Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 13, Issue 1, 2015

Heart rate is a fundamental determinant of cardiac oxygen consumption and plays a pivotal role in the pathophysiology of chronic stable angina (CSA). Ivabradine selectively and specifically inhibits the sino-atrial If current, slowing selectively heart rate without other significant haemodynamic effects. The consequent clinical effects are a sinus rate reduction similar to that obtained with beta-blockers, but without the related haemodynamic side effects. Ivabradine clinical benefits have been demonstrated both in patients with stable coronary artery disease (CAD) with associated systolic left ventricular dysfunction or in patients with congestive heart failure (HF). In this review we focused on the pharmacology and clinical research about ivabradine in the context of anti-ischemic therapy for CAD patients. Actually most guidelines suggest ivabradine therapy as last resort antianginal drugs in patients with uncontrolled symptoms or excessive heart rate despite maximum tolerated beta-blockade. However, the peculiar pharmacologic effects of the drug suggest that most patients with CAD might benefit from adding ivabradine to their therapeutic schemata. In fact, even if the recently released main analysis of the SIGNIFY study seems not to support an employ of ivabradine in primary prevention, it is easy to imagine a future wider use of this drug in elderly patients with incomplete myocardial revascularization and in patients with total chronic coronary occlusions and failure or unacceptable risk for percutaneous or surgical coronary revascularization.

Cardiovascular diseases and in particular coronary atherosclerotic disease are the leading cause of mortality and morbidity in the industrialized countries. Coronary atherosclerosis has been recognized for over a century and it was the subject of various studies. Pathophysiological studies have unravelled the interactions of molecular and cellular elements involved in atherogenesis; during the last decades the basic research has focused on the study of the instability of atherosclerotic plaque. Plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes including ST – segment elevation myocardial infarction and non ST – segment elevation myocardial infarction. This is a brief review of the pathophysiology of atherosclerotic plaque development.

Chronic angina represents a condition that impairs quality of life and is associated with decreased life expectancy in the industrialized countries. Current therapies that reduce angina frequency include old drugs such as nitrates, β -blockers and calcium antagonists. Several new investigational drugs are being tested for the treatment of chronic angina. This review will focus on ranolazine, a drug approved by the US Food and Drug Administration (FDA) in 2006 for patients with chronic angina who continue to be symptomatic despite optimized therapies. The main molecular mechanism underlying ranolazine-mediated beneficial effects has been identified as inhibition of the late Na+ current during the action potential, which potentially improves oxygen consumption, diastolic dysfunction and coronary blood flow. The aim of this review is to update the evidence for ranolazine treatment in chronic angina and discuss its therapeutic perspectives based on the most recent clinical and experimental studies.

Since the first human catheterization performed by Forssman in 1929 angioplasty equipment and medical therapies have undergone considerable evolution and technical improvement allowing interventionalists to perform more complex procedures and solving most of the percutaneous limitations. While percutaneous coronary intervention (PCI) has dramatically changed the outcome in the Acute Coronary Syndrome (ACS) setting, its role in the treatment of chronic stable angina is still debated. Stable coronary artery disease (SCAD) is a major public health issue and its prevalence is still increasing in the industrialized world. The correct treatment sees a multi-strategy approach aimed to a relief of symptoms, prevention of future cardiac events and survival improvement. In so forth, treatment strategies include optimal medical therapy (OMT) alone or combined with percutaneous or surgical coronary revascularization. Despite this, angina remains poorly controlled in the vast majority of CAD patients. Traditional agents such Beta-blockers or Calcium channel blockers or short and long acting nitrates have been used as first-line anti-anginal therapy for several years. Nowadays newer and more effective drugs usually used on top of older medical treatment have become available.

Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine’s antiarrhythmic efficacy has been provided by the MERLIN-TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias.

Antiplatelet therapy is a first-line medical treatment for patients with acute coronary syndrome (ACS). As percutaneous coronary interventions (PCI) increase in number and complexity, more patients must be treated with antiplatelet therapy for cardiovascular diseases in which arterial thrombosis plays a major role. Current anti-platelet therapy is highly effective in preventing atherothrombotic complications. Nevertheless, a significant number of patients continue to experience recurrent complications despite being properly treated, due to pharmacokinetics and interactions of drugs, genetic background and increased thrombus formation. This has lead to big research efforts to provide new antiplatelet drugs with better preventive properties without increased bleeding risk. Up to 8% of patients receiving 81 mg-dose of aspirin have significantly less platelet inhibition than those receiving higher dose. Patients with poor responsiveness to clopidogrel are at high risk of thromboembolic complications, especially in the setting of ACS and stent implantation. Several options have been proposed. Firstly, to increase loading and maintenance doses up to 600 mg and 75-mg twice daily associated with high-dose aspirin (300-325 mg). A second option would be to change from clopidogrel to new antiplatelet agents like prasugrel and ticagrelor which were investigated in large clinical trials in patients with different entities of ACS. Because of conflicting results & without large scale clinical studies, routine platelet function measurement cannot be recommended at this point of time. Prasugrel is an ADP-P2Y12 receptor inhibitor that has a faster and more consistent inhibitory effect of platelet aggregation and was shown to reduce cardiovascular mortality in the setting of ACS undergoing PCI. Subgroups with increased risk of bleeding were patients with prior stroke, age over 75 and body weight under 60 kg. In this population, prasugrel is discouraged despite its increased in efficacy. Ticagrelor binds reversibly to P2Y12 receptor. The reversibility action makes it attractive for situations when dual antiplatelet therapy needs to be interrupted. Both the drugs demonstrated superiority with respect to the primary composite endpoint. As compared to clopidogrel, both prasugrel and ticagrelor do not depend on loss-offunction genetic variants. The efficacy safety ratio of both compared to clopidogrel is better, even if both these compounds increased the risk of spontaneous major bleedings significantly. Due to lack of head-to-head comparison, potential differences between prasugrel and ticagrelor are hypothetical and both these drugs should be used according to guidelines. The novel intravenous antiplatelet cangrelor cut thrombotic complications of PCI with some increase in bleeding, a pooled analysis of the three CHAMPION(Cangrelor versus Standard Therapy to Achieve Optimal management of Platelet Inhibition) trials showed. Protease-activated-receptor 1(PAR 1) antagonist vorapaxar did not reduce the primary composite ischemic end point in TRACER (Thrombin Receptor Antagonist Clinical Event reduction in acute coronary syndrome) trial, but major bleeding and intracranial hemorrhage rates were substantially increased. Further large randomized trials would be required to decide the superiority of one agent over another and the duration of the therapy.

The treatment of systemic hypertension (HTN) in patients with Aortic stenosis (AS) requires a careful balance of lowering the systemic blood pressure without compromising vital organ perfusion and worsening of the symptoms of AS. Treatment of systemic HTN is beneficial because the combination of HTN and AS provides additional overload to the left ventricle. This leads to secondary Left ventricular hypertrophy (LVH), which has been shown to increase cardiovascular risks and mortality and thus early presentation of symptoms of AS. Additionally, presence of HTN may affect the accurate assessment of AS. Different treatment options are available, however no specific treatment guidelines have been established for patients with concomitant AS and HTN. Improved control of HTN is the key to prevent symptom progression and inadvertent early surgery. Angiotensin converting enzyme inhibitors (ACEi) and Angiotensin receptor blockers (ARB) appear to be beneficial. Reassessment of the aortic valve by echocardiography is recommended after HTN is well controlled before deciding on aortic valve replacement (AVR).

Calcium channel blockers (CCB) are widely used in cardiovascular medicine expressing high hopes upon decreasing cardiovascular risk, morbidity and mortality. Here, the potency of CCBs on 58 Romanian asymptomatic hypertensive patients, with no atherothrombotic cardiovascular disease, was studied by clinical and in silico methods. In our study, arterial elasticity/stiffness was assessed; anthropometric, metabolic (lipidic) parameters were quantified. We concluded that lercanidipine 10 mg once daily, during three weeks, is able to dramatically improve central aortic systolic blood pressure, aortic pulse wave velocity. Lipid profile improvement is an essential condition to improve elastic vascular properties in order to decrease the risk for further cardiovascular events. Besides, the potency of lercanidipine is expressed as the contribution of molecular descriptors (van der Waals and solvent accessible surface areas), electronic (molecular polarisability) and hydrophobic (water/octanol partition coefficient) by means of blocker effect on calcium channel, compared with cilnidipine and other 30 dihydropyridines, using molecular simulation techniques.

Background: Secundum atrial septal defect (ASD) is a common congenital heart defect in adults. If untreated, ASD leads to right ventricular (RV) failure, atrial arrhythmias, and pulmonary hypertension. The aim of this study is to analyze published data on outcomes and complications of percutaneous ASD closure in adults. Methods: PubMed searches performed for published literature on percutaneous ASD closure using the terms ASD, ASD closure or repair, and percutaneous or transcatheter closure. Results: A total of 23 studies, 1958 patients, were analyzed. Baseline characteristics showed mean age of 49.1 ± 1.7 years, Qp:Qs of 2.2 ± 0.05, defect size 19.4 ± 1 and device size 24.0 ± 0.7. The percentage of patients in NYHA class I, II and III was 42.4 ± 6.3, 40.0 ± 6.5, and 9.3 ± 3.0, respectively. Mean follow-up was 12.6 ± 4.9 months with a closure rate of 96.9% ± 1.4. Echocardiographic parameters of improvement included decrease in RV volume from 157.2 to 100.2 mL (p = 0.02), RV end-diastolic dimensions from 40.8 to 32.4 mm (p < 0.0001) and pulmonary artery systolic pressures from 42.2±2.2 to 34.4±2.4 (p < 0.0001). The percentage of patients in NYHA class II and III decreased from 55±7.5 to 15.9±4.4 (p = 0.0013). At the end of follow-up, complications included 1% mortality rate, 0.8% device embolization, 5.8% new onset arrhythmias and 1.2% need for surgical closure. Conclusion: Our study confirms that percutaneous ASD closure in adults with moderate pulmonary hypertension and RV dilation is safe and effective with reverse remodeling and better functional capacity. Prospective studies are needed to evaluate efficacy of percutaneous ASD closure in adults with large defects, higher shunt ratios, and severe pulmonary hypertension.