脂毒性心肌病的发病机制及治疗进展

心肌游离脂肪酸的摄入和利用的失协调导致心肌中脂质积聚并进而引起脂毒性心肌病。脂质通过何种机制导致心肌功能的改变,以及如何来干预脂毒性心肌病成为当今心血管领域倍受关注的研究方向。现就脂毒性心肌病的发病机制及治疗进展做一综述。     

脂毒性与增龄

脂类积聚过多会导致细胞功能障碍(脂毒性)和脂质介导的细胞程序性死亡(脂凋亡).脂肪储库在中年或早老年之后逐渐下降,并伴有脂肪组织功能失调和重新分布<'[1]>.衰老与非脂肪组织脂质积聚的生理性增加有关,这可能是随着年龄的增长,2型糖尿病、脂肪肝和心血管疾病等慢性病增加的原因.总之,肥胖可能通过其脂毒性作用加速衰老的进程.     

脂毒性与肥胖型2型糖尿病

2型糖尿病是一类严重危害人类健康的疾病，它与肥胖密切相关。瘦素及其受体的功能缺或降低可导致大量的脂质在胰岛内的积聚，从而损害B细胞的功能，引起B细胞的凋亡。即所谓的‘脂毒性’，而且前针对'脂毒性'的治疗还待于进一步的研究。     

抗疟药物的心脏毒性

虽然长期应用抗疟药物诱发心脏毒性者罕见,但后果严重。临床主要表现为心脏传导阻滞、充血性心力衰竭、心律失常及心肌病。确诊需行心肌心内膜活检。光学显微镜下组织病理学改变为心肌细胞内大量空泡形成,电子显微镜下见髓样体及特征性的曲线体。抗疟药物被溶酶体选择性摄取后使溶酶体pH值升高,从而干扰溶酶体中酶类活性,导致糖原及磷脂积聚。     

心脏脂肪变性与肥胖相关性心脏病

肥胖病是心脏病的危险因素,传统观点认为,在肥胖患者中,由于血流动力学异常和脂代谢异常导致的心脏重构是患者易发展为冠状动脉性疾病和心力衰竭的原因。但最近研究发现,脂肪在心脏沉积可以直接损伤心脏,影响左室重建,导致扩张型心肌病。对肥胖动物模型的研究发现,心肌中脂质过度沉积可导致左室肥厚和缺血性、扩张型心肌病。通过基因治疗或药物干预降低心脏的脂质沉积,可以预防肥胖相关性心脏病的发生。临床研究也提示,心肌的脂质含量可以作为肥胖患者心脏病的生物指标,并且可以成为治疗的靶点。但这方面的研究才刚刚开始,有待进一步的研究。     

肥胖、脂毒性与心力衰竭

肥胖中脂肪组织扩张到最大限度后脂质溢出,非脂肪组织如心脏等也出现了脂质累积。心脏由最初代偿性改变,而后出现脂毒性状态,最终出现收缩功能不全。非酯化脂肪酸的过度供应加上代谢失调（包括脂肪酸不充分的氧化）导致线粒体功能不全是发病过程中的一个重要环节。     

阿霉素心脏毒性中的细胞凋亡

阿霉素(ADR)在临床上广泛用于治疗多种恶性肿瘤,其作用无可争议。但是ADR长期使用可以出现不可逆转的心肌病、充血性心力衰竭(CHF)而使它的应用受到限制。ADR心脏毒性的发病机制仍有争议。越来越多的证据表明,细胞凋亡在ADR心肌病的发病过程中起关键性作用。这里我们主要讨论阿霉素心脏毒性中的细胞凋亡的研究最新进展。     

脂毒性在糖尿病心肌病发病机制中的研究进展

糖尿病心肌病(diabetic cardiomyopathy,DCM)定义为糖尿病患者在排除冠状动脉疾病、高血压或心脏瓣膜病的情况下发生的心脏功能障碍的心肌疾病。其是一种慢性疾病,有复杂的病理生理过程,在早期不易被察觉,而往往只在病变进展到心力衰竭时才得以被发现。糖尿病患者发生心力衰竭病死率高,但发病机制仍不明确,目前已初步认识到心肌脂毒性在DCM中的作用。因此,本文主要对近些年关于脂毒性在DCM发病机制中的作用作一综述。     

动脉粥样硬化发生机制的当代概念

动脉粥样硬化病变的特征为:内膜平滑肌细胞增生,损伤的内膜层被转变为巨噬细胞的单核细胞侵入,和大量结缔组织基质(包括胶原、蛋白多糖和弹力纤维)与大量脂质的积聚。在早期病变中,多数脂质为细胞内的胆固醇酯。胆固醇酯小滴可以在病变中的“泡沫细胞”中见到,后者以其脂质小滴内涵物在显微镜下呈空泡样外观而得名。在更进一步的病变中,也可以见到未酯化的胆固醇结晶,出现细胞坏死,并在细胞内和细胞外均找到脂质。     

Perilipin 5与心血管疾病的研究进展

脂滴积聚造成脂质代谢紊乱易诱发动脉粥样硬化性血脂异常、血压升高、促炎状态等,perilipin 5是脂滴蛋白PAT家族成员之一,其作为脂滴分解屏障可保护脂滴免受脂肪酶的分解并调控脂质代谢,perilipin 5在脂肪酸氧化能力强的组织中显著表达,提示了其在调节氧化组织中脂质储存和分解代谢的重要作用,并将脂肪分解代谢与能量需求相匹配。越来越多的研究证实,perilipin 5作为脂滴调控蛋白参与心血管疾病的发生、发展。现主要对perilipin 5在心血管疾病中的研究进展做一综述。     

CD36 deficiency rescues lipotoxic cardiomyopathy

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARalpha (myosin heavy chain [MHC]-PPARalpha) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARalpha mice were crossed with CD36-deficient mice (MHC-PPARalpha/CD36-/- mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARalpha phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARalpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARalpha mice was unchanged in the CD36-deficient background. However, PPARalpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARalpha/ CD36-/- mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARalpha mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.     

Cardiac Lipotoxicity: Molecular Pathways and Therapeutic Implications

Diabetes and obesity are both associated with lipotoxic cardiomyopathy exclusive of coronary artery disease and hypertension. Lipotoxicities have become a public health concern and are responsible for a significant portion of clinical cardiac disease. These abnormalities may be the result of a toxic metabolic shift to more fatty acid and less glucose oxidation with concomitant accumulation of toxic lipids. Lipids can directly alter cellular structures and activate downstream pathways leading to toxicity. Recent data have implicated fatty acids and fatty acyl coenzyme A, diacylglycerol, and ceramide in cellular lipotoxicity, which may be caused by apoptosis, defective insulin signaling, endoplasmic reticulum stress, activation of protein kinase C, MAPK activation, or modulation of PPARs.     

Ectopic fat and cardiovascular disease: What is the link?

Aimof this paper is to review the recent literature on the relationship between ectopic fat accumulation and cardiovascular disease.Data synthesisEctopic fat is an important predictor of metabolic (in particular insulin resistance) and cardiovascular disease, carrying more risk than general fat accumulation. Recent studies have shown a link between ectopic fat accumulation, as cardiac (epicardial or intra-myocardial fat) and/or visceral and/or hepatic fat, and development of atherosclerosis, coronary heart disease and hypertension.ConclusionsEctopic fat accumulation is not only a marker of cardiometabolic disease, since through the release of adipocitokines, lipotoxic and glucotoxic agents, participates in the crosstalk with insulin-sensitive organs leading to metabolic, cardiac and vascular dysfunctions.     

Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice

The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenitally unleptinized obese rodents is far greater than in hyperleptinemic diet-induced obesity rodents has suggested an antilipotoxic role. To test this hypothesis, mice with severe lipotoxic cardiomyopathy, induced transgenically by cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS) gene, were made hyperleptinemic by treatment with recombinant adenovirus containing the leptin cDNA. Normoleptinemic control ACS-transgenic mice developed severe dilated cardiomyopathy with thickened left ventricular walls and profound impairment of systolic function on echocardiogram; histologically, there was severe myofiber disorganization and interstitial fibrosis, with intracytoplasmic lipid vacuoles identifiable by electron microscope. By contrast, the hearts of hyperleptinemic ACS-transgenic mice appeared normal, with normal echocardiograms and cardiac triglyceride (TG) contents. Their lower myocardial TG content was ascribed primarily to profound lowering of plasma TG and free fatty acids; free fatty acids were 17% of normal at 8 weeks. Additionally, enhanced myocardial AMP-activated protein kinase phosphorylation may have increased fatty acid oxidation, thereby contributing to the lowering of lipid stores. We conclude that obesity-level hyperleptinemia protects the heart from lipotoxicity.     

Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome

The obesity crisis in the United States has been associated with an alarming increase in the prevalence of the metabolic syndrome (MSX) disease cluster. Here we review evidence that the MSX reflects a failure of a system of intracellular lipid homeostasis that prevents lipotoxicity in the organs of overnourished individuals by confining the lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Normally, early in obesity, adipocytes increase leptin and adiponectin secretion, hormones that enhance oxidation of surplus liquids in nonadipose tissues by activating AMP-activated protein kinase and reducing the activity and expression of lipogenic enzymes. These events combine to lower malonyl coenzyme A. Deficiency of and/or unresponsiveness to leptin prevents these protective events and results in ectopic accumulation of lipids. Increased de novo ceramide formation is probably the most damaging lipid and is a cause of lipoapoptosis, abetted by a decline in tissue Bcl-2. Pancreatic beta-cells and myocardiocytes are cellular victims of the process, leading to non-insulin-dependent diabetes and lipotoxic cardiomyopathy. The MSX is particularly prevalent in visceral obesity, probably because visceral adipocytes make less leptin than sc adipocytes. Cushing's syndrome, the lipodystrophy associated with protease inhibitor therapy of AIDS, polycystic ovarian disease, as well as diet-induced visceral obesity, all have a high waist/hip ratio, and all exhibit MSX. Increased lipid content in the heart and skeletal muscle organs of such patients is now under study.     

Cardiac Metabolism and Mechanics are Altered by Genetic Loss of Lipoprotein Triglyceride Lipolysis

Introduction Most circulating fatty acids are contained in lipoprotein triglycerides. For the heart to acquire these lipids, they must be broken down into free fatty acids via the enzyme lipoprotein lipase (LpL). Although it has long been known that hearts primarily use esterified fatty acids as fuel, different sources of fatty acids were thought to be interchangeable. Materials and methods By creating mice with neonatal and acute LpL deletion we showed that lipoprotein-derived fatty acids could not be replaced by albumin-associated free fatty acids. Loss of cardiac LpL forces the heart to increase its uptake of glucose, reduce fatty acid oxidation, and eventually leads to cardiac dysfunction. In contrast, cardiomyocyte specific overexpression of an anchored form of LpL leads to excess lipid uptake, induction of fatty acid oxidation genes, and dilated cardiomyopathy. Conclusion Increasing lipid secretion from the heart or redirecting lipids to adipose tissue can alleviate this lipotoxic situation.     

Nontriglyceride Hepatic Lipotoxicity: The New Paradigm for the Pathogenesis of NASH

Lipid droplet accumulation and oxidant stress, once thought to play essential roles in the pathogenesis of nonalcoholic steatohepatitis (NASH), may actually represent parallel epiphenomena. Emerging data now point to nontriglyceride lipotoxicity and complex mechanisms of hepatocyte injury and apoptosis as the major contributors to the disease phenotype currently recognized as NASH. Although specific mediators of hepatic lipotoxicity have not been identified with certainty, abundant evidence from animal studies and recent data in humans indicate that free fatty acids in the liver can serve as substrates for formation of nontriglyceride lipotoxic metabolites that cause liver injury. The accumulation of triglyceride in droplets may actually be protective, and thus therapeutic efforts directed at fat accumulation as a sole endpoint may be misguided. This review examines the new evidence supporting the role of nontriglyceride fatty acid metabolites in causing NASH and how adipose and muscle insulin resistance contribute to hepatic lipotoxicity.