Cardiovascular & Haematological Disorders - Drug Targets - Volume 8, Issue 2, 2008

Recently, frequency domain and entropy analysis of fetal heart rate (FHR) have been assessed in several studies, providing new insights into physiologic regulatory mechanisms, constituting appealing tools for pharmacodynamic assessment, namely during fetal life. There is evidence that entropy and frequency domain analysis convey information on cortical and autonomic nervous system activities, respectively. Use of internal versus external FHR acquisition sensors and the signal sampling frequency may dramatically affect results. Most FHR frequency domain indices are significantly increased with rising fetal activity, namely during active wakefulness and active sleep, whereas the opposite occurs with nonlinear indices. This is in favour of increased activity of the autonomous nervous system and decreased activity of the central nervous system complexity control systems, during periods of fetal activity. Progression of labor is associated with a significant increase in FHR frequency domain indices, whereas entropy indices are significantly decreased. This denotes activation of the autonomic nervous system in the final minutes of labour, associated with decreased central nervous system activity. The emerging knowledge on FHR frequency domain and entropy analysis substantiates a continued interest of these methods in evaluation of the fetal pathophysiologic regulatory mechanisms, and opens new perspectives for clinical and pharmacodynamic assessment.

Platelets play a complex role in hemostasis and thrombosis. The expression of multiple membrane receptors, both constitutive and activation-dependent, mediates platelet adhesion and aggregation at sites of vascular lesion. Platelet activation leads to exocytosis of granular constituents, release of newly synthesized mediators, and discharge of membrane- bound transcellular signaling molecules. Many of the same mechanisms that play a role in hemostasis and thrombosis facilitate platelet participation in other physiological or pathological processes including inflammation, malignancy and the immune response. Platelet receptors such as GPIb/IX/V, P-selectin, P-selectin glycoprotein ligand 1, CD40 and the αIIbβ3 integrin, crucial to hemostasis, have been implicated in the progression of such inflammatory conditions as atherosclerosis, rheumatoid arthritis and inflammatory bowel disease, in the progression and metastatic spread of malignancies, and in the immune response to bacterial challenge. The release of platelet granular contents, including adhesive proteins, growth factors and chemokines/cytokines, that serve to facilitate hemostasis and wound repair, also function in acute and chronic inflammatory disease and in tumor cell activation and growth. Platelets contribute to host defence as they recognise bacteria, recruit traditional immune cells to the site of infection and secrete bactericidal mediators. The primary focus of this review is the “non-haemostatic” functions of platelets in physiological and pathological states.

With its superior sensitivity and specificity, cardiac troponin has gradually replaced other cardiac enzymes, and is now the biomarker of choice in making the critical diagnosis of an acute coronary syndrome (ACS). The early stratification of risk from unstable angina to non-ST segment elevation myocardial infarction (NSTEMI), is crucial in the timing and treatment of the ACS. Troponin elevations have also been shown to be powerfully prognostic in a variety of clinical settings and because of this predictive value, may be useful in determining benefit of various clinical interventions. However, inherent in this improved sensitivity and specificity of the measurement tools is the inclusion of non-ACS patients with abnormal troponin measurements. Increased understanding of the alternative diagnoses associated with elevated troponins as well as assays which allow more rapid and accurate diagnosis of ACS, are needed to further improve patient care. Clinical trials of risk stratification controlling for concomitant associated diagnoses including renal insufficiency, pulmonary embolism, atrial fibrillation and congestive heart failure will provide data to optimize this tool.

Diuretics play an essential role in modern cardiovascular therapy, and are currently recommended for the treatment of congestive heart failure. Torasemide has been developed as a newer type of loop diuretic with a longer halflife, longer duration of action, and higher bioavailability compared to the most commonly used loop diuretic, furosemide. Torasemide also appears to have additional actions beyond the pure diuretic effect, such as anti-aldosterone effect and vasorelaxation effect. Studies have also investigated whether the superior pharmacokinetics and pharmacological activity of torasemide result in a favorable clinical outcome. Their results have indicated that, in comparison with furosemide, torasemide improves left ventricular function, reduces mortality as well as the frequency and duration of heart failurerelated hospitalization, and improves quality of life, exercise tolerance and NYHA functional class in patients with congestive heart failure. Thus, torasemide appears to be a promising loop diuretic that contributes to a better management of patients with heart failure. Definitive clinical trials in a double-blind fashion are warranted.

Apart from promoting GH secretion and to regulate appetite and metabolism, it has become increasingly clear that GH secretagogues (GHS) and ghrelin exert a number of effects on the cardiovascular system. The main cardiovascular actions of GHS are possible inotropic effects, vasodilation, reported cardioprotective effects against ischemia, and in vitro effects on cardiomyocytes involving cell proliferation and anti-apoptotic actions. An interesting and intriguing feature of the cardiovascular effects of GHS is that they may be exerted directly on the heart and vasculature rather than being mediated by growth hormone. Evidence to suggest this is the finding of GHS binding sites on cardiomyocytes and the fact that some of the effects of GHS can be expressed also in the absence of GH. Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of GHS and ghrelin in the treatment of cardiovascular disease are warranted.

Glycoprotein IIb/IIIa receptor antagonists are potent antiplatelet agents by inhibiting the final common pathway of platelet aggregation. Tirofiban binds specifically to the glycoprotein IIb/IIIa receptor resulting in immediate and extensive inhibition of platelets. Studies have shown that intravenous administration of tirofiban in combination with aspirin and heparin reduces major adverse cardiac events in patients undergoing percutaneous coronary intervention and in those patients with acute coronary syndromes. Large randomised trials using tirofiban demonstrate early clinical and long-term survival benefit in all patient subgroups including high-risk patients undergoing urgent percutaneous coronary intervention, patients undergoing elective intracoronary stent placement and in the medical management of acute coronary syndromes. The use of high-dose bolus tirofiban may provide additional protection in patients at highest risk, whereas the role of tirofiban in the facilitation of primary angioplasty is less well defined. Similar to the other glycoprotein IIb/IIIa receptor antagonists, tirofiban increases the risk of haemorrhagic complications. However, the risk of serious bleeding, including intracranial haemorrhage, remains low and tirofiban does not appear to increase the risk of thrombocytopenia. Overall, the use of tirofiban in coronary artery disease has been shown to be effective, has an acceptable safety profile and is potentially cost-effective.

The importance of diabetes mellitus (diabetes) as a cause of mortality and morbidity is well known. The number of patients increases alongside aging of the population and increase in the prevalence of obesity and sedentary life style.Diabetes affects approximately 8% of the USA population.Type I (insulin-dependent) diabetes occurs in 20% of cases, and type II (insulin-independent or maturity onset) diabetes occurs in 80% of the diabetic populationiabetes mellitus type II is preceded by longstanding asymptomatic hyperglycemia, which accounts for the development of long-term diabetic complications. The main macrovascular complications for which diabetes has been a well established risk factor throughout the cardiovascular system, are: coronary artery disease (CAD), peripheral vascular disease (PVD), increased intima-media thickness (IMT) and stroke. Considering the cardiovascular surgeon, diabetes is associated with an increased rate of early and late complications following coronary artery bypass grafting. Diabetic patients have also been known to have an increased incidence of complications after elective major vascular surgery such as carotid endarterectomy (CEA) and leg amputations due to PVD. Cardiovascular surgeons frequently treat diabetic patients either because diabetes is incidental to another disease requiring surgery, or due to diabetes-related complication such as occlusive vascular disease, neuropathy or infection. Approximately 50% of diabetics undergo one,or more operations during their lifetime. This paper reviews the relationship between diabetic patients and their cardiovascular surgeons. In order to understand this relationship, one must first examine the underlying mechanisms by which hyperglycemia causes hazardous pre and post operative consequences. Then, one must examine the existing evidence of how diabetes correlates with these cardiovascular consequences, followed by the need for multidisciplinary team work which helps the surgeon to cope with diabetic patients.

The signaling pathways that control the life-death switch of a cell are of primary interest in modern biology. In this respect, NF-??B has emerged as a decisive transcription factor in the cell's response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, liver, nervous system and recently in heart . In this review we analyze the pivotal role of the transcription factor NF-κB in the normal functioning of the cardiac cell and its implication in common cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-κB is usually cytoprotective, it can also be pro-apoptotic depending on the inducing stimulus and the cellular context. Significant progress has been made in elucidating NF-κB's mode of action and its interplay with other key factors. These studies identified some anti- and pro-apoptotic NF-κB regulated genes that mediate its activity. These important new insights fuel hope that novel approaches will be developed to control the effects of NF-κB in cardiac pathologies.