Protease-activated receptor-1 antagonists in long-term antiplatelet therapy. Current state of evidence and future perspectives.

Atherothrombosis and its clinical manifestations are among the leading causes of death in the developed world. The current standard-of-care antiplatelet therapy for the treatment of such events comprises aspirin and a thienopyridine or ticagrelor. However, recurrent ischemic events due to residual cardiovascular risk are a common phenomenon in these patients. It is believed that this residual risk is caused, at least in part, by thrombin, which signals through protease-activated receptors (PARs) and especially PAR-1. Thus, PAR-1 antagonism could represent an effective approach in the treatment of atherothrombotic disease. In this context, two potent and selective agents have been developed, vorapaxar and atopaxar. However, only vorapaxar has completed phase 3 clinical trials. In the present review, the main pharmacodynamic and pharmacokinetic properties of the PAR-1 antagonists are briefly described and the latest clinical data on vorapaxar are presented.

Modelling eating practices in non-fatal acute coronary syndrome or stroke development: a case/case-control study.

BACKGROUND AND AIMS: Although significant evidence exists regarding the role of specific foods and dietary patterns on the development of cardiovascular disease, the influence of eating practices has not been thoroughly examined and understood. The aim of the present work was to evaluate the independent role of eating practices on the likelihood of developing an acute coronary syndrome (ACS) or ischemic stroke. METHODS AND RESULTS: During 2009-2010, 1000 participants were enrolled; 250 were consecutive patients with a first ACS, 250 were consecutive patients with a first ischemic stroke and 500 were population-based control subjects (250 age-sex matched one-for-one with ACS patients, and 250 age-sex matched one-for-one with stroke patients). Eating practices were evaluated using a special questionnaire. Socio-demographic, clinical, psychological, dietary and other lifestyle characteristics were also measured. After controlling for potential confounding factors, each 20 min prolongation of dinner-to-sleep time was associated with 10% lower likelihood of ischemic stroke (95%CI: 0.83-0.98). Furthermore, eating practices related to stress (i.e., eating while being stressed, eating while working at the same time, skipping a meal due to work obligations) were associated with higher likelihood of having an ACS. Finally, eating while watching television was associated with lower likelihood of having an ACS (OR: 0.46, 95%CI: 0.27-0.78) or stroke event (OR: 0.42, 95%CI: 0.23-0.77). CONCLUSION: Results of this work, present novel information, indicating the significance of eating practices, in addition to dietary patterns, regarding the development of coronary heart disease and stroke, and could be used in the primary prevention of CVD.

Mediterranean diet and coronary heart disease: is obesity a link? - A systematic review.

AIMS: Adherence to a healthy dietary pattern, such as the Mediterranean diet, exerts a beneficial role regarding the development of coronary heart disease. In addition, several studies support the protective role of the Mediterranean diet as far as obesity is concerned. This review, examining results from prospective cohort and cross-sectional studies, as well as clinical trials, aims to clarify whether the beneficial effect of the Mediterranean dietary pattern on coronary heart disease is due to the impact of this diet on weight loss and obesity status or an independent effect. DATA SYNTHESIS: 35 original-research studies that were published in English until 2009, selected through a computer-assisted literature search are discussed, from which 3 were prospective, 11 were cross-sectional studies, and 21 were clinical trials. CONCLUSION: Although not all studies show a protective effect of the Mediterranean diet on body weight and obesity, the evidence suggests a possible beneficial role of this dietary pattern. Thus the Mediterranean diet protects against the development of coronary heart disease not only because of its beneficial role regarding cardiovascular risk factors, but also due to a possible effect on body weight and obesity.

Atrial fibrillation and marijuana smoking.

Marijuana is the most commonly used illicit drug while its abuse and dependence has an increasing prevalence among the young population. Marijuana smoking affects the circulatory system triggering various cardiovascular events. Of note, recent case reports indicate a possible association with atrial fibrillation (AF). In this article, we provide a brief systematic review of all reported cases implicating marijuana smoking in AF development and we concisely discuss the potential underlying mechanisms as well as the clinical implications of this emerging association.

Do statins have an antiarrhythmic activity?

Sudden cardiac death, which is mainly associated with the presence of life-threatening ventricular arrhythmias, is a common 'killer' among patients with coronary artery disease. Moreover, atrial fibrillation is the most common arrhythmia encountered in the clinical practice. The beneficial effect of statins on cardiovascular morbidity and mortality is well-established, while the exact role of this class of drugs against arrhythmias remains unclear. This review discusses the effect of statin treatment on arrhythmias that are commonly seen in the clinical setting. The underlying pathophysiological mechanisms are also overviewed. Compelling evidence from the majority of the studies reviewed shows that statins exhibit a protective effect against the occurrence of ventricular arrhythmias and atrial fibrillation.

Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation.

OBJECTIVE: To assess the effectiveness and safety of pharmacological conversion of persistent atrial fibrillation (AF) with a combined propafenone plus ibutilide regimen. METHODS AND RESULTS: 100 consecutive patients (66 men, mean (SD) age 65 (10) years) with persistent AF (mean (SD) duration 99 (92) days) admitted for elective pharmacological cardioversion were randomly assigned to treatment with either intravenous ibutilide (1 mg plus an additional 1 mg, if required; n = 51) or oral propafenone (600 mg) plus intravenous ibutilide at the same dose (n = 49). Success rates were 41.1% (21 of 51 patients) for ibutilide alone and 71.4% (35 of 49 patients) for propafenone plus ibutilide (p = 0.0044). However, cardioversion occurred earlier in the ibutilide alone group (55 (20) minutes) compared with the combination group (81 (32) minutes, p = 0.0019). A comparable increase in the QTc interval was observed in both groups but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group. No other complications were noted during the hospitalisation period. CONCLUSION: Concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent AF is safe and more effective than ibutilide alone.

Serum uric acid levels and risk for acute ischaemic non-embolic stroke in elderly subjects.

BACKGROUND: Elevated serum uric acid (SUA) levels have been proposed as an independent risk factor for cardiovascular (CV) morbidity and mortality. Recent evidence suggests that treatments with a hypouricaemic action have a favourable effect on CV event prevention. OBJECTIVES: The association between SUA and acute ischaemic/non-embolic stroke was assessed in a population-based case-control study in the prefecture of Ioannina, Epirus, Greece. SUBJECTS AND METHODS: A total of 163 patients aged older than 70 years (88 men and 75 women) admitted due to a first-ever-in-a-lifetime acute ischaemic/non-embolic stroke and 166 volunteers (87 men and 79 women) without a history of CV disease were included. The association between SUA and stroke was determined by multivariate logistic regression modelling after adjusting for potential confounding factors. RESULTS: Stroke patients showed higher concentrations of SUA compared with controls (333.1+/-101.1 micromol L(-1) vs. 285.5+/-83.3 micromol L(-1); P<0.001). In univariate analysis elevated SUA levels were associated with increased risk for ischaemic stroke [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.21-1.64, P<0.0001]. Compared to patients with SUA levels in the lowest quintile, those within the highest quintile had a 2.8-time increase in the odds of suffering an ischaemic stroke (OR 2.81, 95% CI 1.67-4.73, P<0.001). This association was strong even after controlling for gender, age, body mass index, the presence of hypertension and diabetes mellitus, drug treatment and lipids (OR 2.90, 95% CI 1.59-5.30, P=0.001). CONCLUSION: Elevated SUA is associated with an increased risk for acute ischaemic/non-embolic stroke in a strictly defined population of elderly individuals independently of concurrent metabolic derangements. This association may need to be considered when treating the elderly.

Variation of inflammatory indexes after electrical cardioversion of persistent atrial fibrillation. Is there an association with early recurrence rates?

Inflammation has been recently implicated in the pathophysiology of atrial fibrillation (AF). The aim of this study was to examine the variation of inflammatory indexes during the first week after successful electrical cardioversion of persistent AF. Successive measurements of white blood cell (WBC) count, C-reactive protein (CRP) and fibrinogen levels were performed in 30 cardioverted patients. At the end of the 7-day follow-up period, AF had recurred in 30% of patients. A significant variance was found in serial measurements of fibrinogen levels in the two groups (non-relapse and relapse, p = 0.005). Fibrinogen levels increased significantly in patients who relapsed into AF, but remained stable in patients who remained in sinus rhythm. In the latter patients, CRP values tended to decrease post-cardioversion, but WBC count was significantly lower (p < 0.001) on the 7th day (6083 +/- 1335), compared with baseline values (6648 +/- 1395). The variation of inflammatory indices post-cardioversion might have prognostic implications with regard to sinus rhythm maintenance.

Treatment of acute lower limb ischemia following the use of the Duett sealing device: report of three cases and review of the literature.

Three cases of local thrombolysis in the treatment of acute lower limb ischemia complicating the utilization of the Duett sealing device are presented. Routine usage of several vascular closure devices after cardiac catheterization and percutaneous coronary intervention (PCI) has been adopted in our institution during the last 3 years (September 1999 to April 2003). The Duett closure device has been used in 420 patients (post-coronary angiography, 359; post-PCI, 61). Three patients (0.7%) demonstrated acute leg ischemia used by inadvertent intravascular administration of the sealing material related to this device. All three were treated successfully by catheter-directed local thromolysis (tissue plasminogen activator 5 mg bolus followed initially by 1 mg/hr and consequently by 0.5-1.0 mg/hr depending upon the development of significant hematoma and lasting for 24 hr). In conclusion, interventional treatment using local thrombolysis should be the first-line treatment in acute lower limb ischemia complicating the utilization of the Duett sealing device.

An epidemiologic study of acute coronary syndromes in northwestern Greece.

Acute coronary syndromes (ACS) represent the most common cause of morbidity and mortality in the Western world. Relative epidemiologic data for Greece, a Mediterranean country, are sparse. The aim of the study was to determine the incidence and the clinical presentations of ACS. Over a 1-year period we conducted a prospective, population-based survey of ACS cases in an isolated area of northwestern (NW) Greece with 170,000 inhabitants. Every patient living in the study area, aged <80 years, without history of coronary artery disease, who presented with symptoms suspicious for ACS and was hospitalized for at least 24 hours was eligible for inclusion in the study. For sudden cardiac deaths, relative information was obtained from the autopsy report or the physician who documented death. Additional information regarding timing and associated conditions was obtained from relatives. The diagnosis and classification of the studied cases was performed according to World Health Organization and European Society of Cardiology criteria. The authors identified 352 patients (265 men, 87 women, mean age 62.5 +/-10 and 68 +/-9.5 years, respectively) with first-appeared ACS (174 non-ST elevation, 105 ST elevation, 73 sudden cardiac deaths). Fifty-six patients with other forms of ischemic heart disease (stable angina, heart failure, and silent ischemia) were not included in the analysis. Moreover, 154 patients with chest pain and normal appearing EGG at rest, normal values for enzymes (CK, troponin), and negative exercise testing, as well as 77 patients with normal findings from coronary angiography studies, were also excluded. The annual incidence for the age group of 30-79 was 39/10,000 inhabitants (60.6 for men and 19 for women). The incidence of ACS increased with age in both sexes and was higher in men even after the age of 70. About one third of the ACS and half of the sudden cardiac deaths occurred in the age group of 70-79. Only 3 patients were successfully resuscitated. ACS are common in this area of NW Greece and the majority of them present in a form amenable to therapeutic manipulations. Twenty percent of patients died suddenly, and a very small percentage of these were successfully resuscitated. Preventive measures and acute management facilities need to be improved, even in a Mediterranean country where the incidence of ischemic heart disease is relatively lower than in northern European countries.

Electrocardiographic changes in elderly patients during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Cardiorespiratory complications may occur during gastrointestinal endoscopy, and elderly people seem to be more vulnerable to these complications during endoscopic procedures involving the manipulation of abdominal viscera. OBJECTIVES: To determine the incidence of cardiac arrhythmias, changes in oxygen saturation, heart rate and blood pressure during endoscopic retrograde cholangiopancreatography (ERCP) via Holter monitoring in elderly patients older than 70 years of age. METHODS: Holter monitoring and 12-lead electrocardiograms were performed in 30 elderly patients undergoing ERCP and in 30 control subjects undergoing routine chest, abdomen, bone and upper gastrointestinal small bowel follow-through studies. A computerized nontriggered template system was used to analyze the electrocardiograms qualitatively and quantitatively. Arrhythmias, cardiac axis, conduction defects, pauses, ST segment changes, ectopic beats, oxygen desaturation and changes in blood pressure and rate-pressure product were evaluated. RESULTS: Increased heart rate, ST segment changes resulting from myocardial ischemia, oxygen desaturation and transient atrial and ventricular ectopic beats were frequent during ERCP compared with the control group. In one patient, transient left bundle branch block developed and this was attributed to pre-existing hypertension with cardiomegaly. One patient developed ventricular tachycardia and one other sinus bradycardia, but this was attributed to sick sinus syndrome. CONCLUSIONS: Transient myocardial ischemia and various cardiac arrhythmias are frequent in elderly patients undergoing ERCP. Appropriate noninvasive monitoring seems to be justified during this procedure.

Platelet hyperaggregability to platelet activating factor (PAF) in non-ST elevation acute coronary syndromes.

It is known that myocardial ischaemia increases platelet aggregatory response to various agonists, ex vivo. We investigated the platelet aggregatory response to platelet activating factor (PAF), ex vivo, in patients with non-ST elevation acute coronary syndromes and determined the specificity and sensitivity of this response. Thirty-two consecutive patients with non-ST elevation acute coronary syndromes and 20 healthy volunteers were studied. Platelet aggregation in platelet-rich plasma was studied on the day of admission. The maximal aggregation achieved within 2 min after the addition of PAF (100 nM) was expressed as a percentage of 100% light transmission. PAF EC50 values were defined as the concentration that induces 50% of maximal aggregation. The PAF EC50 values of the non-ST elevation acute coronary syndromes patients were significantly lower compared to those of the controls (p < 0.0001). The maximal percentage of aggregation was also significantly higher (p < 0.0005). Ninety-one per cent of the patients were correctly classified using PAF EC50 values (specificity 90.0% and sensitivity 91.2%); the corresponding results using the maximal percentage of aggregation were 80% (specificity 70.0% and sensitivity 87.5%). The estimated values used as thresholds were 22.47 nM and 17.97 for the PAF EC50 and the maximal percentage of aggregation, respectively. The results of the present study suggest that platelet hyperaggregability to PAF, ex vivo, in non-ST elevation acute coronary syndromes is characterised by a high specificity and sensitivity, and thus it may represent a mechanism contributing to the pathophysiology of acute coronary syndromes.

Serum lipoprotein(a) concentrations and apolipoprotein(a) isoforms: association with the severity of clinical presentation in patients with coronary heart disease.

OBJECTIVE: The aim of this study was to investigate the possible associations between lipoprotein(a) [Lp(a)] concentrations or apolipoprotein(a) isoforms and the mode of clinical presentation of coronary heart disease (CHD) (acute thrombotic event or not). METHODS: A total of 131 CHD patients and 71 age- and gender-matched individuals without known CAD (free of symptoms of heart disease) were enrolled in the study. CHD patients were classified into patients with a history of an acute coronary syndrome (ACS, n=94) and patients with stable angina (SA, n=37). Lp(a) levels were measured with an ELISA method, whereas apolipoprotein(a) isoform analysis was performed (in all patients and 33 controls) by electrophoresis in 1.5% SDS-agarose gels followed by immunoblotting. Isoform size was expressed as the number of kringle 4 (K4) repeats. RESULTS: ACS patients had higher Lp(a) plasma levels 121.9 (0.8-84.1) mg/dl] and a greater proportion of elevated (> or = 30 mg/dl) Lp(a) concentrations (25.5%) compared with SA patients [9.2 (0.8-50.5) mg/dl, P < 0.01 and 10.8%, P < 0.05] and controls [8.0 (0.8-55.0) mg/dl, P < 0.01 and 11.2%, P < 0.05], while there were no differences between SA patients and controls. The median apolipoprotein(a)-isoform size was 26 K4. In 17 (10%) patients we could not detect any apolipoprotein(a) isoform bands by immunoblotting. ACS patients had a higher proportion of isoforms < 26 K4 (low molecular weight) than SA patients (56/85 vs. 12/33, P < 0.005) and controls (10/29, P < 0.005). CONCLUSIONS: CAD patients with a history of ACS have higher Lp(a) plasma levels and a significantly higher proportion of low molecular weight apolipoprotein(a) isoforms compared with patients with SA or to controls.

The effect of atorvastatin on serum lipids, lipoprotein(a) and plasma fibrinogen levels in primary dyslipidaemia--a pilot study involving serial sampling.

We conducted an open-label study to test the effects of atorvastatin on serum lipids, lipoprotein(a) [Lp(a)] and plasma fibrinogen levels. A total of 90 dyslipidaemic, non-smoking patients (45 patients with primary hypercholesterolaemia and 45 patients with primary mixed hyperlipidaemia) aged 48 +/- 11 years were studied. The patients were treated with 20 mg of atorvastatin for 24 weeks, in a single nocturnal dose. At baseline and every eight weeks, the fasting lipid profile, together with serum Lp(a) and plasma fibrinogen levels (Clauss method), were measured. Atorvastatin was highly effective in normalising the serum lipid profile. No significant change in median serum Lp(a) levels was observed in the whole group of patients (0.14 g/l before, vs. 0.16 g/l after, treatment) as well as in patients with raised (> 0.30 g/l) baseline levels (n = 32). A small non-significant increase of plasma fibrinogen was found (3.04 g/l vs. 3.14 g/l) after 24 weeks of atorvastatin administration. The effects of atorvastatin on both these variables did not differ in patients with hypercholesterolaemia or mixed hyperlipidaemia. In conclusion, our findings suggest that the effect of atorvastatin on plasma fibrinogen levels in dyslipidaemic patients without evident vascular disease is not clinically relevant. Furthermore, any rise in fibrinogen levels that may occur is likely to be transient in nature. Further studies are necessary to clarify this issue. There was no evidence that atorvastatin influences serum Lp(a) levels.

Treatment of refractory unstable angina in geographically isolated areas without cardiac surgery. Invasive versus conservative strategy (TRUCS study).

AIMS: We compared invasive (on-site coronary angioplasty or emergency air-ambulance transfer for bypass grafting surgery) vs conservative (persistent medical treatment) strategies in the management of refractory unstable angina in geographically isolated hospitals without cardiac surgical facilities. METHODS AND RESULTS: One hundred and forty eight randomized patients with refractory unstable angina were compared on an intention-to-treat basis. Outcomes (invasive vs conservative): (a) in hospital: stabilization (96% vs 43%, P=0.0001), non-fatal myocardial infarction (2.6% vs 4.2%, P=ns), death (1.3% vs 8.3%, P=0.046), combined outcome (3.9% vs 12.5%, P=0.053) and hospitalization (11.4+/-6.3 vs 12.4+/-8.0 days, P=ns). (b) 30-days follow-up: non-fatal myocardial infarction (2.6% vs 4.2%, P=ns), death (2.6% vs 11.1%, P=0.030) and combined outcome (5.3% vs 15.3%, P=0.031). (c) 12 month follow-up: non-fatal myocardial infarction (3. 9% vs 4.2%, P=ns), death (3.9% vs 12.5%, P=0.053), combined outcome (7.9% vs 16.7%, P=ns), re-admissions for unstable angina: (17.1% vs 23.6%, P=ns), late coronary angioplasty: (15.8% vs 11.1%, P=ns) and (d) late coronary bypass grafting: (7.9% vs 12.5%, P=ns). CONCLUSION: Invasive treatment of patients with refractory angina in remote areas without surgical back-up results in significant in-hospital stabilization and a reduction in major events in-hospital and at 30 days. Coronary angioplasty in stand-alone units and air-transfer of these patients seems safe.