生成素能明显降低心肌细胞凋亡,促红细胞生成素能抑制血管内皮细胞发生凋亡,刺激内皮前体细胞有丝分裂,使用促红细胞生成素治疗合并贫血的慢性心力衰竭患者,可显著改善患者的心功能及临床症状。临床研究表明促红细胞生成素可明显提高慢性心力衰竭合并贫血患者的血红蛋白浓度,改善心功能,提高运动耐量,尽管促红细胞生成素在治疗肾性贫血过程中可能有导致血压增高、血栓形成的危险,但促红细胞生成素治疗心肌缺血和慢性心力衰竭是安全的。目前,对促红细胞生成素的应用,有可能开辟治疗慢性心力衰竭的新途径。但促红细胞生成素用于慢性心力衰竭的预后的影响还需在经过精确设计的前瞻性研究中进行检测,其长期治疗心脏的不良反应有待进一步探讨及促红细胞生成素起始治疗时间、选用以及血红蛋白浓度的靶目标也尚需进一步探讨。其作用机制尚待进一步探讨。     

糖尿病大鼠心力衰竭时心肌细胞凋亡的研究

目的探讨糖尿病大鼠心力衰竭时是否存在心肌细胞凋亡.方法建立STZ糖尿病大鼠模型,饲养12周,经心功能检测后确认为糖尿病心力衰竭的大鼠,采用TUNEL法及TEM法,检测糖尿病大鼠左室心肌的凋亡细胞.结果 糖尿病大鼠出现心功能异常并可见凋亡的心肌细胞,而对照组左室心肌组织中未见心肌细胞凋亡.结论心肌细胞凋亡与糖尿病大鼠心力衰竭密切相关.     

Role of Nitric Oxide in the Regulation of Substrate Metabolism in Heart Failure

Solid experimental evidence indicates that nitric oxide (NO) inhibits oxygen utilization in vitro and in vivo. The role played by NO in cellular metabolism is likely extended to the control of substrate utilization. Studies performed in normal hearts show that NO inhibits glucose uptake and that a reduced synthesis of NO impairs free fatty acid consumption. Interestingly, we found also that myocardial free fatty acid utilization decreases while glucose consumption is enhanced in end stage heart failure, when cardiac NO production falls dramatically. This phenomenon led us to the hypothesis that the reduced synthesis of NO could be at least in part responsible for myocardial metabolic alterations occurring in severe heart failure. The present review mentions some of the seminal studies that defined the function of NO as metabolic modulator. A particular emphasis is put on available data suggesting a role for NO in the control of cardiac substrate utilization in normal and failing hearts.     

Prognostic Significance of ECG Abnormalities for Mortality Risk in Acute Heart Failure: Insight From the Sub-Saharan Africa Survey of Heart Failure (THESUS-HF)

ObjectiveThe aim of this study was to assess the predictive utility of 12-lead electrocardiogram (ECG) abnormalities among Africans with acute heart failure (HF).Methods and ResultsWe used the Sub-Saharan Africa Survey of Heart Failure, a multicenter prospective cohort study of 1,006 acute HF patients, and regression models to relate baseline ECG findings to all-cause mortality and readmission during a 6-month follow-up period. Of 814 ECGs available, 523 (49.0% male) were obtained within 15 days of admission, among which 97.7% showed abnormalities. Mean age was 52.0 years and median follow-up was 180 days, with 77 deaths (Kaplan-Meier 17.5%) through day 180 and 63 patients with death or readmission to day 60. QRS width, QT duration, bundle branch block, and ischemic changes were not associated with outcomes. Increasing ventricular rate was associated with increasing risk of both outcomes (hazard ratio [HR] 1.07 per 5 beats/min increase for 60-day death or readmission, 95% confidence interval [CI] 1.02–1.12; P = .0047), and the presence of sinus rhythm was associated with lower risk (HR 0.58, 95% CI 0.34–0.97; P = .0385). There was a strong association between survival and heart rate in patients in sinus rhythm, with heart rate >119 beats/min conveying the worst mortality risk.ConclusionsECG abnormalities are almost universal among Africans with acute HF, which may add to the immediate diagnosis of patients presenting with dyspnea. Although some ECG findings have prognostic value for risk of adverse outcomes, most of them are nonspecific and add little to the risk stratification of these patients.     

糖尿病急性心肌梗死后易发心力衰竭的机制

在糖尿病的患者,如果不合并冠心病心肌缺血,基本均处于亚临床状态的心肌损害,心功能表现为早期舒张功能不全以及晚期合并收缩功能不全,其机制是心肌能量代谢的异常导致一系列的病理生理学改变,包括糖类代谢紊乱、脂肪酸的氧化和心肌脂质聚集等,也就是目前常说的糖尿病心肌病。对于严重的糖尿病患者如果遭遇心肌缺血的打击,其更加容易发生心力衰竭和死亡,拥有明显更差的预后,其机制是什么呢？现将详细加以阐述。     

Activated Oxygen Species in Heart Failure

Congestive heart failure (CHF) is defined by inability of the heart to provide adequate blood flow, oxygen, and nutrients to tissues and organs. There is now overwhelming evidence suggesting that oxygen-derived free radicals are involved in the pathogenesis of CHF. In vitro studies suggest that the highly toxic radical species damage sub-cellular membranes leading to the disruption in excitation-contractile coupling and eventually the dysfunction of the myocardium. In addition, these radicals destroy nitric oxide, a potent signaling molecule responsible for maintaining cardiovascular tone. Antioxidants hold great promise in minimizing the damage occurring as a result of the excessive generation of the free radicals during ischemia/reperfusion injury and CHF.     

左旋卡尼汀对心力衰竭患者血清游离脂肪酸浓度的影响

目的 :探讨左旋卡尼汀 （L - CN ）治疗充血性心力衰竭 （CHF）的临床疗效及对血清游离脂肪酸 （FFA ）浓度的影响。方法 :CHF患者 5 0例 ,分为 L - CN组 （2 5例 ）和对照组 （2 5例 ）。对照组采用常规药物治疗 ,L - CN组常规药物加L - CN治疗 ,采用酶比色法测定治疗前、后血清 FFA浓度 ,并观察心功能改变情况。结果 :CHF患者治疗后血清中FFA浓度较治疗前明显下降 （P<0 .0 5或 P<0 .0 1） ,且 L - CN组 FFA浓度在治疗后显著低于对照组 （P<0 .0 5 ） ;治疗后两组心功能较治疗前明显改善 ,L - CN组心功能改善程度较对照组更明显 ,L - CN组治疗显效率及总有效率均高于对照组 （P<0 .0 5 ）。结论 :L - CN治疗不但能改善心功能 ,而且能降低血清 FFA水平。     

Prevalence of Conduction Abnormalities in a Systolic Heart Failure Population by Race,Ethnicity, and Gender

Background : There is paucity of data regarding conduction abnormalities in the Hispanic population with systolic heart failure (HF). We aimed to evaluate the prevalence of electrocardiogram (ECG) abnormalities in a systolic HF population, with attention to the Hispanic population. Methods : A cross sectional study of 926 patients enrolled in a systolic HF disease management program. ECGS were obtained in patients with an ejection fraction (EF) ≤ 40% by echocardiography at enrollment. Univariate and multivariate analysis adjusted by ethnicities was performed. Results: White patients exhibited higher prevalence of atrial fibrillation (14.7%) than black patients (8.0%, P = 0.01) whereas Hispanics presented higher prevalence of paced rhythm (14.3% in Hispanics vs. 6.5% in whites and 5.2% in blacks, P<0.01 for both comparisons), higher prevalence of left bundle branch block (LBBB, 14.5% in Hispanics vs. 8.8% in whites and 5.8% in blacks, P = 0.002) and increased frequency of abnormal QT intervals (76.7% in Hispanics) than whites (59.6%) and blacks (69%) patients (P< 0.01 for both comparisons). A QRS interval greater than 120 ms was less prevalent among blacks (15.8% vs. 26.0% in whites and 25.3% in Hispanics, P = 0.01 for both comparisons). Univariate and multivariate analysis disclosed no influence of other characteristics (age, sex, coronary artery disease, hypertension, ejection fraction, medications) in the ECG findings. Conclusions: Hispanics with Systolic HF presented with increased prevalence of paced rhythm, LBBB, and abnormal QT intervals. Attention should be addressed to these ECG variations to recommend additional guidance for therapeutic interventions and provide important prognostic information.     

Effects of POCA on metabolism and function in the ischemic rat heart

Summary Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) inhibits carnitine palmityltransferase I and fatty acid oxidation. The effects of POCA on cardiac function and on tissue levels of carnitine and coenzyme A esters were studied in the isolated rat heart subjected to 90 minutes of ischemia with and without 15 minutes of reperfusion. The perfusion medium contained 1.2 mM palmitate and 5.5 mM glucose plus or minus 0.5 mM POCA. This compound prevented accumulation of long-chain acylcarnitine and coenzyme A esters during ischemia and significantly improved the recovery of cardiac output after ischemia and reperfusion. Short-chain acylcarnitine levels were increased during ischemia by POCA. No effects were noted on tissue ATP and lactate levels. POCA may protect the ischemic heart by preventing accumulation of these toxic metabolites and by stimulating glucose utilization during ischemia.Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylateThis work was supported by the Veterans Administration and NIH HL 17736