Benefit and risk of exercise on myocardial function in diabetes.

Regular physical activity promotes cardiorespiratory fitness and has been considered a cornerstone for non-pharmacological treatment of more than 17 million Americans with diabetes mellitus. Physical exercise has been shown to positively affect certain cardiovascular risk factors such as insulin resistance, glucose metabolism, blood pressure and body fat composition, which are closely associated with diabetes and heart disease. With the increasingly sedentary life style in our society, routine daily exercise of moderate intensity is highly recommended to reduce cardiovascular risk, the leading cause of death in diabetic patients. Exercise produces many beneficial effects to the heart function such as reduced incidence of coronary heart disease, attenuated severity of diabetic cardiomyopathy, improved cardiac performance, cardiac reserve and autonomic regulation. Nevertheless, many diabetic patients do not appear to gain much benefit from exercise or may even be at risk of performing physical exercise. This review summarizes the benefit and risk of exercise on diabetic heart function, with a special emphasis on myocardial and autonomic function.     

Efficacy of metabolic modulators in ischemic heart disease: an overview

Myocardial ischemia results in a decrease in oxygen supply to the heart, leading to cardiac dysfunction. Present therapeutic strategies for treating myocardial ischemia or infarction focus on maintaining coronary artery patency by either fibrinolysis or primary percutaneous intervention. Although these approaches have dramatically improved the prognosis in patients with angina pectoris and myocardial infarction, the complication of myocardial ischemia remains a major cause of mortality and morbidity worldwide. A novel approach that entails improving and optimizing cardiac energy metabolism of the ischemic myocardium by pharmacologically manipulating different metabolic pathways in the heart holds promise in limiting myocardial damage. Metabolic support of the ischemic myocardium is aimed at increasing glycolysis and residual oxidative phosphorylation of glucose along with decreasing fatty acid oxidation. This review discusses the various metabolic modulators, both conventional and new, along with documented evidence in both acute and chronic angina.     

Metabolic therapy of heart failure

Alterations of cardiac metabolism can be present in several cardiac syndromes. Heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation, and determining an increased utilization of non-carbohydrate substrates for energy production. In fact, fasting blood ketone bodies as well as fat oxidation have been shown to be increased in patients with heart failure. The result is depletion of myocardial ATP, phosphocreatine and creatine kinase with decreased efficiency of mechanical work. A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the failing heart. To date, the most effective metabolic treatments include several pharmacological agents, such as trimetazidine and perhexiline, that directly inhibit fatty acid oxidation. These agents have been originally adopted to increase the ischemic threshold in patients with effort angina. However, the results of current research is supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism could be an effective adjunctive treatment in patients with heart failure, in terms of left ventricular function and glucose metabolism improvement. In fact, these agents have also been shown to improve overall glucose metabolism in diabetic patients with left ventricular dysfunction. In this paper, the recent literature on the beneficial therapeutic effects of modulation of cardiac metabolic substrates utilization in patients with heart failure is reviewed and discussed.     

Angiotensin II and the cardiac complications of diabetes mellitus

The prevalence of diabetes has reached epidemic proportions in the developed world and is expect to increase to 5.4% by 2025. This has resulted in an unprecedented number of patients experiencing the macro- and micro-vascular complications of diabetes, such as renal, retinal, neurological and cardiac dysfunction. Premature coronary artery disease and cardiac failure are vastly over-represented in the diabetic population, with significant morbidity and mortality. In fact, the rate of cardiac events in patients with diabetes is equivalent to non-diabetic patients with a previous myocardial infarction. Epidemiological evidence, combined with the results of large scale trials blocking the renin-angiotensin system (RAS) have provided data to support the hypothesis that angiotensin II and its interaction with the metabolic changes associated with diabetes mellitus is responsible for the pathogenesis of many of these complications. This review focuses on the role of the RAS and the development of diabetic cardiac disease.     

Effectiveness of nicorandil in the preservation of myocardium stressed by transient ischemia and its influence on cardiac metabolism during coronary artery occlusion with subsequent reperfusion: a comparison with isosorbide dinitrate

Summary This study was designed to investigate the effects of nicorandil in comparison to isosorbide dinitrate (ISDN) on hemodynamics, on myocardial metabolism and on effectiveness in the preservation of ischemically stressed myocardium.Repeated ischemia (3 min) was produced in anaesthetized open-chest mongrel dogs by proximal, intermittent left anterior descending artery occlusion with subsequent reperfusion. In each experiment 2–3 control occlusions were compared to 2–3 occlusions under nicorandil or ISDN. Application of both nicorandil (0.64 mol·kg^–1 body weight, i.v.) and ISDN (1.27 mol·kg^–1 body weight, i.v.) led to a significant afterload reduction and to a decrease of the coronary vascular resistance. The efficiency of the compounds in the protection of ischemic myocardium was examined by quantification of oxygen-debt and oxygen-repayment in the occlusion and reperfusion periods. Compared to control, premedication with nicorandil led to a significant increase of oxygen-debt, whereas ISDN reduced it significantly. Oxygen-repayment remained unchanged. The influence of the drugs on the metabolism of glucose, lactate and free fatty acids (FFA) was examined under basic conditions, in ischemia and during reperfusion. For all substrates, extraction, extraction ratio and oxygen extraction ratio were calculated. Under basic conditions, glucose metabolism was significantly enhanced in both groups but FFA metabolism was inhibited only by ISDN. In ischemia, FFA metabolism was enhanced by nicorandil and depressed by ISDN.Data obtained in this study suggest that nicorandil may even aggravate the metabolic and energetic situation of ischemic myocardium and, on the other hand, clearly support the well documented protective effects of ISDN.Abbreviations CO cardiac output - CVR coronary vascular resistance - E_t myocardial energy demand - EX extraction - EXR extraction ratio - FFA free fatty acids - ISDN isosorbide dinitrate - LAD left anterior descending artery - MBF myocardial blood flow - MVO₂ myocardial oxygen consumption - OER oxygen extraction ratio - PVR peripheral vascular resistance     

Diabetes mellitus: a cardiovascular disease

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes mellitus (DM). The pathophysiology of CVD in diabetes involves traditional and novel cardiac risk factors, including hypertension, dyslipidemia, smoking, genetic factors, hyperglycemia, insulin resistance/hyperinsulinemia, metabolic abnormalities, oxidative/glycoxidative stress, inflammation, endothelial dysfunction, a procoagulant state and myocardial fibrosis. Specific vascular, myopathic and neuropathic alterations have been suggested to be responsible for the excessive cardiovascular morbidity and mortality in diabetes. These alterations manifest themselves clinically as coronary heart disease, congestive heart failure and/or sudden cardiac death. In order to contain the emerging epidemic of CVD in DM, diabetic patients should ideally have excellent glycemic control, a low normal blood pressure and low levels of low-density lipoprotein cholesterol, and be taking an angiotensin-converting enzyme inhibitor and aspirin, which may go some way to containing the emerging epidemic of CVD in DM.     

Changes in regional myocardial metabolism during partial stenosis in the presence of coronary vasodilators

The relation of regional myocardial metabolism to coronary blood flow during pharmacologic flow elevation with dipyridamole was studied in four unsedated dogs. Chronic catheters were implanted in the aorta, left atrium, and coronary sinus at the anterior cardiac vein for determination across the left anterior descending coronary vascular bed of arteriovenous O2 content, glucose, free fatty acids, and lactate. A flowmeter and inflatable occluder were placed on the left anterior descending coronary artery, and mean aortic pressure and heart rate were recorded. Flow was increased with dipyridamole (0.4 mg/kg i.v.) and subsequently lowered by a partial stenosis in order to examine effects of relative flow decrease on metabolism without reducing flow below resting control or producing ischemia. Regional metabolism was compared at maximum flow and at submaximal flow with partial stenosis. Resting flow, maximal flow, and submaximal flow values were 72 +/- 3, 231 +/- 12, and 121 +/- 10 ml/min/100 g, respectively. When flow was lowered from maximal to submaximal levels, there was a significant decrease in both MVO2, from 8.2 +/- 0.7 to 6.4 +/- 0.5 ml/min/100 g, and free fatty acid uptake, from 23.9 +/- 5.5 to 6.8 +/- 1.0 muEq/min/100 g, p less than 0.01. There was no significant change in glucose uptake, lactate uptake, or external work (heart rate-pressure product). These results demonstrate that coronary blood flow and/or distal coronary pressure is a primary determinant of myocardial metabolism in the absence of changes in external metabolic demand, ischemia, or shifts in substrate utilization. We suggest that this phenomena accounts for the relative infrequency of anginal pain in the presence of perfusion defects during diagnostic imaging.     

Medical management of the diabetic patient with coronary artery disease

The prevalence of type 2 diabetes is rising at an alarming rate worldwide. Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the diabetic population. Future CAD risk should be routinely assessed in patients with diabetes as specific subgroups might benefit from information derived from cardiac stress testing and other diagnostic procedures. Risk factor control is of paramount importance in all cases and it usually requires sustained lifestyle modifications, coupled with pharmacological interventions. Statins and angiotensin-converting enzyme (ACE) inhibitors are the first-line agents for the treatment of dyslipidaemia and hypertension, respectively. Microvascular, but not macrovascular, complications of diabetes are effectively prevented by good glycaemic control. Metformin is considered the first-choice agent in overweight diabetic subjects, while the role of thiazolidinediones is currently the focus of medical research. The diagnosis of acute coronary events in patients with diabetes is often challenging because of the high prevalence of silent ischaemia in these subjects. All acute cardiac events need to be promptly treated and myocardial reperfusion attempted without delay. Maintaining glucose levels as close to normal as possible, during and shortly after an acute event, improves prognosis in patients with diabetes. Risk factor control remains the cornerstone of secondary prevention; beta-blockers, ACE-inhibitors and antiplatelet agents confer additional symptomatic and survival benefit. Similar therapeutic principles also apply to patients with type 1 diabetes. This article addresses the complex problem of managing patients with diabetes and coronary artery disease.     

糖代谢异常对急性冠状动脉综合征患者近期预后的影响

目的探讨糖代谢异常对急性冠状动脉综合征患者近期预后的影响。方法172例急性冠状动脉综合征（ACS）患者，根据入院24h空腹血糖及住院5～7d的口服葡萄糖耐量试验（OGTT）结果分为血糖正常组、单纯应激组、2型糖尿病（T2DM）组、糖耐量异常和（或）空腹血糖受损组四组，分别观察心肌酶CK-MB峰值，左室射血分数（LVEF），近期（30d）病死率，平均住院日及心源性休克、心律失常、肺部感染等并发症发生率。结果T2DM组心肌酶CK-MB峰值，近期（30d）病死率，心源性休克、心律失常、肺部感染等并发症发生率明显高于血糖正常组，平均住院日延长；单纯应激组心肌梗死比例较高，并发症发生率与T2DM组相近。结论各种糖代谢异常不同程度地增加急性冠状动脉综合征患者并发症的发生率，增加病死率，延长住院时间。     

Cardiac effects of HDL and its components on diabetic cardiomyopathy

Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease and hypertension under diabetes mellitus. Hyperglycemia, hyperinsulinemia, and hyperlipidemia, characteristic metabolic disturbances evident in diabetes mellitus, all three lead to a specific altered cardiac structure and function. Recently, it has been demonstrated that altered HDL, be it low HDL or dysfunctional HDL is not only a consequence of diabetes mellitus, but can also contribute to the development of diabetes mellitus, and therefore also of diabetic cardiomyopathy. This review summarizes how HDL can indirectly affect diabetic cardiomyopathy via their influence on the metabolic triggers hyperglycemia, hyperinsulinemia, and hyperlipidemia, and how they can directly influence the cardiac cellular consequences, typical for diabetic cardiomyopathy, including inflammation, oxidative stress, apoptosis, fibrosis, Ca2+ handling, glucose homeostasis, and endothelial dysfunction.     

Effects of beta 2-adrenoceptor stimulation on cardiac metabolism in the conscious dog.

1 The effects of the beta 2-adrenoceptor stimulant, salbutamol, on cardiac metabolism have been studied in conscious mongrel dogs. The potential effects of anaesthesia on the study of cardiac metabolism have been avoided by prior implantation of arterial (A) and coronary sinus (CS) catheters for blood sampling and a central venous catheter for infusion. Extraction of substrates for myocardial energy metabolism (CA-CS) was assessed 3 to 24 days post-operatively. A 100 micrograms bolus of salbutamol was given followed by an infusion of 3 micrograms/min for 1 h. 2 Although heart rate increased significantly from 106 to 165 beats/min, fractional extraction of oxygen tended to fall from 84% to 77%. Thus an increase in coronary blood flow rather than in oxygen extraction must have maintained an oxygen supply commensurate with the salbutamol-induced tachycardia. 3 Neither CA-CS glucose nor fractional glucose extraction altered significantly during salbutamol infusion despite increases in arterial concentration (CA) of glucose and arterial insulin immunoreactivity and a decrease in CA of free fatty acids (FFA). This suggests that an insulin-antagonistic action accompanies the infusion of salbutamol. 4 The fractional extraction of lactate increased during salbutamol infusion. In part, this may have been a reflection of a decreased myocardial extraction of FFA with salbutamol in this model.     

Hemodynamic and metabolic effects of dopamine and insulin during acute left ventricular failure in dogs

Acute ischemic heart failure was induced in eight dogs by coronary embolization. Severe depression of the left ventricular (LV) performance was evidenced. At 15 min after the embolization procedure, dopamine was infused at a dosage sufficient to increase the maximum rate of LV pressure rise (LVdP/dtmax) by approximately 50%. The significant improvement in cardiac performance was obtained at unaltered myocardial oxygen consumption (MVo2). Dopamine infusion was concluded, and after a stabilization period 300 IU of insulin was injected. This was followed by the infusion of glucose and potassium to maintain levels. Insulin significantly improved the performance of the failing left ventricle at unaltered MVo2, but to a lesser extent than did dopamine. Additional dopamine infusion further significantly improved cardiac performance. The net effect of insulin and dopamine in combination as compared with dopamine alone was a significantly greater increase in stroke volume and cardiac output due to a more pronounced decrease in total peripheral resistance. Dopamine increased arterial concentrations and myocardial uptake of free fatty acids (FFA). The net metabolic effect of insulin and dopamine in combination as compared with dopamine alone was a shift in myocardial substrate uptake from FFA to carbohydrates.     

Is it Time to Discard β-Blockers in Patients Undergoing Noncardiac Surgery?

Prevention of cardiac complications in patients undergoing major surgical or vascular procedures should be approached as the prevention of these complications in other common situations. β-Adrenoceptor antagonists (β-blockers) should be indicated in patients who are candidates for those treatments, regardless of whether surgery is performed. Current guidelines include patients with acute coronary syndrome, systolic dysfunction, chronic coronary artery disease (CAD), vascular disease, and diabetes as candidates for long-term β-blocker therapy. Therefore risk stratification prior to surgery is indeed required to identify patients with existing CAD or myocardial ischemia in order to be able to treat them as such. In addition, β-blockers may reduce ischemic complications in high-risk patients. However, initiating treatment at high dosages immediately before surgery has been associated with an increased risk of hypotensive strokes.     

糖尿病与非糖尿病冠心病患者冠脉弥漫长病变经介入治疗的预后观察

目的：以非糖尿病冠心病患者做对照组,评价冠心病合并糖尿病冠脉弥漫长病变患者经药物支架治疗1年后的预后。方法：共入选238例经雷帕霉素药物涂层支架治疗的患者,糖尿病组77例,非糖尿病组161例,均为冠脉弥漫长病变（病变长度大于20mm）。详细记录所有入选患者的姓名,性别,年龄,联系电话,入院时血压,血脂（LDL-C）,是否吸烟,心脏彩超的E值,A值及左室射血分数（LVEF）,冠脉病变长度、部位、平均支架数、支架管径、支架长度。通过电话、门诊随访记录1年后患者心脏不良事件（MACE）的发生率,包括再发心绞痛,心肌梗死,冠脉搭桥及心源性死亡。门诊复查心脏超声记录二尖瓣血流频谱舒张早期速度E和舒张晚期速度A,以及左心室射血分数（LVEF）,以E/A作为评价左心室舒张功能指标,并进行统计学处理。结果：糖尿病组与非糖尿病组间的临床基本资料除LDL-C糖尿病组高于非糖尿病组外,其余均无统计学差异。除糖尿病组1年后再发心绞痛发生率高于非糖尿病组外（P=0.029）,差异有统计学意义,其他1年后再发心肌梗死（P=0.732）,冠脉搭桥手术（CABG）（P=0.400）,心源性死亡的发生率（P=0.448）,左心室的功能（P=0.236）两组间差异均无统计学意义。两组患者治疗1年后EF值较1年前有明显的提高,糖尿病组治疗前后分别为52.74±11.70vs66.67±2.38;非糖尿病组分别为55.13±9.52vs66.12±3.33;E/A比值也由1年前的〈1改善到〉1,糖尿病组治疗前为0.70±0.19/0.85±0.21,治疗后为0.85±0.14/0.72±0.09;非糖尿病组治疗前为0.68±0.19/0.83±0.18,治疗后为0.85±0.18/0.73±0.09。结论：糖尿病与非糖尿病冠心病患者冠脉弥漫长病变经介入治疗1年后,心肌梗死、CABG、心源性死亡发生率和左心室功能相当;而糖尿病组再发心绞痛的发生率高于非糖尿病组。糖尿病与非糖尿病冠心病患者冠脉弥漫长病变经雷帕霉素药物涂层支架治疗可以明显改善1年的预后。     

Resveratrol modifies risk factors for coronary artery disease in swine with metabolic syndrome and myocardial ischemia

Resveratrol has been purported to modify risk factors for obesity and cardiovascular disease. We sought to examine the effects of resveratrol in a porcine model of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were fed either a normal diet (control), a high cholesterol diet (HCD), or a high cholesterol diet with supplemental resveratrol (HCD-R; 100mg/kg/day) for 11 weeks. After 4 weeks of diet modification a baseline cardiovascular MRI was performed and an ameroid constrictor was placed on the left circumflex coronary artery of each animal to induce chronic myocardial ischemia. At 7 weeks, a second cardiovascular MRI was performed and swine were sacrificed and myocardial tissue harvested. Resveratrol supplementation resulted in lower body mass indices, serum cholesterol, and C-reactive protein levels, improved glucose tolerance and endothelial function, and favorably augmented signaling pathways associated with myocardial metabolism. Interestingly, serum tumor necrosis factor-α levels were not influenced by resveratrol treatment. Immunoblotting for markers of metabolism demonstrated that insulin receptor substrate-1, glucose transporters 1 and 4, and phospho-AMPK were increased in the HCD-R group. Peroxisome proliferator-activated receptor γ and retinol binding protein 4 were downregulated in the HCD-R group as compared to the HCD group. Myocardial perfusion and function at rest as assessed with magnetic resonance imaging were not different between groups. By favorably influencing risk factors, resveratrol may decrease the burden of chronic metabolic disease and improve cardiovascular health.     

Optimization of cardiac metabolism in heart failure

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.     

Optimizing treatment of diabetes and cardiovascular disease with combined α,β‐blockade

ABSTRACT

Background: Cardiovascular risk factors of the diabetic patient should be treated as aggressively as those of the nondiabetic patient who has had a myocardial infarction. β‐Blockers are established to reduce cardiovascular risk in patients with hypertension, coronary heart disease, and heart failure. Despite this benefit of β‐blockers, physicians have been reluctant to use them in patients with diabetes, in whom they are even more effective, because of the negative effects on carbohydrate and lipid metabolism.

Objective: This paper reviews (based on a Medline literature search to December 2004) the relationship between diabetes and cardiovascular risk factors, describes the metabolic consequences of insulin resistance, and discusses the impact of different β‐blockers on the treatment of cardiovascular disease in patients with diabetes.

Results: There is a large cardioprotective benefit with the use of β‐blockers in patients with diabetes; however, metabolic risks are associated with some β‐blockers. Newer, vasodilating, nonselective β‐blockers do not have the same adverse metabolic consequences observed with earlier β‐blockers. Recent evidence has shown that they have a neutral effect on metabolic parameters and lipid profile. They do not promote insulin resistance and can be used safely in heart failure patients with diabetes.

Conclusions: Nonselective vasodilating β‐blockers, such as carvedilol, may be used in patients with cardiovascular disease and diabetes without the same negative metabolic consequences seen with the use of earlier generation β‐blockers.     

Effects of a 2',3',5'-substituted adenosine derivative on systemic and coronary hemodynamics and on cardiac metabolism in the anesthetized dog

Hemodynamic and metabolic effects of 2',3'-O-methoxyethylidene-adenosine-5'-(Nethyl-carboxamide) (744-98), an adenosine analogue with long-lasting coronary dilator activity, were studied in the anesthetized, closed-chest dog. The coronary sinus outflow increased 5fold following administration of the compound (5 microgram/kg i.v.) and still remained three thimes higher than the control level after 4 h. Total peripheral resistance decreased markedly, accompanied by a baroreceptor-mediated increase in heart rate, left ventricular dp/dtmax and myocardial oxygen consumption. Blood glucose levels and glucose uptake by the heart increased concomitantly, whereas plasma free fatty acid (FFA) levels decreased markedly, without consistent changes in myocardial FFA balance. These effects are explained by antilipolytic and glucagon-releasing activities of the adenosine analogue. The myocardial oxygen extraction ratio for glucose greatly exceeded the aerobic metabolic requirement, a finding already previously obtained with coronary dilators.     

Myocardial insulin resistance and cardiac complications of diabetes

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.