游离脂肪酸对2型糖尿病心肌能量底物代谢及心功能的影响

目的探讨游离脂肪酸(FFA)在2型糖尿病(DM)中对心肌能量底物代谢以及心功能的影响。方法采用高脂喂养(40%脂肪)加小剂量链脲佐菌素(STZ)建立2型DM大鼠模型,成模后随机分为2组实验对照组继续高脂喂养,实验治疗组给予高脂喂养加罗格列酮(RSG)3mg·kg-1·d-1治疗2周。正常对照组为普通饮食(12%脂肪)喂养。3组大鼠均左室插管检测心功能后进行30min等容体外心脏灌注,测定葡萄糖摄取量及3H2O计数,评估心肌葡萄糖和脂肪酸氧化率。结果模型鼠的血糖、血浆胰岛素及FFA水平均高于正常鼠,与临床2型DM的代谢特征相似。实验对照组与正常对照组比较,心肌葡萄糖总摄入量明显减少[(30.7±4.0)∶(69.0±5.7)μmol/g干重,P<0.01],葡萄糖氧化率降低(12%∶25%,P<0.05)、软脂肪酸氧化率增加(88%∶75%,P<0.05);同时,左室舒张末期压(EDP)明显增加,-dp/dtmax降低,+dp/dtmax无明显改变。与实验对照组比较,实验治疗组大鼠血糖明显改善、血浆胰岛素和FFA显著降低;心肌葡萄糖的总摄入量升高,葡萄糖和软脂肪酸的氧化率分别为21%和79%;同时EDP和-dp/dtmax均改善(P<0.05)。结论2型DM循环FFA水平增高可以导致心肌能量底物代谢的异常和左室舒张功能的降低。早期使用RSG可改善胰岛素抵抗、降低FFA,能提高心肌对葡萄糖的利用、抑制脂肪酸氧化,有助于保护2型DM的心功能。     

Early detection of myocardial ischemia by myocardial free fatty acid extraction in patients with exercise-induced angina pectoris

This study investigated whether the measurement of plasma free fatty acids (FFAs) could assist in the early detection of exercise-induced myocardial ischemia. Fifteen subjects with effort angina pectoris underwent angina-limited supine bicycle ergometer exercise testing. Myocardial FFA extraction decreased significantly from 22.8 +/- 3.1% at rest to 7.7 +/- 1.5% at peak exercise (p less than 0.05). Myocardial lactate extraction showed no significant change between rest and peak exercise. After control exercise testing, 8 subjects were given a single oral dose of nilvadipine (6 mg) and then again underwent exercise testing for the same duration. Nilvadipine lessened or abolished chest pain and there was less depression of the ST segment at peak exercise. Furthermore, myocardial FFA extraction showed no significant change between rest and peak exercise after nilvadipine administration. These results suggest that myocardial FFA extraction can be used to assess the presence of exercise-induced myocardial ischemia at an earlier stage than myocardial lactate extraction.     

高血压合并代谢综合征患者血清脂联素与游离脂肪酸谱等代谢参数关系研究

目的 研究原发性高血压合并代谢综合征和未合并代谢综合征患者血清脂联素水平、游离脂肪酸谱特征及与其他糖脂代谢参数间关系.方法 用放射免疫分析法测定128例高血压合并或未合并代谢综合征患者与43例正常对照组血清脂联素,同时用气相色谱/质谱测定其游离脂肪酸成分.结果 高血压合并代谢综合征患者血清脂联素低于未合并代谢综合征组和正常对照组(P＜0.05或P＜0.01),总脂肪酸、不饱和脂肪酸(亚油酸、油酸、花生四烯酸、二十二碳六烯酸、花生三烯酸)、多不饱和脂肪酸(PUFA)和n6PUFA高于未合并代谢综合征组和正常组,差异有统计学意义(P＜0.05或P＜0.01).在研究对象中,脂联素与体重指数、腰围、腰臀比、甘油三酯呈负相关(r=-0.222,-0.235,-0.179,-0.194,P＜0.01或P＜0.05),与高密度脂蛋白胆固醇呈正相关(r=0.336,P＜0.01).总脂肪酸、多不饱和脂肪酸与体重指数、腰围、空腹血糖、平均血压呈正相关(r=0.241和0.280,0.198和0.188,0.226和0.298,0.274和0.334,P＜0.01或P＜0.05).结论 脂联素与游离脂肪酸代谢紊乱、n6系多不饱和脂肪酸升高,可能在原发性高血压合并代谢综合征的发病中起重要作用.     

老老年高血压合并2型糖尿病患者游离脂肪酸水平分析

目的：研究老老年高血压患者2型糖尿病与血清游离脂肪酸之间的关系。方法：纳入老老年原发性高血压患者152例,其中伴有2型糖尿病者74例,为1组;非2型糖尿病者78例,为2组;两组患者均检测血脂,比较两组血脂水平的差异。结果：2组患者比较,BMI:1组（28.73±5.49）＞2组（23.21±5.83）,空腹血糖：1组（7.01±2.71）＞2组（5.30±0.85）,游离脂肪酸水平：1组（0.62±0.32）＞2组（0.51±0.28）,总胆固醇：1组（4.16±1.04）＞2组（3.87±0.93）,甘油三酯：1组（1.56±0.84）＞2组（1.31±0.66）,高密度脂蛋白：1组（1.06±0.25）＞2组（1.22±0.32）,极低密度脂蛋白：1组（0.35±0.29）＞2组（0.27±0.15）,APOA1：1组（1.10±0.17）＜（1.17±0.19）,脂蛋白A：（14.64±15.64）＜（21.89± 21.46）,均P＜0.05,差异有统计学意义;Spearman相关性分析显示：BMI（r=0.468,p=0.002）、游离脂肪酸（r=0.147,p=0.027）、总胆固醇（r=0.147,p=0.028）、高密度脂蛋白（r=-0.261,p=0.000）、VLDL（r=0.148,p=0.026）、APOA1（r=-0.162,p=0.014）、脂蛋白A（r=-0.219,p=0.001）均与2型糖尿病存在相关性。二元Logistic回归分析显示,血清游离脂肪酸水平与老老年高血压合并2型糖尿病关系最为密切。结论：老老年高血压合并2型糖尿病患者脂质代谢紊乱更加严重,应予以足够的重视,而血清游离脂肪酸水平或许可以作为一干预靶点和预测指标。     

Early recognition of exercise-induced myocardial ischemia by plasma free fatty acid

To investigate whether or not myocardial free fatty acid (FFA) uptake is useful for early recognition of exercise-induced myocardial ischemia compared with myocardial lactate uptake, we studied in 8 patients with stable effort angina pectoris by measuring hemodynamic and metabolic parameters during supine multistage bicycle ergometer exercise (BEx). Analysis of FFA composition was performed by high performance liquid chromatography. The exercise endpoint in the control study was moderate chest pain in all cases. In all cases, BEx testing using the same method, duration and workload was repeated 1.5 hours after the oral administration of 6 mg of nilvadipine (a new calcium antagonist). Exercise time of the subjects studied was 463 +/- 40 sec (mean +/- SE, 180-540 sec). After administration of nilvadipine, chest pain was not induced in 6 patients and was lessened in severity in 2 patients. Mean ST segment depression was 0.21 +/- 0.05 mV in the control period and it was significantly reduced to 0.08 +/- 0.03 mV after nilvadipine administration (p less than 0.05). Myocardial FFA uptake decreased from 21.1 +/- 4.4% at rest to 8.1 +/- 2.1% at peak exercise in the control study (p less than 0.05). Myocardial lactate uptake was unchanged at rest and peak exercise in the control study (21.6 +/- 2.7 vs 22.2 +/- 3.3%). After administration of nilvadipine, myocardial FFA uptake did not change during BEx (25.3 +/- 2.7 at rest and 21.3 +/- 3.6% at peak exercise). At peak exercise, myocardial FFA uptake increased significantly after administration of nilvadipine (21.3 +/- 3.6 vs 8.1 +/- 2.1%, p less than 0.05). In FFA composition, the percentage of each of 12 FFA did not change during myocardial passage at rest and peak exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal myocardial fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging

The radioidinated synthetic fatty acid iodine-123 phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 +/- 11 vs 18 +/- 4, p less than 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 +/- 8 vs 17 +/- 6 for the apical short-axis section, p less than 0.05; 26 +/- 7 vs 18 +/- 5 for the basal short-axis section, p less than 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p less than 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.     

New directions in the treatment of heart failure: Targeting free fatty acid oxidation

The possibility of modifying cardiac metabolism by switching the fuel used by the myocardium could become increasingly important. Inhibitors of free fatty acid (FFA) oxidation could have an important role in therapeutic strategy for patients with heart failure, and shifting the energy substrate preference away from FFA metabolism and toward glucose metabolism may be an effective adjunctive treatment. Additionally, abnormalities of glucose homeostasis in patients with heart failure contribute to the progression of the primary disease. If not adequately treated, these abnormalities can contribute to the occurrence of complications, including severe left ventricular dysfunction. Apart from meticulous metabolic control of frank diabetes, special attention should be paid to insulin resistance, a distinct clinical entity. The observed combined beneficial effects of FFA inhibitors on left ventricular function and glucose metabolism represent an additional advantage of these drugs, especially when abnormalities of myocardial and glucose metabolism coexist.     

Effect of heparin-induced free fatty acid elevation on myocardial oxygen consumption in man

To determine whether acute elevation of plasma free fatty acids influences myocardial oxygen consumption in man, 17 patients underwent a metabolic study consisting of serial measurements of coronary sinus blood flow, heart rate and aortic blood pressure and arterial and coronary sinus determinations of oxygen, carbon dioxide, glycerol and free fatty acids both before and for 30 minutes after the intravenous administration of a bolus dose of 5,000 units of heparin. Of the 17 patients, 9 (group A) were fasting, and 8 (group B) ingested 100 g of fat 3 hours before the study in order to enhance post-heparin lipolysis.     

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。     

Different effects of interventions suppressing free fatty acid metabolism on myocardial ischemia

We studied the effects of different metabolic interventions, which stimulate oxidative myocardial carbohydrate metabolism, on ischemic stress during repeated coronary occlusions of three minutes in open-chest dog hearts. Increase of glucose concentration in plasma and decrease of peripheral lipolysis by glucose-insulin-potassium (n = 6) had no substantial beneficial effects on myocardial damage indicated by hemodynamic, electrocardiographic, and metabolic parameters. Infusion of lactate and pyruvate (10 mM, n = 6) was detrimental. Only activation of pyruvate dehydrogenase by dichloroacetate (n = 6) without influence on plasma osmolality reduced epicardial ST-segment elevations (-42%) and myocardial release of potassium (-36%), phosphate (-58%), and lactate (-39%). Elevations of plasma osmolalities by 10 and 20 mOsm with the metabolically inert mannitol increased ECG changes, functional loss and release of potassium, phosphate, and lactate during ischemia in our model. It is suggested, that the oxygen-saving potency of metabolic interventions can exert univocal beneficial effects in experimental and in clinical conditions only when systemic hyperosmolality and hypervolemia are avoided.     

Distribution of carbon flux within fatty acid utilization during myocardial ischemia and reperfusion

Twenty-nine intact, working pig hearts were extracorporeally perfused and divided into two study groups (16 Aerobic and 13 Ischemic/Reflow hearts). Step function, equilibrium labeling with [14C]palmitate was used to develop uptake and washout curves of radioactive fatty acid products contained in coronary effluent during either aerobic perfusion or reperfusion after ischemia (60% reduction in left anterior descending coronary flow for 30 minutes). Left anterior descending control flows were slightly overperfused in Aerobic hearts (18% higher than in Ischemic/Reflow hearts); otherwise, circumflex and right coronary flows, left ventricular pressure, and serum fatty acids and blood sugar levels were comparable between groups. As expected in Ischemic/Reflow hearts, recovery of regional systolic shortening and myocardial oxygen consumption in reperfusion was only modestly impaired (-20% and -19%, respectively, not significant and p less than 0.011 compared with preischemic values, not significant from Aerobic hearts). The only significant metabolized product to be released from labeled fatty acid utilization in either group was 14CO2. A smaller fatty acid pool also was measured and accounted for by that contained in the coronary intravascular volume. We could determine no significant back diffusion of fatty acids from myocardium in either perfusion condition. Uptake time constants of the early phase of 14CO2 production also were virtually identical in both groups (19.9 +/- 3.2 versus 16.7 +/- 3.2 minutes in Aerobic and Ischemic/Reflow hearts, respectively) and strongly correlated with hemodynamics as described by heart rate. In washout studies, tissue radioactivity in the aqueous soluble and fatty acid pools declined in both study groups, and counts in complex lipids and cholesterol/cholesteryl esters remained steady, whereas those in triacylglycerols varied. Washout of 14CO2 in both groups never reached background radioactivity over a 40-minute sampling after cessation of isotope infusion into the perfusate, suggesting slow release of trapped substrate from intracellular pools, which then proceeded to fatty acid oxidation. In conclusion, these experiments have demonstrated very similar findings with respect to fatty acid uptake, storage, and release characteristics between aerobic and reperfused myocardium. We found no differences in preferred substrate utilization and oxidation as a result of reversible ischemia followed by reflow.     

Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans

Introduction: The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. Aims: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy (¹H‐MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with ¹⁸F‐fluorodeoxyglucose and ¹¹C‐palmitate. ¹H‐MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. Results: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P= NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P≤ 0.01). TMZ halved total and triglyceride‐derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 μmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 μmol/min, respectively; P≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10², NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10², P= 0.036). Conclusions: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA‐derived energy for mechanical work. TMZ reduced the oxidation of triglyceride‐derived myocardial FAs improving myocardial efficiency.     

Improvement in fatty acid utilization in relation to a change in left ventricular hypertrophy in spontaneously hypertensive rats

Although fatty acid metabolism is reportedly impaired in myocardial hypertrophy, it is unclear whether the antihypertensive drugs are associated with improved fatty acid metabolism. In order to evaluate the effects of antihypertensive drugs on fatty acid metabolism and myocardial perfusion, the simultaneous uptake of iodine-125(125I)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and thallium-201 (Tl) were measured in 3 groups of rats: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR chronically treated with captopril (SHR-C), and (3) SHR chronically treated with hydralazine (SHR-H). Captopril and hydralazine were administered to their respective groups for 3 weeks from 12 weeks of age. The hearts were removed 10 min after simultaneous intravenous injections of BMIPP and Tl and the 125I and 201Tl counts were measured to calculate the uptake ratio. The systolic blood pressure (SBP) in SHR-N was 222+/-10 mm Hg, whereas the SHR-C and SHR-H groups showed significant SBP reduction (156+/-11, and 158+/-10 mm Hg, respectively) (p<0.01 each). The heart/bodyweight ratio was significantly lower in SHR-C (2.48+/-0.09) than in SHR-N (2.74+/-0.11) (p<0.05). However, there was no significant difference in the heart/bodyweight ratio between SHR-N and SHR-H (2.65+/-0.09). The ratio of BMIPP uptake to Tl uptake (BMIPP/Tl) was significantly higher in SHR-C (0.71+/-0.13) than in SHR-N (0.50+/-0.09) (p<0.05). However, BMIPP/Tl in SHR-H (0.53+/-0.09) was similar to that in SHR-N. These results suggest that captopril improves fatty acid metabolism in the hypertrophied ventricle in SHR. The metabolic alterations may improve with left ventricular hypertrophy regression but are not effected by the reduction of blood pressure only.