Energy metabolism in preconditioned and control myocardium: Effect of total ischemia

Myocardium which has been preconditioned by one or several brief episodes of ischemia has much slower energy utilization during a subsequent sustained episode of ischemia. Since preconditioned tissue also is 'stunned', the reduced energy utilization of preconditioned tissue may be due to reduced contractile effort. This study was done to assess whether differences in energy utilization persisted or disappeared under conditions of total ischemia, in vitro, when contractile activity was abolished in both control and preconditioned regions by hyperkalemic cardiac arrest. Preconditioned myocardium was produced in open-chest anesthetized dogs by exposing the circumflex bed to four 5-min episodes of ischemia each followed by 5 min of arterial reperfusion. Non-preconditioned anterior descending bed was used as control myocardium. Hearts were arrested with hyperkalemia after the last reperfusion period in order to reduce or eliminate the effects of contractile activity. Metabolite content was measured in sequential biopsies of the tissue. Large differences in the rate of energy metabolism of the two regions were noted during the first 15 minutes of ischemia. During this time, the preconditioned tissue utilized less glycogen, and produced less lactate, glucose-6-phosphate (G6P), glucose-1-phosphate (G1P), and alpha-glycerol phosphate (alpha GP), than did control myocardium. Moreover, there was a much smaller decrease in net tissue ATP in the preconditioned than in the control tissue. Thus, the decrease in the demand of preconditioned tissue for energy, which has been observed in vivo, persisted despite the elimination of differences in contractile effort between control and preconditioned myocardium. Although the cause of this decrease in energy demand in preconditioned myocardium remains unknown, the present results suggest that it is not due to concomitant stunning.     

Energy metabolism in cancer patients

The presence of cachexia as defined by a series of clinical symptoms, such as anorexia, weight loss, muscular atrophy, tissue wasting, altered organ function, is frequently observed in cancer and makes a decisive contribution to morbidity and mortality. The onset of neoplastic cachexia is characterized by two events: the presence of primary or secondary anorexia and alterations of the host's intermediate metabolism. Among the most frequent metabolic alterations described in cancer patients is an absolute or relative increase in basal energy consumption with lack of adaptation to fasting. The causes of increased energy consumption in cancer patients are still not clear. Numerous studies on glucose, fat and protein metabolism induced by cancer have significantly contributed to our understanding of the phenomenon. The main alterations of the glucose metabolism are increased glucose turnover and reduced peripheral utilization, both of which probably depend on the presence of the tumour, as shown by their normalization after treatment. Increased gluconeogenesis, from lactate and from gluconeogenetic AA, is the main factor responsible for increased glucose turnover. The main alterations of the fat metabolism are increased mobilization of lipids from adipose tissues, reduced use of exogenous triglycerides and increased oxidation of free fatty acids that cannot be suppressed by glucose. The main alterations of protein metabolism are increased protein turnover with reduced synthesis and increased degradation of muscular proteins and increased hepatic protein synthesis. Knowledge of the pathogenesis of neoplastic cachexia represents a valuable aid for its effective prevention and treatment.     

Cellular and mitochondrial energy metabolism in the stunned myocardium

Summary The influence of cardiac stunning on the oxidation of fatty acids and the oxidative phosphorylation in mitochondria was investigated. Rat hearts were perfused for 15 min according to the working mode with a Krebs-Henseleit buffer containing glucose (11 mM). The hearts were then maintained in normoxic conditions (C group) or subjected to a 15-min global no-flow normothermic ischemia followed by a 30-min reperfusion (R group). Throughout the perfusion, the aortic and coronary flows, and the heart rate and oxygen consumption were monitored. At the end of the perfusion procedure, a bolus of 1-¹⁴C palmitate was injected in the coronary arterial bed to evaluate the fatty acid oxidation. Two sub-populations of mitochondria were isolated from each heart by either mechanical (ME mitochondria) or enzymic (EE mitochondria) extraction and their respiration properties were evaluated. Furthermore, the mitochondrial energy production (ATP and creatine phosphate) was assessed. During ischemia, the aortic flow was suppressed and recovered only to approximately 50% of the preischemic value during reperfusion. This mechanical stunning was associated with an important reduction of the stroke volume (–37%,p<0.01) and a slight decrease in heart rate (–20%,p<0.001). At the end of reperfusion, the beta-oxidation rate constituted 55±1.7% of the cell palmitate and was similar to that assessed in the C group. The oxygen consumption was decreased to 216±31.0L O₂/min/gww and the venous O₂ concentration increased to 5.1±0.572 L O₂/mL (instead of 2.9±0.342 L O₂/mL in the C group), although due to large SD, only the latter was statistically significant. A decrease in metabolic effeciency (42±14.4 vs 106±16.8 mL/L O₂ in the C group) and an increase in palmitate oxidation to oxygen consumption ratio (77±10.1 vs 47.6±4.25 % beta-oxidized palmitate/L O₂ in the C group) were observed. This increased fatty acid contribution in the oxidation metabolism could be responsible for some oxygen wasting and could contribute to decrease the energy available for the contraction despite the normal cardiac oxygen uptake. Furthermore, the respiration parameters of the mitochondria were similar in the C and R groups when glutamate (20 mM) or palmitoylcarnitine (25 M) were used as substrate. ME mitochondria of R group displayed a reduced rate of ATP production (118±29.5 vs 180±14.5 nmoles/min/mg proteins in the C group) without altered creatine phosphate production. The presence of calcium in the medium (10^–5 M) provoked a decrease in ATP production. These effects were not observed with EE mitochondria. Thus, a decreased energy production resulting from a substrate effect and/or a decreased mitochondrial phosphorylative capacity could be associated with the mechanical stunning.     

Enhancement of metabolism of jeopardized myocardium by nifedipine

To define effects of nifedipine on regional metabolism in jeopardized myocardium we quantified accumulation of carbon-11 labeled palmitate ([11C]palmitate) in patients with acute myocardial infarction by positron emission tomography in a randomized, double-blind, placebo controlled study. Tomographic studies were performed prior to treatment as soon as possible after hospital admission. Subsequent studies were performed seven days later. Twenty-two patients with acute myocardial infarction were randomized to treatment with nifedipine (n = 13) or placebo (n = 9). The dosage of active medication was guided by a "third party observer" to avoid iatrogenic hypotension. Treatment was initiated within 9.6 +/- 1 hours after the onset of symptoms of infarction. The extent of the zone of abnormal accumulation of [11C]palmitate was similar in pre-treatment positron emission tomograms from patients subsequently given nifedipine compared with those given placebo. In subsequent positron emission tomography studies, patients treated with nifedipine exhibited improved metabolism of [11C]palmitate (by 16 +/- 10%, SE, P less than 0.05) compared with no change in patients given placebo. Neither enzymatic estimates of infarct size nor scintigraphic estimates of left ventricular ejection fraction differed in the two groups. Patients given nifedipine and manifesting substantial improvement in accumulation of [11C]palmitate had a high incidence of chest pain and recurrent infarction compared with those given placebo in whom no improvement was evident. These observations suggest that some regions of myocardium were benefited transiently by nifedipine but that they remained at high risk for recurrent injury. Thus, patients benefited transiently by drugs early after the onset of infarction may require aggressive intervention such as angioplasty or early coronary bypass surgery. Accordingly, they should be evaluated angiographically early for identification of lesions with unusually high risk.     

缺血后适应心肌线粒体能量代谢研究

目的研究缺血后适应心肌线粒体能量代谢特点。方法以Langendofff离体心脏灌注系统构建缺血后适应大鼠模型,随机分为对照组．再灌注组和后适应组,每组16只。平衡20min后,对照组灌注60min;再灌注组停灌30min,再灌注30min;后适应组停灌30min之后,循环6次再灌注10s,停灌10s,再灌注28min。记录心率和冠状动脉流量。冉灌注末取心肌．用高效液相色谱法测定高能磷酸化合物三磷腺苷、二磷腺苷和一磷腺苷含量;用差速离心法提取心肌线粒体,用氧电极法测定线粒体3态呼吸、4态呼吸和线粒体呼吸控制率。结果与再灌注组比较,后适应组明显提高再灌注末的心率和冠状动脉流量,明显提高心肌内二磷腺苷和一磷腺苷含量,三磷腺苷在各组差异无统计学意义。线粒体3态呼吸和线粒体呼吸控制率改善。结论心肌线粒体能量代谢改善,是缺血后适应心肌保护的可能机制之一。     

Energy metabolism in myocardial stunning.

We investigated the effect of reversible ischemia, leading to persistent contractile dysfunction (stunning), on myocardial energy metabolism. The balance of energy metabolism is expressed by the phosphorylation state of cytosolic nucleotides. This variable cannot be measured directly because of nucleotide compartmentation, but in the isolated heart it can be estimated by the release of purine catabolites. We have previously shown that increased energy consumption or impaired energy production cause purine release to increase, while primary reduction in energy consumption has the opposite effect. Isolated working rat hearts were reperfused after 10 min of global ischemia, measuring hemodynamic variables, tissue high energy phosphate compounds and purine release. In post-ischemic recovery, aortic flow and minute work decreased to 82 +/- 3% and 77 +/- 4% of control, adenine nucleotide pool was reduced by 4.6 mumol/g dry wt, phosphocreatine to creatine ratio increased significantly and purine release decreased to 42 +/- 6% (P < 0.01). The rate of purine salvage, as evaluated by the incorporation of exogenous 3H-adenosine and 14C-hypoxanthine into tissue nucleotides, was much lower than net purine release, and was unchanged after ischemia and reperfusion. The adenine nucleotide pool could be depleted to the same extent as in the stunned myocardium by prolonged (60 min) aerobic perfusion. In this group the hemodynamic variables were unchanged and purine release averaged 87 +/- 9% of control (P = NS). In other experiments prolonged perfusion was combined with preload reduction in order to decrease energy demand. This protocol reproduced the effects of ischemia-reperfusion: aortic flow and minute work averaged 79 +/- 4% and 73 +/- 9% of control, adenine nucleotide depletion was 4.4 mumol/g dry wt and purine release decreased to 38 +/- 5% (P < 0.01). Our findings support the view that stunning is not due to adenine nucleotide depletion or to impairment in energy production, which would cause purine release to increase, but rather to primary reduction in energy utilization.     

黄芪多糖改善糖尿病仓鼠心肌糖脂代谢

探讨黄芪多糖对糖尿病仓鼠心肌糖脂代谢影响.观察糖尿病仓鼠血浆指标、脂肪和心肌病理、心肌超微结构、PPAR-α和葡萄糖转运蛋白(GLUT)4表达.黄芪多糖组糖脂代谢紊乱、心肌超微结构改善、PPAR-α和GLUT4的表达增高.黄芪多糖部分保护糖尿病心肌.     

Energy metabolism homeostasis in cardiovascular diseases

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Energy metabolism disturbance is found in various CVDs, such as coronary heart disease, diabetic cardiomyopathy and heart failure (HF).^[1] Maintaining heart energy homeostasis requires a balance among energy supply, energy expenditure, and substrates selection.^[2] The heart is a very high energy demanding organ and able to metabolize different substrates including fatty acids (FAs), glucose, lactate, and ketones.^[3,4] It is well known that 60%−80% of cardiac energy metabolism relies on the FA oxidation (FAO), while 20%−40% on glucose, lactate, and ketones in adult healthy heart.^[5] “Randle cycle”, first defined in 1960s, also called as “glucose-fatty acid cycle”,^[6] describes that the adult heart has the ability to switch to different substrates for adenosine triphosphate (ATP) generation depending on feeding, hormonal status, and overall nutritional supply.^[7-9] Myocardial metabolic phenotype can be defined as the substrate preference by the heart at a given metabolic status (e.g., arterial concentrations of glucose, lactate, FAs, insulin, catecholamines, and oxygen), hemodynamic condition (heart rate, preload, afterload, and coronary blood flow), and inotropic state.^[10] This phenotype is primarily dependent on the enzymes or transporters that facilitate flux through the metabolic pathways, the structure and integrity of key cellular organelles, such as mitochondria.^[10]In this article, we summarized lipid-, glucose- and pyruvate-related metabolism in the heart, focused on metabolic regulation during neonatal and the ageing heart, proposed possible metabolic mechanisms for cardiac regeneration and degeneration. We also raised some potential targets for keeping heart young through metabolic regulations.     

Energy substrate metabolism in cardiac hypertrophy

Cardiac hypertrophy is a response to long-term pathologic (eg, hypertension) or physiologic (eg, exercise) hemodynamic overload accompanied by changes in energy substrate utilization. The pattern of substrate utilization (or metabolic phenotype) differs dramatically between pathologic and physiologic cardiac hypertrophy with directionally opposite changes in oxidation of fatty acids and glucose and glycolysis. These findings indicate that the metabolic response to long-term alterations in hemodynamic workload is not stereotypical, but is influenced by the nature of the stimulus leading to cardiac hypertrophy. Although the changes in substrate utilization are adaptive, in the case of pathologic stimuli, the changes in metabolism interfere with functional resiliency of the heart to metabolic stress, as occurs during ischemia-reperfusion. The distinct metabolic phenotypes of hearts hypertrophied in response to pathologic or physiologic stimuli are due not only to alteration in expression of metabolic enzymes and proteins, but also to post-translational modulation of metabolic enzymes and proteins.     

Noradrenaline turnover and metabolism in myocardium following aortic constriction in rats

STUDY OBJECTIVE--The aim was to provide meaningful information on the function of the sympathetic system soon after an increased pressure overload on the heart. DESIGN--Noradrenaline storage, turnover, uptake, and synthesis were investigated at 3, 14, and 28 d after aortic banding in rats. Sham operated rats without aortic banding were used as control group. EXPERIMENTAL MATERIAL--Left ventricle, spleen, and kidney from male Sprague-Dawley rats (175-200 g) were used in this study. MEASUREMENTS AND MAIN RESULTS--Cardiac noradrenaline concentration was decreased at 3 d and 28 d after banding and increased at 14 d; left ventricular mass was increased from 14 d onwards. The rate of change in the specific activity of myocardial noradrenaline (noradrenaline turnover) as well as dopamine beta hydroxylase, an enzyme for noradrenaline synthesis, was unaltered at 3 d, increased at 14 d, and decreased at 28 d after aortic banding. Myocardial [3H]noradrenaline uptake, on the other hand, was decreased at all time points studied. The changes observed in the myocardium at day 14 were specific since noradrenaline turnover rate was unaltered in other peripheral organs such as spleen and kidney. Furthermore, after ganglionic blockade with pentolinium, both sham operated control and banded animals had identical, low noradrenaline turnover rate constants, and significant restoration of cardiac weight and noradrenaline stores was observed in the hearts from banded animals. CONCLUSIONS--Noradrenaline turnover and metabolism are altered soon after imposing increased workload on heart. Whether or not the changes in the sympathetic activity are a prerequisites for hypertrophy still remains to be seen.     

Mitochondrial DNA mutations and disturbances of energy metabolism in myocardium.

Since mitochondria occupy a pivotal position in energy metabolism, mitochondrial dysfunction is directly linked with disturbances in cellular function. Mitochondria possess their own DNA, which codes 13 subunits of the mitochondrial energy transducing system; the other subunits are coded by nuclear DNA. Recent advances in gene technology, especially the polymerase chain reaction (PCR), permit us to analyze mitochondrial DNA mutations in a small quantity of tissue. We devised rapid and accurate methods to detect mitochondrial DNA mutations, i.e., the primer shift PCR method and the PCR-Southern method. We also developed a method to determine DNA sequences directly without cloning. Using these methods, we revealed that multiple mitochondrial DNA mutations exist in the myocardium of patients with cardiomyopathy. One mutation was based on the following directly repeated sequence: 5'-CATCAACAACCG-3'. This sequence exists in both the ATPase6 gene and the D-loop region, and pseudo-recombination occurs at that directly repeated sequence resulting in a 7.4 kbp deletion. Accordingly, some subunits of the mitochondrial energy transducing system can not be biosynthesized by these deleted mitochondrial DNA, and energy transduction is substantially depleted. Even without reduction of blood supply, mitochondrial DNA mutations can induce a chronic ischemia-like state in the myocardium, which might be a factor in the genesis of cardiomyopathy.