Chronopharmacology of cardiovascular medications

The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern in the cardiovascular system. This observation bares implications for drug treatment, e.g. regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-dependent effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. There is sound evidence that “time-of-day” has to be included in our diagnostic and therapeutic strategies.     

磷酸二酯酶的心血管功能调节作用

磷酸二酯酶(phosphodiesterase,PDE)是细胞内第二信使cAMP和cGMP降解的关键酶,作为药物研发的靶点受到广泛关注。近年研究发现,PDE在心肌细胞中能与β-肾上腺素受体及一些与兴奋收缩相关的蛋白形成复合物而使细胞内信号传递区室化分布,该现象可能为PDE抑制剂治疗慢性心力衰竭提供新的启示。血管平滑肌功能调节主要为血管张力和表型的调控,PDE5抑制剂舒张血管的作用已成功应用到勃起障碍的治疗。PDE4和PDE1C等在增殖的平滑肌细胞中表达量增高,单独抑制PDE的某一亚型将为治疗与平滑肌增殖有关的疾病(如肺动脉高压、血管成行术后再狭窄)提供新的途径。本文将重点阐述近年来PDE在心血管系统功能调节研究中的主要进展,以及PDE抑制剂在心血管系统疾病治疗中的应用。     

Gene therapy of cardiovascular disorders

More than 300 protocols have been developed for human gene therapy, but, it has not yet been proved to be a successful therapeutic strategy. One of the most important barriers to success is the development of efficient gene delivery systems. We have developed HVJ-liposomes by combining fusion proteins of HVJ (Hemagglutinating virus of Japan; Sendai virus) with liposomes containing DNA. This vector system has been very effective for in vivo gene delivery, especially in cardiovascular systems. Using HVJ-liposomes, we have reported successful gene therapy experiments such as prevention of restenosis after balloon injury, suppression of dysfunction of vein graft, and experimental ischemic disorders. Indeed, the success in the treatment of arteriosclerosis obliterance by VEGF (vascular endothelial growth factor) gene transfer was reported recently. These cardiovascular gene therapy strategies appear to be very promising therapeutics in future.     

Undergraduates' understanding of cardiovascular phenomena

Undergraduates students in 12 courses at 8 different institutions were surveyed to determine the prevalence of 13 different misconceptions (conceptual difficulties) about cardiovascular function. The prevalence of these misconceptions ranged from 20 to 81% and, for each misconception, was consistent across the different student populations. We also obtained explanations for the students' answers either as free responses or with follow-up multiple-choice questions. These results suggest that students have a number of underlying conceptual difficulties about cardiovascular phenomena. One possible source of some misconceptions is the students' inability to apply simple general models to specific cardiovascular phenomena. Some implications of these results for teachers of physiology are discussed.     

Genetics of human cardiovascular disease

Cardiovascular disease encompasses a range of conditions extending from myocardial infarction to congenital heart disease, most of which are heritable. Enormous effort has been invested in understanding the genes and specific DNA sequence variants that are responsible for this heritability. Here, we review the lessons learned for monogenic and common, complex forms of cardiovascular disease. We also discuss key challenges that remain for gene discovery and for moving from genomic localization to mechanistic insights, with an emphasis on the impact of next-generation sequencing and the use of pluripotent human cells to understand the mechanism by which genetic variation contributes to disease.     

The cardiovascular paradox of pregnancy

Despite widespread accessibility to prenatal care, little is known on the mechanisms initiating early maternal adaptation to pregnancy. Moreover, preeclampsia and intrauterine growth retardation remain the most frequent and serious complications of pregnancy. Recent studies, both in humans and in laboratory animals, have shown that very early events in gestation may be important determinants for the continuation of healthy pregnancy. Certain of these early adaptations appear to be linked to the corpus luteum of pregnancy, as ovarian steroid hormones (especially progesterone) would set the basic hemodynamic conditions, more specifically, generalized vasodilation. This new hemodynamic setup initiates a vicious cycle in which the renin - angiotensin - aldosterone system is activated, together with the resetting of the control of antidiuretic hormone secretion relative to plasma osmolality. This leads to a gradual and substantial increase in plasma volume and a parallel increase in cardiac function (both heart rate and stroke volume) with the goal of maintaining blood pressure in the face of the generalised vasodilation. This includes the creation of a functional arterio-venous shunt represented by the utero-placental circulation. By the end of the first trimester, the decrease in peripheral vascular resistance is marked relative to the increase in cardiac output, resulting in a significant decrease in blood pressure that will be maintained until the third trimester. It is proposed that in preeclampsia, these very early events (vasodilation - increased plasma volume) fail to occur, resulting in an absence of the usual decrease in blood pressure, which is normally seen in the second trimester of pregnancy, and hypertension in the third trimester. Experimental animals, especially the rat, are suitable models to study this early maternal adaptation to pregnancy, since both endocrine and hemodynamic changes appear to be similar to humans.     

Chronophysiology of the cardiovascular system

The development of ambulatory blood pressure monitoring devices and the beat-by-beat measurement of heart rate have enabled it to be established that there are circadian rhythms in heart rate and blood pressure in subjects living normally. Investigations of these variables have led to quantification of their fall at night, and rapid rise on awakening and becoming active in the morning. These changes are of particular interest insofar as abnormalities in them are associated with cardiovascular problems and morbidity in patients and also act as risk factors in otherwise healthy individuals. It has also been shown that there are many other variables of the cardiovascular system. The causes of the circadian rhythms in heart rate and blood pressure are outlined, with particular stress upon the role of the autonomic nervous system, as assessed from low- and high-frequency components of the variation in heart rate measured beat-by-beat. Activity increases blood pressure, but there is evidence that this “reactivity” varies with time of day, and this also might be related to cardiovascular morbidity. Based upon data from several sources, including night work, resting subjects and bed-ridden patients, it is concluded that the contribution of the “body clock” to producing the circadian rhythm in heart rate and blood pressure is relatively small. A bias towards an exogenous cause applies also to most other circadian rhythms in the cardiovascular system. Knowledge of circadian rhythmicity in cardiovascular system, together with an understanding of its causes, provides a rationale for advice to reduce cardiovascular risk and to assess the efficacy of therapies.     

Pharmacogenetics of cardiovascular drugs.

Pharmacogenetics is a field aimed at understanding the genetic contribution to inter-patient variability in drug efficacy and toxicity. Treatment of cardiovascular disease is, in most cases, guided by evidence from well-controlled clinical trials. Given the solid scientific basis for the treatment of most cardiovascular diseases, it is common for patients with a given disease to be treated in essentially the same manner. Thus, the clinical trials have been very informative about treating large groups of patients with a given disease, but are slightly less informative about the treatment of individual patients. Pharmacogenetics and pharmacogenomics have the potential of taking the information derived from large clinical trials and further refining it to select the drugs with the greatest likelihood for benefit, and least likelihood for harm, in individual patients, based on their genetic make-up. In this paper, the current literature on cardiovascular pharmacogenetics is emphasised, and how the use of pharmacogenetic/pharmacogenomic information may be particularly useful in the future in the treatment of cardiovascular diseases is also highlighted.     

A cardiovascular EST repertoire: progress and promise for understanding cardiovascular disease

The application of expressed sequence tag (EST) technology has proven to be an effective tool for gene discovery and the generation of gene expression profiles. The generation of an EST resource for the cardiovascular system has revealed significant insights into the changes in gene expression that guide heart development and disease. Furthermore, an important genetic resource has been developed for cardiovascular biology that is valuable for data mining and disease gene discovery.     

Systems biology approaches to metabolic and cardiovascular disorders: network perspectives of cardiovascular metabolism

In this review, we examine cardiovascular metabolism from three different, but highly complementary, perspectives. First, from the abstract perspective of a metabolite network, composed of nodes and links. We present fundamental concepts in network theory, including emergence, to illustrate how nature has designed metabolism with a hierarchal modular scale-free topology to provide a robust system of energy delivery. Second, from the physical perspective of a modular spatially compartmentalized network. We review evidence that cardiovascular metabolism is functionally compartmentalized, such that oxidative phosphorylation, glycolysis, and glycogenolysis preferentially channel ATP to ATPases in different cellular compartments, using creatine kinase and adenylate kinase to maximize efficient energy delivery. Third, from the dynamics perspective, as a network of dynamically interactive metabolic modules capable of self-oscillation. Whereas normally, cardiac metabolism exists in a regime in which excitation-metabolism coupling closely matches energy supply and demand, we describe how under stressful conditions, the network can be pushed into a qualitatively new dynamic regime, manifested as cell-wide oscillations in ATP levels, in which the coordination between energy supply and demand is lost. We speculate how this state of "metabolic fibrillation" leads to cell death if not corrected and discuss the implications for cardioprotection.