Cryptogenic Stroke: To Close a Patent Foramen Ovale or Not to Close?

A patent foramen ovale (PFO) has been shown to be highly prevalent in patients diagnosed with strokes of unknown cause, which are also called cryptogenic strokes (CSs). It has been a long-running controversy as to whether a PFO should be closed or not to prevent recurrent strokes in patients diagnosed with CS. A paradoxical embolism that is produced through a PFO is hypothesized to be a leading cause of CS, especially in younger patients with low risk factors for stroke. It remains controversial as to which anticoagulation therapy, defined as antithrombin or antiplatelet therapy, is better for patients with CS and a PFO. In addition, surgical and transcutaneous closure of a PFO has been proposed for the secondary prevention of stroke in patients with CS with PFO. Several randomized controlled trials have been conducted in recent years to test whether a PFO closure gives a significant benefit in the management of CS. Three earlier randomized controlled trials failed to show a statistically significant benefit for a PFO closure; thus, many investigators believed that a PFO was an incidental bystander in patients with CS. However, meta-analyses and more recent specific trials have eliminated several confounding factors and possible biases and have also emphasized the use of a shunt closure over medical therapy in patients with CS. Therefore, these latest studies (the CLOSE and REDUCE trials) can possibly change the treatment paradigm in the near future.

The Utility of Anti-Inflammatory Agents in Cardiovascular Disease: A Novel Perspective on the Treatment of Atherosclerosis.

Approximately 40% of heart attack survivors remain at increased risk of recurrent cardiovascular events, despite the current treatment options showing that atherothrombosis is not exclusively a disorder of lipoprotein aggregation in the arterial wall. Clinical and experimental data suggest that inflammation plays an important role in atherothrombosis independent of the cholesterol level. Acute-phase reactants, such as C-reactive protein, increase in patients with coronary artery disease and are known to predict adverse outcomes in such patients. The recent CANTOS trial published in The New England Journal of Medicine provides evidence that interleukin-1ß along with other cytokines play central roles in the inflammatory reaction that drives the interleukin-6 signaling pathway and have profound effects on cardiovascular outcomes. Several other ongoing studies are focused on multiple immune mediators involved in this process to support the inflammatory hypothesis of cardiovascular diseases. These new classes of drugs could represent the biggest breakthrough in cardiovascular medicine, which could have the greatest impact on cardiovascular mortality since the advent of statins. The drug canakinumab has shown promise in lowering atherosclerosis, and other drugs, such as colchicine and methotrexate, are gaining interest and are being investigated in multiple ongoing trials. A major concern is the affordability of these drugs, as most cardiovascular diseases are noted among people of lower socioeconomic statuses. The LoDoCo trial showed some benefits of colchicine, and whether this old drug can be marketed with a new label for cardiovascular disease remains in question. Therefore, a clear understanding of the different inflammatory pathways involved in atherosclerosis is needed to help develop more effective treatment modalities that will benefit humankind.

Association of Dioxin and Dioxin-like Congeners With Hypertension.

Although 7 of 8 studies found moderate evidence of an association with hypertension in patients with at least 1 chemical congener, these studies cannot prove a causal relationship.

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.

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.

Cholesteryl Ester Transfer Protein Inhibitors: Trials and Tribulations.

The cholesteryl ester transfer protein (CETP) is a plasma protein that plays an important role in the transfer of lipids between plasma lipoproteins. The CETP inhibitors have been widely studied as a pharmacologic therapy to target plasma cholesterol in order to reduce the risk of atherosclerotic cardiovascular disease . Using CETP inhibitors as cholesterol modifiers was based on the genetic research that found correlations between CETP activity and cholesterol levels. Although CETP inhibitors are successful at altering targeted cholesterol markers, recent phase 3 outcome trials have shown limited benefit on cardiovascular outcomes when combined with the current standard of care. We discuss the science of CETP inhibition, compare the CETP inhibitors developed (torcetrapib, evacetrapib, dalcetrapib, and anacetrapib), the findings from the CETP inhibitor trials, and the future outlook for CETP inhibitors in cholesterol modification.

Bodily isomerism is an independent risk factor for pulmonary hypertension in adults with congenital heart disease.

INTRODUCTION: Bodily isomerism, or heterotaxy is a unique entity on which there is mirror imagery in various organ systems, leading to a deviation from the normal lateral arrangements of the viscera. Adults with such isomerism and associated congenital malformations of the heart are now reaching adulthood and developing long-term complications. This study investigates the prevalence and characteristics of pulmonary hypertension in adults with isomerism. METHODS: The 2012 iteration of the Nationwide Inpatient Sample was utilized and patients were identified as having or not having bodily isomerism and having or not having pulmonary hypertension. Univariate analysis utilizing Chi-square tabulation was done to assess characteristics associated with pulmonary hypertension. Next, a multivariate analysis was done on all patients to identify predictors of pulmonary hypertension followed by a multivariate analysis of patients with only isomerism to identify predictors of pulmonary hypertension specific to this subset. RESULTS: A total of 6,907,109 admissions were included in the analysis. Of these, 861 had isomerism (0.01%). Of those with isomerism, 5.6% were found to have pulmonary hypertension. When all patients were included in the multivariate analysis, isomerism was found to be an independent risk factor for pulmonary hypertension with an odds ratio of approximately 1.79. When only patients with isomerism were included in the multivariate analysis, advanced age, obesity, and history of anomalous pulmonary venous connection were independent risk factors of pulmonary hypertension. CONCLUSION: Pulmonary hypertension is more common in those with isomerism, with isomerism being an independent risk factor for pulmonary hypertension. The prevalence of pulmonary hypertension is 5.6% in the setting of isomerism. Independent risk factors for pulmonary hypertension in patients with isomerism include age, obesity, and history of anomalous pulmonary venous connection.

Acute Myocardial Infarction in Adult Congenital Patients with Bodily Isomerism.

INTRODUCTION: Children born with congenital malformations of the heart are increasingly surviving into adulthood. This population of patients possesses lesion-specific complication risks while still being at risk for common illnesses. 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 myocardial infarction in adults with bodily isomerism. METHODS: We utilized the 2012 iteration of the Nationwide Inpatient Sample to identify adult inpatient admissions associated with acute myocardial infarction in patients with isomerism. Data regarding demographics, comorbidities and various procedures were collected and compared between those with and without isomerism. RESULTS: A total of 6,907,109 admissions were analyzed with a total of 172,394 admissions being associated with an initial encounter for acute myocardial infarction. The frequency of myocardial infarction did not differ between those with and without isomerism and was roughly 2% in both groups. Similarly, the number of procedures and in-hospital mortality did not differ between the two groups. CONCLUSIONS: The frequency and short-term prognosis of acute myocardial infarction is similar in patients with and without isomerism.

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.

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.

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.

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.

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.

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.

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.

Oxygen in the Setting of Acute Myocardial Infarction: Is It Really a Breath of Fresh Air?

INTRODUCTION: Supplemental oxygen has been used in the setting of acute myocardial infarction (AMI). Once an official recommendation in the guidelines for the management of acute ST-segment elevation myocardial infarction, it is now mentioned as an intervention to be considered. Data for the use of supplemental oxygen or AMI are limited, and some data have suggested associated harm. METHODS: We performed a systematic review of the literature and a subsequent meta-analysis of the data to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. The following end points were studied: in-hospital mortality, opiate use, percentage of infarcted myocardium by magnetic resonance imaging (MRI), and mass of infarcted myocardium by MRI. RESULTS: No significant difference was noted with end points when comparing those randomized to high-concentration oxygen versus those randomized to titrated oxygen or room air in the setting of AMI. No significant publication bias was identified although this could not be assessed for all end points. CONCLUSION: High-concentration oxygen may not offer any benefit when compared to titrated oxygen or room air. A large, randomized trial is warranted to further delineate these differences with respect to multiple end points.

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.

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.