Use of nitrates in ischemic heart disease

Short-acting nitrates are beneficial in acute myocardial ischemia. However, many unresolved questions remain about the use of long-acting nitrates in stable ischemic heart disease. The use of long-acting nitrates is weakened by the development of endothelial dysfunction and tolerance. Also, we currently ignore whether lower doses of transdermal nitroglycerin would be better than those presently used. Multivariate analysis data from large nonrandomized studies suggested that long-acting nitrates increase the incidence of acute coronary syndromes, while data from another multivariate study indicate that they have positive effects. Because of methodological differences and open questions, the two studies cannot be compared. A study in Japanese patients with vasospastic angina has shown that, when compared with calcium antagonists, long-acting nitrates do not improve long-term prognosis and that the risk for cardiac adverse events increases with the combined therapy. We have many unanswered questions.     

曲美他嗪在缺血性心脏病中的应用

缺血性心脏病（IHD）其病理特点是冠状动脉内粥样斑块,管腔狭窄或阻塞,导致心肌缺血,患者出现胸痛.斑块破裂提供了血小板聚集和血栓形成的场所,导致不稳定性心绞痛或心肌梗死.稳定性心绞痛常规应用β阻滞剂、硝酸酯类和钙阻滞剂,这些药物是通过增加心肌供氧或减少心肌需氧发挥作用的.近年来,作为代谢调节剂的一组药物,已充分显示其优势.曲美他嗪是该类药物的代表药,已发现在缺血心肌中,脂肪酸氧化增强,葡萄糖氧化受抑制,曲美他嗪通过抑制缺血心肌中脂肪酸的氧化,直接发挥心肌细胞的保护作用.其他的一些研究尚在进行中,以进一步阐明在与IHD有直接或间接关系的其他疾病中曲美他嗪的作用.本综述目的是总结近年来世界范围内所做的各种临床试验研究的结果,以评价该药在IHD中的作用及其确切机制,进一步认识其在心肌保护中的真正价值.     

Stem cell therapy in ischemic heart disease

Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be addressed. To name a few: 1) Which patient population should be considered for stem cell therapy? 2) What type of stem cell should be used? 3) What is the best route for cell delivery? 4) What is the optimum number of cells that should be used to achieve functional effects? 5) Is stem cell therapy safer and more effective than conventional therapies? The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of ischemia, species of donors and recipients, techniques of cell delivery, cell types, cell numbers and timing of the experiments have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseases in the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Non-ischemic cardiomyopathy, peripheral vascular disease, and aging may be treated by stem cells. Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with pharmacological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.     

Chronobiology and chronotherapy of ischemic heart disease

The occurrence of the clinical manifestations of ischemic heart disease (IHD)--myocardial ischemia and angina pectoris, acute myocardial infarction, and sudden cardiac death--is unevenly distributed during the 24 h with greater than expected events during the initial hours of the daily activity span and in the late afternoon or early evening. Such temporal patterns result from circadian rhythms in pathophysiological mechanisms plus cyclic environmental stressors that trigger ischemic events. Both the pharmacokinetics (PK) and pharmacodynamics (PD) of many, though not all, anti-ischemic oral nitrate, calcium channel blocker, and beta-adrenoceptor antagonist medications have been shown to be influenced by the circadian time of their administration. The requirement for preventive and therapeutic interventions varies predictably during the 24 h, and thus therapeutic strategies should also be tailored accordingly to optimize outcomes. During the past decade, two first generation calcium channel blocker chronotherapies have been developed, trialed, and marketed in North America for the improved treatment of IHD. Nonetheless, there has been relatively little investigation of the administration-time (circadian rhythm) dependencies of the PK and PD of conventional anti-ischemic medications, and there has been little progress in the development of new generation IHD chronotherapies. Available epidemiologic, pharmacologic, and clinico-therapeutic evidence demonstrates how the chronobiologic approach to IHD can contribute new insight and opportunities to improve drug design and drug delivery to enhance therapeutic outcomes.     

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

Microvascular pericytes and the more recently discovered adventitial pericyte-like progenitor cells are a subpopulation of vascular stem cells closely associated with small and large blood vessels respectively. These populations of perivascular cells are remarkably abundant in the heart. Pericytes control important physiological processes such as angiogenesis, blood flow and vascular permeability. In the heart, this pleiotropic activity makes pericytes extremely interesting for applications in regenerative medicine. On the other hand, dysfunction of pericytes could participate in the pathogenesis of cardiovascular disease, such as arterial hypertension, fibro-calcific cardiovascular remodeling, myocardial edema and post-ischemic coronary no-reflow. On a therapeutic standpoint, preclinical studies in small animal models of myocardial infarction have demonstrated the healing potential of pericytes transplantation, which has been ascribed to direct vascular incorporation and paracrine pro-angiogenic and anti-apoptotic activities. These promising findings open the door to the clinical use of pericytes for the treatment of cardiovascular diseases.     

Tolerance to organic nitrates in ischemic heart disease

The development of tolerance to organic nitrates in patients with ischemic heart disease is reviewed, with particular interest in alterations to both the hemodynamic and antiischemic effects over time. The article primarily focuses on how tolerance is defined, what biochemical mechanisms are involved when this condition occurs, which agents have been associated with the development of tolerance, and what can be done to prevent or reverse the condition in patients taking nitrates for ischemic heart disease. From a historical perspective, tolerance to organic nitrates has been a recognized phenomenon since the last century. The role that blood-level determinations and nitroglycerin pharmacokinetics have in the development of tolerance is discussed, and an extensive overview of currently marketed organic nitrate preparations and a few others available only through approved investigational protocols is presented. The role of cross-tolerance is discussed as is the role that nitrate-free intervals play in partially or completely reversing the effects of tolerance during chronic nitrate therapy. Additionally, a discussion of which specific nitrate formulation are least likely to have tolerance associated with their use is included, such as short-acting nitrate formulations with the exception of the intravenous dosage form. Finally, buccal nitroglycerin is presented as another new formulation that appears to be associated with minimal tolerance in studies already completed.     

Gender differences in the treatment of ischemic heart disease

Ischemic heart disease (IHD) is a leading cause of mortality and morbidity in most developed countries. Many studies revealed gender differences in the presentation, prevalence, and clinical outcomes of IHD. Compared with females, ST-segment elevation myocardial infarction is more often diagnosed in men. They also have a higher prevalence of IHD. These findings indicate that gender may have an important influence on IHD. Appropriate prevention, rapid diagnosis, and optimal treatment may essentially improve the care of all patients. It is therefore necessary to take into account gender differences in the features of IHD between males and females.     

Vitamin E in the prevention of ischemic heart disease

Ischemic heart disease (IHD) has now assumed a global dimension. It still remains one of the major health problems not only in the advanced countries, but also, is becoming a serious health issue in the developing and the economically weaker countries. Apart from other factors, changing economic scenario, stress and strain in daily life as well as altered dietary habits in the populations appear responsible for the increased incidence of cardiovascular disease (CVD). The treatment modalities, invasive, non-invasive and pharmacological are economically no dearer, even to population of affluent countries. Likewise, treatment costs of serious cardiovascular diseases are becoming difficult to be borne by population of the developing nations. Prevention of IHD would be a better way to protect the population from physical and economic disaster. The current article comprehensively describes the relation between oxidative stress and cardiac disease, explains the direct effect of reactive oxygen species on cardiac function and projects how the use of vitamin E can be of benefit in the prevention of IHD with concluding remarks highlighting the need for inclusion of a fruit and vegetable rich diet and regular exercise to keep the dearer heart active and healthy.     

Effect of ildamen on the heart conduction system in ischemic heart disease patients

Thirty-four patients with ischemic heart disease (IHD) were studied: 18 IHD patients with latent forms of disturbances of conductivity in the atrioventricular junction and sinus node sickness syndrome revealed at frequency stimulation of the heart; 16 patients with acute myocardial infarction complicated with the atrioventricular junction blockade of II and III degrees. Ildamen solution (4 mg) was slowly intravenously infused to all patients under study. Exerting the beta-stimulating effect, ildamen positively influences restoration of the disordered function of the pacemaker and conduction system of the heart: through immediate action on these systems and an increase of the coronary blood flow contributing to improvement of nutrition of the condition system of the heart.     

Therapeutic potential of H11 kinase for the ischemic heart

H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac-specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol-3-kinase/Akt pathway, the AMP-dependent protein kinase, the PKCepsilon pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage.     

Therapeutic potential of vitamin E in heart disease

Low density lipoprotein (LDL) oxidation is considered an important step in the atherogenic process. Oxidatively modified particles induce the expression of adhesion molecules, stimulate the production of inflammatory cytokines and impair endothelial function. The measurement of oxidised LDLs in vivo is very difficult, therefore most investigators rely on the measurement of in vitro oxidability of these particles to evaluate their deleterious effects. Supplementation with water and lipid soluble anti-oxidant vitamins, especially vitamin C and E, significantly increase the resistance to LDL oxidation. Vitamin E supplementation also improves endothelium-dependent vasodilation in hypercholesterolaemic and subjects who smoke cigarettes. Epidemiological studies have not consistently demonstrated a protective effect of vitamin E consumption as food or supplements on coronary events or stroke. Likewise, only one of five large prospective trials has shown a beneficial effect of vitamin E supplementation on cardiovascular events or mortality. One report showed that supplemented haemodialysed patients had a lower incidence of cardiovascular events. Thus, presently, there is not enough evidence to widely recommend the use of vitamin E supplements for vascular protection.     

Therapeutic potential of vitamin E in heart disease

Low density lipoprotein (LDL) oxidation is considered an important step in the atherogenic process. Oxidatively modified particles induce the expression of adhesion molecules, stimulate the production of inflammatory cytokines and impair endothelial function. The measurement of oxidised LDLs in vivo is very difficult, therefore most investigators rely on the measurement of in vitro oxidability of these particles to evaluate their deleterious effects. Supplementation with water and lipid soluble anti-oxidant vitamins, especially vitamin C and E, significantly increase the resistance to LDL oxidation. Vitamin E supplementation also improves endothelium-dependent vasodilation in hypercholesterolaemic and subjects who smoke cigarettes. Epidemiological studies have not consistently demonstrated a protective effect of vitamin E consumption as food or supplements on coronary events or stroke. Likewise, only one of five large prospective trials has shown a beneficial effect of vitamin E supplementation on cardiovascular events or mortality. One report showed that supplemented haemodialysed patients had a lower incidence of cardiovascular events. Thus, presently, there is not enough evidence to widely recommend the use of vitamin E supplements for vascular protection.     

The roles of cytochrome p450 in ischemic heart disease

Cytochrome P450 (CYP) represents a large family of enzymes that catalyze the oxidation of endogenous and exogenous compounds. The functions of CYP enzymes in the metabolism of xenobiotics have well been established in the liver. However, some CYP enzymes are highly expressed in the heart and catalyze arachidonic acid oxidation to a variety of eicosanoids, which attenuates ischemia-reperfusion injury of the heart. CYP-mediated cardioprotection is associated with activation of multiple pathways such as sarcolemmal and mitochondrial potassium channels, p42/p44 MAPK and PI3K-AKT signaling in cells. CYP enzymes also represent a significant source of reactive oxygen species (ROS) that may target cellular homeostatic mechanisms and mitochondria. CYP isoforms expressed in the heart are critical for generation of epoxyeicosatrienoic acids (EETs) and ROS. It has been demonstrated that CYP2J2 generates cardioprotective EETs, whereas another isozyme in the heart, CYP2C, generates EETs as well as detrimental ROS. Genetic polymorphisms of CYP2C or CYP2J2 have a pathologic impact on coronary artery diseases. Cardiac CYP enzymes can be involved in drug metabolism within the heart and influence pharmacologic efficacy. Metabolism mediated by CYP enzymes influences the survival of cardiomyocytes during ischemia, which is critical for treatment of human ischemic heart disease. In this review, we summarize current knowledge of this enzyme family and discuss the roles of CYP in ischemia-reperfusion injury of the heart.