Protease-Activated Receptor 1 Inhibitors: Novel Antiplatelet Drugs in Prevention of Atherothrombosis.

Protease-activated receptor (PAR)-1 inhibitors have recently become popular in the use of atherosclerosis among clinicians. Atherosclerosis can cause cardiovascular and cerebrovascular events leading to one of the major causes of mortality worldwide. Thrombin-mediated platelets can cause atherosclerotic plaques, and these platelets are activated by thrombin through the PAR-1. Vorapaxar and atopaxar are novel antiplatelet drugs that inhibit the thrombin-induced platelet activation by antagonizing the PAR-1. The objective of this article is to review the mechanism of action of vorapaxar and atopaxar and explain the rationale for using them in atherothrombosis patients including myocardial infarction, peripheral arterial disease, and stroke.

Arrhythmias in Adults with Congenital Heart Disease: What Are Risk Factors for Specific Arrhythmias?

INTRODUCTION: An increasing number of patients with congenital heart disease are now surviving into adulthood. This has also led to the emergence of complications from the underlying congenital heart disease, related surgical interventions, and associated combordities. While the prevalence of particular arrhythmias with specific congenital heart disease has been previously described, a detailed analysis of all lesions and a large number of comorbidities has not been previously published. METHODS: Admissions with congenital heart disease were identified in the National Inpatient Sample. Associated comorbidities were also identified for these patients. Univariate analysis was done to compare those risk factors associated with specific arrhythmias in the setting of congenital heart disease. Next, regression analysis was done to identify what patient characteristics and comorbidities were associated with increased risk of specific arrhythmias. RESULTS: A total of 52,725,227 admissions were included in the analysis. Of these, 109,168 (0.21%) had congenital heart disease. Of those with congenital heart disease, 27,088 (25%) had an arrhythmia at some point. The most common arrhythmia in those with congenital heart disease was atrial fibrillation, which was noted in 86% of those with arrhythmia followed by atrial flutter which was noted in 20% of those with congenital heart disease. The largest burden of arrhythmia was found to be in those with tricuspid atresia with a 51% prevalence of arrhythmia in this group followed by Ebstein anomaly which had an arrhythmia prevalence of 39%. Increasing age, male gender, double outlet right ventricle, atrioventricular septal defect, heart failure, obstructive sleep apnea, transposition of the great arteries, congenitally corrected transposition, and tetralogy of Fallot were frequently noted to be independent risk factors of specific arrhythmias. CONCLUSION: Approximately, 25% of adult admissions with congenital heart disease are associated with arrhythmia. The burden of arrhythmia varies by the specific lesion and other risk factors as well. Understanding of these can help in risk stratification and can help devise strategies to lower this risk.

The Need for Extracorporeal Membrane Oxygenation in Adults Undergoing Congenital Heart Surgery: Impact and Trends of Utilization.

INTRODUCTION: Adults with congenital heart disease (ACHD) represent a population with unique health-care needs. Many patients require cardiac surgery, with some requiring postoperative extracorporeal membrane oxygenation (ECMO). This study aimed to identify the risk factors for the need of postoperative ECMO and characterize the impact of ECMO on admission characteristics. METHODS: Data from the 2005-2012 iterations of the Nationwide Inpatient Sample were used. ACHD admissions over 18 years with a documented cardiac surgery were included. Univariate analysis was conducted to compare the characteristics between those requiring ECMO and those who did not. Regression analysis was done to identify the independent risk factors associated with ECMO and to determine the impact of ECMO on length, cost, and mortality of the admission. RESULTS: A total of 186,829 admissions were included. Of these, 446 (0.2%) admissions required ECMO. Those with acute kidney injury, double-outlet right ventricle, or total anomalous pulmonary venous connection were more likely to require ECMO. ECMO was also significantly more utilized in patients undergoing septal defect repair, complete repair of tetralogy of Fallot, atrial switch, and heart transplant. The use of ECMO significantly increased length, cost, and mortality of stay. Overall mortality was 62.6% in the ECMO group. CONCLUSION: ECMO is only needed in a small proportion of postoperative ACHD patients. The use of ECMO significantly increases cost, length of stay and mortality in these patients. Improved identification of postoperative ACHD patients who are more likely to survive ECMO may facilitate improved survival and decreased resource utilization.

Coronary Artery Disease in the Human Immunodeficiency Virus Seropositive Population.

The development of efficient combined antiretroviral therapies has lengthened the mean life span of the population affected with human immunodeficiency virus (HIV) transforming this terminal infection to a chronic yet manageable disease. Nonetheless, patients with HIV--treatment naive or not--exhibit larger risks for coronary artery disease than the noninfected population. Moreover, coronary atherosclerosis/arteriosclerosis may be the most prevalent condition in the HIV-infected population that is being accentuated by the effects of viral agents and the antiretroviral drugs, especially protease inhibitors. Nonetheless, generalized metabolic dysfunctions and premature senescence are often attributed to the viremia caused by the HIV infection directly and primarily. Therefore, a multifactorial approach is to be considered when attempting to explain the strong correlation between HIV and coronary artery disease, including co-opportunistic viremias and vitamin D insufficiency/deficiency.

Statin Use Mitigate the Benefit of Omega-3 Fatty Acids Supplementation-A Meta-Regression of Randomized Trials.

During last 2 decades, multiple studies have evaluated omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation for cardiovascular prevention. The benefit found in previous studies was not demonstrated in more contemporary trials. We aimed to investigate effect of study characteristics, particularly concomitant statin therapy on results of randomized controlled trials. We systematically searched electronic databases for randomized controlled trials evaluating ω-3 PUFA supplementation and reporting clinical outcomes. A meta-analysis was performed using a random effect model, followed by a meta-regression of dose, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio, and duration of treatment and use of lipid-lowering/statin therapy in control group. Twenty-three studies with 77,776 patients (38,910 PUFA; 38,866 controls) were included. PUFA had no effect on total mortality [risk ratio (RR) = 0.96; 95% confidence interval (CI), 0.92-1.01] and myocardial infarction (RR = 0.87; 95% CI, 0.73-1.02), but marginally reduced cardiovascular mortality (RR = 0.93; 95% CI, 0.87-0.98). Lower control group statin use (b = 0.222, P = 0.027) and higher DHA/EPA (b = -0.105, P = 0.033) ratio was associated with higher reduction in total mortality. Duration and dose had no effect. None of the variables except duration had significant effect on reduction in cardiovascular mortality by PUFA supplementation. There was evidence of publication bias. Statin use may mitigate, and higher DHA/EPA ratio is associated with the beneficial effect of PUFA supplementation.

Organic Cation Transporter-Mediated Clearance of Cardiovascular Drugs: A Pharmacological Perspective.

There exist a number of mechanisms to clear xenobiotics from human circulation. For cationic drugs, clearance is performed by human organic cation transporters 1 and 2 (hOCT1 and hOCT2), which are expressed in the liver and kidney, respectively. Given the prevalence of patients taking cardiovascular drugs, the present review focuses on the elimination of circulating cardiovascular drugs by organic cation transporters (OCTs). A significant number of cardiovascular drugs compete for transport by OCT1 or OCT2, introducing the potential to alter the pharmacokinetic profile of other concomitantly administered medications. The OCT system thereby represents an important site of drug-drug interactions.

Eicosapentaenoic Acid Versus Docosahexaenoic Acid as Options for Vascular Risk Prevention: A Fish Story.

Vascular inflammation is a key component involved in the process of arthrosclerosis, which in turn increases the risk for cardiovascular injury. In the last 10 years, there have been many trials that looked at omega-3 fatty acids as a way to reduce cardiovascular risk. These trials observed the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the traditional lipid panel and found that both EPA and DHA reduce triglyceride (TG) level and increase high-density lipoprotein cholesterol (HDL-C) levels but also increase the low-density lipoprotein cholesterol (LDL-C) levels. In the 2 more recent trials, the MARINE and ANCHOR, EPA was given as an adjunct therapy to high-risk patients and not only was the traditional lipids measured but also examined the vascular inflammatory biomarkers. The results of these 2 trials not only showed reduction in cardiovascular risk because of reduction in vascular inflammation and reduction in the lipid panel but also showed that one of the MARINE-derived omega-3 fatty acid is superior to the other. Data search for omega-3 fatty acids and cardiovascular risk was performed, and articles were selected for review from 2006 to date. The research studies were all double-blind randomized trials except for one, which was a single-blind and focused on the effects of omega-3 fatty acids on the entire lipid panel. The participants received DHA/EPA and compared with a placebo group on the effect seen in the lipid panel. The first 7 studies looked at the effects of omega-3 fatty acids on TG, LDL-C, and HDL-C; of the 7, 1 directly compared DHA and EPA, 2 focused on EPA, and 4 were directed towards DHA alone. The MARINE and ANCHOR trials were more recent and also looked at the same parameter but also monitored vascular inflammatory biomarkers and how they were affected by omega-3 fatty acids. A second data search was performed for vascular biomarkers and cardiovascular risk, and articles that focused on high-sensitivity C-reactive protein and oxidized low-density lipoprotein were selected for review. Omega-3 fatty acids have shown to decrease TG level in multiple trials, but they have also shown to increase LDL and HDL levels, likely because omega-3 fatty acids promote TG conversion into HDL/LDL. The older data suggested that the benefits of omega-3 fatty acids are nullified by their effects on LDL levels. The data from the MARINE and ANCHOR trials have shown that EPA alone at 4 g per day has shown to decrease TG and total cholesterol without affecting the LDL levels. The earlier data showed that both EPA and DHA decreased TG level and increased levels of HDL-C, but that the DHA alone and direct comparison of DHA/EPA showed that DHA has more undesirable effects on LDL. Furthermore, the MARINE and ANCHOR trials have both shown that not only does EPA improve the lipid panel but also helps to decrease the levels of the vascular inflammatory biomarkers, thus further helping to decrease cardiovascular risk. The use of EPA as an adjunct therapy for high-risk patient has shown to help decrease cardiovascular risk. The reduction in risk is performed not only by decreasing TG but also by reducing vascular inflammation. Although because there are no randomized double-blind study looking at this, the research is inconclusive and requires further investigation.

Raw Water Consumption Does Not Affect All-Cause or Cardiovascular Mortality: A Secondary Analysis.

Previous studies have examined water quality and its association with all-cause and cardiovascular mortality. However, there is a lack of data regarding association between the amount of water consumption and risk of mortality. We used the third National Health and Nutrition Examination Survey (NHANES III) database and its subsequent follow-up data. Only patients older than 45 years who reported amount of average water consumption and for whom follow-up mortality data were available were included in the study. Patients were stratified into following groups of average daily raw water consumption: (1) no water consumption, (2) ≤2 cups, (3) >2 to ≤ 4 cups, (4) >4 to ≤6 cups, (5) >6 to ≤8 cups, and (6) ≥8 cups. End points studied were all-cause mortality, ischemia-related mortality, congestive heart failure-related mortality, and stroke-related mortality. Baseline characteristics were compared using t tests and Mann-Whitney U tests. Odds ratios, 95% confidence intervals, and P values were calculated for univariate analysis using >6 cups to ≤8 cups of water a day group as reference. Multivariate analysis was then performed adjusting for various factors. P values of less than 0.05 were considered statistically significant. A total of 7666 patients were ultimately included in the study. Multivariate analysis demonstrated no significant differences in all-cause, ischemia-related, heart failure-related, or stroke-related mortality among various raw water intake groups when compared with the reference group. The significance noted for all-cause mortality in >2 glasses to ≤4 glasses a day group in the univariate analysis was not seen with multivariate analysis (odds ratio: 0.747; 95% confidence interval: 0.437-1.276; P = 0.285). Daily raw water consumption does not seem to impact all-cause mortality or cause-specific cardiovascular mortality.

The Effect of Coffee and Quantity of Consumption on Specific Cardiovascular and All-Cause Mortality: Coffee Consumption Does Not Affect Mortality.

Previous studies have examined whether or not an association exists between the consumption of caffeinated coffee to all-cause and cardiovascular mortality. This study aimed to delineate this association using population representative data from the National Health and Nutrition Examination Survey III. Patients were included in the study if all the following criteria were met: (1) follow-up mortality data were available, (2) age of at least 45 years, and (3) reported amount of average coffee consumption. A total of 8608 patients were included, with patients stratified into the following groups of average daily coffee consumption: (1) no coffee consumption, (2) less than 1 cup, (3) 1 cup a day, (4) 2-3 cups, (5) 4-5 cups, (6) more than 6 cups a day. Odds ratios, 95% confidence intervals, and P values were calculated for univariate analysis to compare the prevalence of all-cause mortality, ischemia-related mortality, congestive heart failure-related mortality, and stroke-related mortality, using the no coffee consumption group as reference. These were then adjusted for confounding factors for a multivariate analysis. P < 0.05 were considered statistically significant. Univariate analysis demonstrated an association between coffee consumption and mortality, although this became insignificant on multivariate analysis. Coffee consumption, thus, does not seem to impact all-cause mortality or specific cardiovascular mortality. These findings do differ from those of recently published studies. Coffee consumption of any quantity seems to be safe without any increased mortality risk. There may be some protective effects but additional data are needed to further delineate this.

Effects of Concurrent Calcium Channel Blocker on Antiplatelet Efficacy of Clopidogrel Therapy: A Systematic Review.

Clopidogrel is a widely used drug in clinical practice. Controversy persists as to whether it interacts with proton pump inhibitors. Recently, research interest has grown in the area concerning an interaction of clopidogrel with calcium channel blockers. Multiple studies have been conducted to evaluate the effect of calcium channel blockers on the efficacy of clopidogrel, both in vitro and in vivo. The authors aim to present a systematic review of the published studies in the literature. Various terms were searched in PubMed, Web of Science, and The Cochrane database. Abstracts of studies were read and based on strict exclusion criteria; a study was included/excluded into the review. A total of 424 studies were initially included. Based on exclusion criteria, 22 studies were finally included in the review. Various studies report widely different results regarding the effects of calcium channel blockers on antiplatelet efficacy of clopidogrel. Large prospective studies are needed to delineate the association or lack thereof.

Role of N-Acetylcysteine to Prevent Contrast-Induced Nephropathy: A Meta-analysis.

It is unclear whether N-acetylcysteine is useful in preventing contrast-induced nephropathy in patients undergoing coronary angiography. Because of different inclusion and exclusion criteria and different definitions of studied parameters, various studies have reported different outcomes. A systematic search was done using PubMed, Ovid, and the Cochrane library, and studies were pooled after strict inclusion and exclusion criteria. Separate analysis was conducted for all endpoints including only studies that used an N-acetylcysteine (NAC) dose of 600 mg, and another separate analysis was conducted for all endpoints including only studies that used oral route NAC to study how the dose and route of administration of NAC affect the outcomes. The results of the pooled analysis significantly favored the use of NAC to prevent contrast-induced nephropathy in patients undergoing coronary angiography but failed to show any significant benefit in terms of creatinine levels preangiography and postangiography, need for dialysis, and all-cause mortality. The effects of route and dose of NAC did not show any significant difference except in respect to incidence of postcatheterization nephropathy. This study shows that NAC may not have any impact on clinical outcomes after peripheral or coronary artery catheterization and that dose and route do not seem to have any effect on these outcomes.

Arrhythmias in Adult Congenital Patients With Bodily Isomerism.

There are an increasing number of adults with congenital heart disease, some of whom have bodily isomerism. Bodily isomerism or heterotaxy is a unique clinical entity associated with congenital malformations of the heart which further increases the risk for future cardiovascular complications. We aimed to investigate the frequency of arrhythmias in adults with bodily isomerism. We utilized the 2012 iteration of the Nationwide Inpatient Sample to identify adult inpatient admissions associated with arrhythmias in patients with isomerism. Data regarding demographics, comorbidities, and various procedures were collected and compared between those with and without isomerism. A total of 6,907,109 admissions were analyzed with a total of 861 being associated isomerism. The frequency of arrhythmias was greater in those with isomerism (20.8 vs. 15.4 %). Those with isomerism were also more five times more likely to undergo invasive electrophysiology studies. Length and cost of hospitalization for patients with arrhythmias also tended to be greater in those with isomerism. Mortality did not differ between the two groups. Arrhythmias are more prevalent in those with isomerism, with a majority of arrhythmias in isomerism being atrial. Those with isomerism and arrhythmias also tended to have greater length and cost of hospitalization.

The efficacy of rivaroxaban in patients with atrial fibrillation.

Atrial fibrillation (AF), the most common form of cardiac arrhythmia, is a major risk factor for cardioembolic stroke. Dose-adjusted warfarin has been the gold standard for stroke prophylaxis in moderate- to high-risk patients with AF. However, the use of warfarin therapy is greatly limited by its narrow therapeutic window, numerous dietary restrictions, and drug-drug interactions, and an increased risk of hemorrhage. As a result, great emphasis has been placed on developing a new anticoagulant agent with fewer risks and limitations. Current data suggest that the oral direct factor Xa inhibitor rivaroxaban is a safe and effective alternative to warfarin. Furthermore, rivaroxaban does not require routine coagulation monitoring, which may improve patient compliance to anticoagulant therapy. The ROCKET AF trial demonstrated that 20-mg oral rivaroxaban taken once daily was noninferior to dose-adjusted warfarin in the prevention of stroke and non-central nervous system systemic embolism and had a comparable risk of bleeding. Based primarily on the ROCKET AF trial results, the US Food and Drug Administration recently approved the use of rivaroxaban for stroke prophylaxis in patients with nonvalvular AF. However, additional postmarketing studies on its safety and cost effectiveness are needed before it can be widely accepted as a sound alternative to warfarin.

The role of exercise in heart failure: a systematic review.

The objective of this study was to examine the long-term effects of exercise on physiological function, functional capacity, and quality of life (QOL) and health status in patients with heart failure. PubMed and CENTRAL were searched (March 2001 to March 2011) for randomized controlled trials for the keyword "exercise heart failure." Data were abstracted by a single author (B.D.R.) and reviewed by another author (R.A.). Fifteen studies were included. Results were mixed between studies for most measures of physiological function, functional capacity, and QOL and health status. In conclusion, compared with usual care, exercise increased a number of measures of functional capacity and QOL in patients with heart failure. Most of the measures of physiological function were not reported across multiple studies; therefore, no trend could be identified for these measures.

Efficacy of colesevelam on lowering glycemia and lipids.

A few trials have investigated the efficacy of colesevelam in the reduction of glycemic and lipid outcomes. These meta-analysis pooled data from 8 such trials and found that colesevelam is associated with significant reductions in plasma fasting glucose, hemoglobin A1c, and low-density lipoprotein. Insignificant reductions in high-density lipoprotein and total cholesterol were also noted along with significant increase in triglycerides. This analysis concludes that colesevelam may be of particular benefit in managing type 2 diabetic patients with hyperlipidemia in whom low-density lipoprotein levels are of particular concern. Caution should be taken in patients who have hypertriglyceridemia or low high-density lipoprotein levels before starting therapy.

Utility of early high dose statins in acute coronary syndrome.

In accordance with the recommendations of the American College of Cardiology/American Heart Association Joint Task Force, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are prescribed before hospital discharge after an episode of acute coronary syndrome. Yet, optimal timing and dosage have not been agreed upon. Recent evidence suggests a pleiotropic mechanism of action including vasoprotective, anti-inflammatory, and antiarrhythmic properties that imply an immediate role for statin medications. Our review suggests that early (<24 hours) high dose (80 mg of atorvastatin) statins may significantly reduce adverse cardiovascular outcomes and may improve long-term mortality.

Fixing the "broken heart": pharmacologic implications.

Broken-heart syndrome also known as Left ventricular apical ballooning syndrome or Stress-induced cardiomyopathy or Takotsubo cardiomyopathy is an important clinical entity, which presents clinically, similar to acute coronary syndrome with an acute onset of chest pain, ST-T changes in electrocardiogram, and moderate cardiac enzyme elevation. Recent studies have shown that it accounts for 1%-2% of cases of ST-elevation infarction. An episode of intense emotional or physiologic stress has been reported before its presentation and is presumed to be the triggering factor in the pathogenesis. The pathophysiology of this syndrome still remains unclear, and management is mostly empiric and supportive. In this review, we have discussed various pathophysiologic mechanisms underlying this cardiomyopathy and their pharmacological implications and role of medications such as aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and statins for patients presenting with this syndrome in treatment and prevention.

Hyperlipidaemia and cardiovascular disease: do fibrates have a role?

PURPOSE OF REVIEW: Fibrates continue to be a viable treatment option for mixed atherogenic dyslipidemia, and recent reports from clinical studies have shed new light on the therapeutic utility of fibrates for the prevention of microvascular and macrovascular disease, especially in combination with statins. RECENT FINDINGS: Data from randomized placebo-controlled trials have shown that fibrates reduce nonfatal coronary events but do not confer any benefit on mortality or other adverse cardiovascular outcomes. The ACCORD Lipid trial studied the additive effect of fenofibrate therapy along with low-dose simvastatin therapy in 5,518 patients with type 2 diabetes mellitus, and found that fenofibrate did not affect any of the adverse cardiovascular outcomes, either individually or as part of a composite outcome, after 4.7 years of follow-up. An a priori subgroup analysis showed a significant benefit from fenofibrate-simvastatin combination therapy over simvastatin alone in participants with moderate hypertriglyceridemia and low HDL-cholesterol on major cardiovascular events, consistent with post-hoc analyses of previous fibrate trials. The ACCORD-Eye study adds to the sparse clinical data on the effect of fenofibrate on diabetic retinopathy, and showed that fenofibrate may be used to reduce the risk of progression of diabetic retinopathy even in patients with established disease. The combination of statin and fibrate was well tolerated. SUMMARY: Fibrate therapy does not reduce mortality but may reduce nonfatal coronary events in patients at risk for cardiovascular disease, including those with type 2 diabetes. The ACCORD Lipid study shows that the combination of low-dose simvastatin and fenofibrate is well tolerated, and is potentially cardioprotective in patients with atherogenic 'mixed' dyslipidemia.

Modulation of toll-like receptors by insulin.

Toll-like receptors (TLRs) are first-line molecules for initiating the innate immune responses and mediating functional activation in immune effector cells. A family of 10 functional human TLRs altogether can recognize the ligands that do not exist in the host and initiate the inflammatory cascades. This triggers the production of inflammatory cytokines, chemokines, and interferons. Overactivation of innate immunity might lead to immune-mediated inflammatory disorders. Besides that, TLRs are currently viewed as active participants in the cross-communication between immunity and metabolic health. Recent data directly implicate the activation of inflammatory pathways in the pathogenesis of type 1 and type 2 diabetes, atherosclerosis, obesity, and also cancer. The following approaches to develop new TLR drugs have been undertaken: generating TLR agonists/antagonists, creating monoclonal antibody to TLRs, blocking the key molecules in the signaling pathways, down-modulating TLR signaling. In this article, we briefly review the involvement of TLRs in diseases associated with metabolic alterations, underscoring the modulation of TLRs by insulin.