Impact of new-onset versus pre-existing atrial fibrillation on outcomes after transcatheter aortic valve replacement/implantation.

Patients with aortic stenosis who undergo transcatheter aortic valve replacement/transcatheter aortic valve implantation (TAVR/TAVI) experience a high incidence of pre-existing atrial fibrillation (pre-AF) and new-onset atrial fibrillation (NOAF) post-operatively. This systematic review and meta-analysis aimed to update current evidence concerning the incidence of 30-day mortality, stroke, acute kidney injury (AKI), length of stay (LOS), and early/late bleeding in patients with NOAF or pre-AF who undergo TAVR/TAVI. PubMed, Google Scholar, JSTOR, Cochrane Library, and Web of Science were searched for studies published between January 2012 and December 2020 reporting the association between NOAF/pre-AF and clinical complications after TAVR/TAVI. A total of 15 studies including 158,220 adult patients with TAVI/TAVR and NOAF or pre-AF were identified. Compared to patients in sinus rhythm, patients who developed NOAF had a higher risk of 30-day mortality, AKI, early bleeding events, extended LOS, and stroke after TAVR/TAVI (odds ratio [OR]: 3.18 [95% confidence interval [CI] 1.58, 6.40]) (OR: 3.83 [95% CI 1.18, 12.42]) (OR: 1.70 [95% CI 1.05, 2.74]) (OR: 13.96 [95% CI, 6.41, 30.40]) (OR: 2.51 [95% CI 1.59, 3.97], respectively). Compared to patients in sinus rhythm, patients with pre-AF had a higher risk of AKI and early bleeding episodes after TAVR/TAVI (OR: 2.43 [95% CI 1.10, 5.35]) (OR: 17.41 [95% CI 6.49, 46.68], respectively). Atrial fibrillation is associated with a higher risk of all primary and secondary outcomes. Specifically, NOAF but not pre-AF is associated with a higher risk of 30-day mortality, stroke, and extended LOS after TAVR/TAVI.

Transcription and translation of human F11R gene are required for an initial step of atherogenesis induced by inflammatory cytokines.

BACKGROUND: The F11 Receptor (F11R; aka JAM-A, JAM-1) is a cell adhesion protein present constitutively on the membrane surface of circulating platelets and within tight junctions of endothelial cells (ECs). Previous reports demonstrated that exposure of ECs to pro-inflammatory cytokines causes insertion of F11R molecules into the luminal surface of ECs, ensuing with homologous interactions between F11R molecules of platelets and ECs, and a resultant adhesion of platelets to the inflamed ECs. The main new finding of the present report is that the first step in this chain of events is the de-novo transcription and translation of F11R molecules, induced in ECs by exposure to inflammatory cytokines. METHODS: The experimental approach utilized isolated, washed human platelet suspensions and cultured human venous endothelial cells (HUVEC) and human arterial endothelial cells (HAEC) exposed to the proinflammatory cytokines TNF-alpha and/or IFN-gamma, for examination of the ability of human platelets to adhere to the inflamed ECs thru the F11R. Our strategy was based on testing the effects of the following inhibitors on this activity: general mRNA synthesis inhibitors, inhibitors of the NF-kappaB and JAK/STAT pathways, and small interfering F11R-mRNA (siRNAs) to specifically silence the F11R gene. RESULTS: Treatment of inflamed ECs with the inhibitors actinomycin, parthenolide or with AG-480 resulted in complete blockade of F11R- mRNA expression, indicating the involvement of NF-kappaB and JAK/STAT pathways in this induction. Transfection of ECs with F11R siRNAs caused complete inhibition of the cytokine-induced upregulation of F11R mRNA and inhibition of detection of the newly- translated F11R molecules in cytokine-inflamed ECs. The functional consequence of the inhibition of F11R transcription and translation was the significant blockade of the adhesion of human platelets to inflamed ECs. CONCLUSION: These results prove that de novo synthesis of F11R in ECs is required for the adhesion of platelets to inflamed ECs. Because platelet adhesion to an inflamed endothelium is crucial for plaque formation in non-denuded blood vessels, we conclude that the de-novo translation of F11R is a crucial early step in the initiation of atherogenesis, leading to atherosclerosis, heart attacks and stroke.

Relationship of Body Mass Index With Outcomes After Transcatheter Aortic Valve Replacement: Results From the National Cardiovascular Data-STS/ACC TVT Registry.

OBJECTIVE: To investigate the relationship of body mass index (BMI) with short- and long-term outcomes after transcatheter aortic valve replacement (TAVR). PATIENTS AND METHODS: The relationship between BMI and baseline characteristics and procedural characteristics was assessed for 31,929 patients who underwent TAVR between November 1, 2011, and March 31, 2015, from the STS/ACC TVT Registry. Registry data on 20,429 patients were linked to the Centers for Medicare and Medicaid Services to assess the association of BMI with 30-day and 1-year mortality using multivariable Cox proportional hazards models. The effect of BMI on mortality was also assessed with BMI as a continuous variable. Restricted cubic regression splines were used to model the effect of BMI and to determine appropriate cut points of BMI. RESULTS: Among 31,929 patients, 806 (2.5%) were underweight (BMI, <18.5 kg/m2), 10,755 (33.7%) had normal weight (BMI, 18.5- 24.9 kg/m2), 10,691 (33.5%) were overweight (BMI, 25.0-29.9 kg/m2), 5582 (17.5%) had class I obesity (BMI, 30.0-34.9 kg/m2), 2363 (7.4%) had class II obesity (BMI, 35.0-39.9 kg/m2), and 1732 (5.4%) had class III obesity (BMI, ≥40 kg/m2). Patients in various BMI categories were different in most baseline and procedural characteristics. On multivariable analysis, compared with normal-weight patients, underweight patients had higher mortality at 30 days and at 1 year after TAVR (hazard ratio [HR], 1.35; 95% CI, 1.02-1.78 and HR, 1.41; 95% CI, 1.17-1.69, respectively), whereas overweight patients and those with class I and II obesity had a decreased risk of mortality at 1 year (HR, 0.88; 95% CI, 0.81-0.95, HR, 0.80; 95% CI, 0.72-0.89, and HR, 0.84; 95% CI, 0.72-0.98, respectively). For BMI of 30 kg/m2 or less, each 1-kg/m2 increase was associated with a 2% and 4% decrease in the risk of 30-day and 1-year mortality, respectively; for BMI greater than 30 kg/m2, a 1-kg/m2 increase was associated with a 3% increased risk of 30-day mortality but not with 1-year mortality. CONCLUSION: Results of this large registry study evaluating the relationship of BMI and outcomes after TAVR support the existence of an obesity paradox among patients with severe aortic stenosis undergoing TAVR.

Red cell distribution width (RDW) as a predictor of long-term mortality in patients undergoing percutaneous coronary intervention.

Red cell distribution width (RDW) has been shown to be an independent predictor of mortality in patients with coronary artery disease and in patients with heart failure. The current study evaluated the prognostic utility of RDW in patients undergoing percutaneous coronary intervention (PCI). We evaluated 859 patients who underwent PCI during January 2003 to August 2005. After a median follow up of four (interquartile range 3.1 to 4.4) years, there were a total of 95 (11%) deaths. RDW was analysed as a categorical variable with empirically determined cut points of 13.3 and 15.7 (low RDW <13.3, medium RDW > or = 13.3 to <15.7, high RDW > or = 15.7) based on differences in hazard ratio (HR) for death among RDW deciles. In univariate analysis, higher RDW was a significant predictor of mortality (p < 0.001). In multivariate analysis there was a significant two-way interaction between RDW and haemoglobin (Hgb). RDW was not an independent predictor of mortality in patients with Hgb <10.4. However, among patients with Hgb >10.4, high RDW was a strong and independent predictor of mortality. For patients with Hgb > or = 10.4 to <12.7, HR for death in patients with high RDW relative to low RDW was 5.2 (95% confidence intervals [CI]: 2.0-13.3). For patients with Hgb > or = 12.7, HR for death in patients with high RDW relative to low RDW was 8.6 (CI:2.8-28.6). Higher RDW was a strong and independent predictor of long-term mortality in patients undergoing PCI who were not anaemic at baseline.

Long-term mortality after bolus-only administration of abciximab, eptifibatide, or tirofiban during percutaneous coronary intervention.

OBJECTIVE: To evaluate the long-term mortality after bolus-only administration of abciximab, eptifibatide, and tirofiban during percutaneous coronary intervention (PCI). BACKGROUND: Studies on platelet glycoprotein IIb/IIIa receptor inhibitors (GPI) administered as bolus-only during PCI suggest that this strategy may be similar in efficacy, safer, and more cost-effective compared to a bolus plus infusion of GPI. METHODS: We evaluated 864 patients (abciximab = 274, eptifibatide = 361, and tirofiban = 229) who underwent PCI with a bolus-only regimen during January 2003 to August 2005. RESULTS: After a median follow up of four (interquartile range, 3-4.5) years, there were a total of 95 (11%) deaths. The survival rate was 83% in the abciximab group, 91% in the eptifibatide group, and 93% in the tirofiban group (P = 0.003 by log-rank test). After adjustment for baseline clinical and procedural characteristics using a Cox proportional hazards model, the abciximab group had a significantly higher mortality compared to the eptifibatide group (P = 0.003; Hazard ratio (HR) for eptifibatide compared to abciximab was 0.49 (95% confidence intervals [CI]: 0.30-0.78). The long-term mortality was not significantly different in the tirofiban group compared to the abciximab group (P = 0.33) or the eptifibatide group (P = 0.20), perhaps because of shorter follow-up period and fewer patients in the tirofiban group. CONCLUSION: When given as bolus-only during PCI, eptifibatide may improve long-term survival compared to abciximab.

Isolation, sequencing, and functional analysis of the TATA-less murine ATPase II promoter and structural analysis of the ATPase II gene.

The P-type Mg2+-ATPase, termed ATPase II (Atp8a1), is a putative aminophospholipid transporting enzyme, which helps to maintain phospholipid asymmetry in cell membranes. In this project we have elucidated the organization of the mouse ATPase II gene and identified its promoter. Located within chromosome 5, this gene spans about 224 kb and consists of 38 exons, three of which are alternatively spliced (exons 7, 8 and 16), giving rise to two transcript variants. Translation of these transcripts results in two ATPase II isoforms (1 and 2) composed of 1164 and 1149 amino acids, respectively. Using RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) we identified multiple transcription start sites (TSS) in messages obtained from heart, lung, liver, and spleen. The mouse ATPase II promoter is TATA-less and lacks a consensus initiator sequence. Luciferase reporter analysis of full and core promoters revealed strong activity and little cell type specificity, possibly because more flanking, regulatory sequences are required to cause such tissue specificity. In the neuronal HN2, N18, SN48 cells and the NIH3T3 fibroblast cells, but not in the B16F10 melanoma cells, the core promoter (-318/+193 with respect to the most common TSS) displayed significantly higher activity than the full promoter (-1026/+193). Serial 5' deletion of the core promoter revealed significant cell type-specific activity of the fragments, suggesting differential expression and use of transcription factors in the five cell lines tested. Additionally distribution of the TSS was organ specific. Such observations suggest tissue-specific differences in transcription initiation complex assembly and regulation of ATPase II gene expression. Information presented here form the groundwork for further studies on the expression of this gene in apoptotic cells.

Baseline plasma adiponectin levels as a predictor of left ventricular systolic dysfunction in patients referred for coronary angiography.

The objective of the present study was to determine the association between plasma adiponectin and left ventricular (LV) systolic function. Baseline plasma adiponectin was measured in 389 patients undergoing coronary angiography for a variety of indications at a Veterans Affairs Medical Center. Detailed demographic, clinical, laboratory, and angiographic data were available for patients. LV systolic function was assessed using ventriculography, and patients were grouped into those with normal or mild dysfunction (ejection fraction > or =45%) versus those with moderate to severe systolic dysfunction (ejection fraction <45%). After adjusting for a variety of clinically relevant covariates known to affect LV systolic function, adiponectin was independently associated with LV systolic function in the entire cohort of patients (p = 0.0002) using multivariate linear regression analysis. In addition, using multivariate logistic regression analysis, adiponectin was an independent predictor of the presence of moderate to severe LV dysfunction (odds ratio 1.54, 95% confidence interval 1.21 to 1.97, p = 0.0005). Moreover, baseline adiponectin was also independently associated with LV function in both the myocardial infarction (MI) and non-MI subpopulations of patients (p = 0.0401 and p= 0.0023, respectively). Finally, in the non-MI subpopulation, baseline adiponectin was an independent predictor of moderate to severe LV systolic dysfunction (odds ratio 1.52, 95% confidence interval 1.15 to 2.02, p = 0.0034). In conclusion, baseline plasma adiponectin was an independent predictor of LV systolic dysfunction in a population of patients referred for coronary angiography.

Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography.

OBJECTIVE: Our objective was to evaluate the prognostic value of baseline plasma RANTES levels in patients with known or suspected coronary artery disease. RANTES is a chemokine produced by a variety of cell types including platelets that has been implicated in atherosclerosis. METHODS AND RESULTS: Baseline plasma RANTES levels were measured in 389 male patients undergoing coronary angiography at a Veterans Affairs Medical Center. The patients were followed-up prospectively for the occurrence of cardiac mortality and myocardial infarction. Follow-up data at 24 months were available for 97% of patients. In the entire cohort of patients, low baseline RANTES levels were an independent predictor of cardiac mortality. For cardiac death at 24 months, the survival rate was 87.3% in the lowest tertile of RANTES values, compared with 94% in the upper 2 tertiles combined (P=0.0298 by log rank test). Furthermore, when patients were risk-stratified into those with and without an acute coronary syndrome, RANTES was an independent predictor of both cardiac mortality and myocardial infarction in those without an acute coronary syndrome. Finally, RANTES was also an independent predictor of cardiac mortality in the diabetic subset. CONCLUSIONS: In a cohort of male patients undergoing coronary angiography, low baseline plasma RANTES levels are an independent predictor of cardiac mortality.

Brugada Pattern in Diabetic Ketoacidosis: A Case Report and Scoping Study.

Brugada syndrome is a rare cardiac arrhythmia which is associated with right bundle branch block pattern (RBBB) and ST-segment elevation in right precordial leads. SCNA5 mutation is the most common genetic abnormality associated with Brugada syndrome. Brugada pattern not related to genetic mutations has been previously reported in the setting of fever, metabolic conditions, lithium use, marijuana and cocaine abuse, ischemia and pulmonary embolism, myocardial and pericardial diseases. Multiple isolated cases of Brugada pattern associated with diabetic ketoacidosis (DKA) have been previously reported. We here present a case of type 1 Brugada pattern in a 23 year-old-male who presented with DKA. Brugada pattern in DKA is attributed to acidosis and multiple electrolyte abnormalities including hyperkalemia which alter ion channel expression in the heart thus leading to Brugada pattern which subsequently resolved with treatment of DKA. In such patients, Brugada pattern is not reproducible on procainamide induction cardiac electrophysiology study (EPS). Our scoping study demonstrates male predominance 20/22 cases of (DELETE this highlighted area) Brugada pattern in DKA, a finding that is consistent with prevalence of this disease among males.

Overview of Impella and mechanical devices in cardiogenic shock.

INTRODUCTION: Cardiogenic shock (CS) is a life-threatening condition associated with significant morbidity and mortality. The Impella (Abiomed Inc.) is an axial flow pump on a pigtail catheter that is placed across the aortic valve to unload the left ventricle by delivering non-pulsatile blood flow to the ascending aorta. It is used for high-risk percutaneous coronary intervention and CS. AREAS COVERED: Percutaneous mechanical support devices are placed in a minimally invasive manner and provide life-saving assistance. We review Impella and other percutaneous devices such as intra-aortic balloon pump, TandemHeart, and extracorporeal membrane oxygenation (ECMO) and the evidence supporting their use in the setting of CS. EXPERT COMMENTARY: Impella has been proven to be safe and may be superior to other mechanical support devices in CS.

Usefulness of Complement C1q to Predict 10-Year Mortality in Men With Diabetes Mellitus Referred for Coronary Angiography.

The complement system consists of a family of proteins that play a critical role in the innate immune system. Complement activation has been implicated in many chronic inflammatory diseases, including atherosclerosis. However, a number of experimental studies have highlighted a beneficial role of component C1q in early atherosclerosis and in diabetes mellitus (DM). Despite these data, there have been no studies that have specifically examined the utility of plasma complement C1q as a clinical biomarker in patients with known or suspected coronary artery disease. In this study, baseline plasma complement C1q levels were measured in 159 men with DM who were referred for coronary angiography and who were followed up prospectively for the development of all-cause mortality for 10 years. After adjustment for baseline clinical, angiographic, and laboratory parameters, reduced plasma complement C1q levels were an independent predictor of all-cause mortality at 10 years (hazard ratio 0.66, 95% confidence interval 0.52 to 0.84, p = 0.0006). In additional multivariate models that adjusted for a variety of biomarkers with established prognostic efficacy, complement C1q remained an independent predictor of all-cause mortality at 10 years. In conclusion, reduced levels of complement C1q are associated with an increased risk of all-cause mortality at 10 years in patients with DM referred for coronary angiography. Furthermore, this association is independent of a variety of clinical, angiographic, laboratory variables, including biomarkers with established prognostic efficacy in the prediction of adverse cardiovascular outcomes.

Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Diabetic and Non-Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Diabetic patients account for an increasing number of patients undergoing percutaneous coronary intervention (PCI). However, diabetes mellitus (DM) is associated with increased residual platelet activity during dual antiplatelet treatment (DAPT) and DM patients have worse clinical outcomes after PCI as compared to non-DM. OBJECTIVE: To evaluate efficacy and safety of short duration DAPT (S-DAPT) and long duration DAPT (L-DAPT) after drug eluting stent (DES) implantation in DM and non-DM patients. METHODS: We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the effect of S-DAPT versus L-DAPT after DES implantation in DM and non-DM patients. Efficacy endpoints were all-cause mortality, cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), target vessel revascularization (TVR), and composite end point of net adverse clinical events (NACE) (all-cause mortality, cardiac mortality, MI, ST, TVR, stroke, major bleeding). Safety endpoints were major bleeding and stroke. Event rates were compared using a forest plot of relative risk using a random effects model. RESULTS: We included eight RCTs that randomized 28,318 patients to S-DAPT versus L-DAPT (8234 DM and 20,084 non-DM). S-DAPT was associated with an increased rate of ST in non-DM patients [3.67 (2.04, 6.59)]. There was no significant difference in the rate of all-cause mortality, cardiac mortality, ST, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in DM patients [1.19 (0.72-1.95); 1.25 (0.69, 2.25); 1.52 (0.70, 3.29); 1.33 (0.88, 2.01); 1.39 (0.89, 2.17); 0.92 (0.19, 4.42); 0.98 (0.29, 3.28); and 0.94 (0.57, 1.54) respectively]. Further, there was no significant difference in the rate of all-cause mortality, cardiac mortality, MI, TVR, major bleeding, stroke and NACE with S-DAPT and L-DAPT in non-DM patients [0.93 (0.58, 1.48); 0.75 (0.42, 1.35); 1.52 (0.81, 2.83); 0.99 (0.71, 1.39); 0.72 (0.28, 1.84); 1.01 (0.40, 2.56); and 1.01 (0.77, 1.32) respectively]. CONCLUSION: Compared to L-DAPT, S-DAPT was associated with significant increase in rate of ST in non-DM patients. Duration of DAPT had no significant impact on rates of all-cause mortality, cardiac mortality, MI, ST and TVR among DM patients.

The F11 receptor (F11R/JAM-A) in atherothrombosis: overexpression of F11R in atherosclerotic plaques.

F11R is the gene name for an adhesion protein, called the F11-receptor, aka JAM-A, which under normal physiological conditions is expressed constitutively on the surface of platelets and localized within tight junctions of endothelial cells (EC). Previous studies of the interactions between human platelets and EC suggested that F11R/JAM-A plays a crucial role in inflammatory thrombosis and atherosclerosis. The study reported here obtained in-vivo confirmation of this conclusion by investigating F11R/JAM-A protein and mRNA in patients with aortic and peripheral vascular disease and in an animal model of atherosclerosis. Molecular and immunofluorescence determinations revealed very high levels of F11R/JAM-A mRNA and F11R/JAM-A protein in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with 12-week-old atherosclerosis-prone apoE-/- mice, an age in which atherosclerotic plaques are well established. Enhanced expression of the F11R/JAM-A message in cultured EC from human aortic and venous vessels was observed following exposure of the cells to cytokines. Determinations of platelet adhesion to cultured EC inflamed by combined cytokine treatment in the presence of F11R/JAM-A - antagonists provided data indicating that de novo expression of F11R/JAM-A on the luminal surface of inflamed EC has an important role in the conversion of EC to a thrombogenic surface. Further studies of these interactions under flow conditions and under in-vivo settings could provide a final proof of a causal role for F11R/JAM-A in the initiation of thrombosis. Based on our in-vitro and in-vivo studies to date, we propose that therapeutic drugs which antagonize the function of F11R/JAM-A should be tested as novel means for the prevention and treatment of atherosclerosis, heart attacks and stroke.

Usefulness of the serum complement component C4 as a predictor of stroke in patients with known or suspected coronary artery disease referred for coronary angiography.

The complement system has been implicated in the pathogenesis of atherosclerosis. In addition, complement activation and complement-mediated brain injury have been found in a variety of central nervous system diseases, including stroke. However, there are limited data about the value of complement components for prediction of stroke. Complement C3 and C4 levels, in addition to a variety of established biomarkers, were measured in 389 men with known or suspected coronary artery disease referred for coronary angiography for a variety of indications at a Veterans Affairs Medical Center. Patients were followed prospectively for the development of stroke, which was defined and classified according to criteria of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). All strokes were confirmed with magnetic resonance imaging or computed tomography. For the 97% of patients in whom 24-month follow-up data were available, there were 23 strokes (5.9%). By multivariate Cox proportional hazard analysis, complement C4 was an independent predictor of stroke, with a hazard ratio of 1.57 (95% confidence interval 1.03 to 2.39, p = 0.0358). The 24-month stroke-free survival rate for the patients whose complement C4 levels were equal to or below the median value for the entire cohort was 96.1% compared with 90.1% for patients whose complement C4 levels were above the median value, p = 0.0127 by log rank test). In conclusion, in a cohort of men across a spectrum of risk referred for coronary angiography, a single baseline determination of serum complement C4 level is an independent predictor of the future development of stroke.

Usefulness of baseline plasma myeloperoxidase levels as an independent predictor of myocardial infarction at two years in patients presenting with acute coronary syndrome.

Baseline plasma myeloperoxidase (MPO) levels have been shown to independently predict the early risk of myocardial infarction (MI) in patients presenting with chest pain. In addition, baseline MPO levels have been demonstrated to predict the development of adverse cardiac events up to 6 months after an acute coronary syndrome (ACS). However, in contrast to other biomarkers, there are no data about the long-term independent predictive value of baseline MPO values in patients with ACS. The present study investigated the long-term prognostic significance of baseline MPO levels in a well-characterized cohort of 193 men with ACS who were referred for coronary angiography at a Veterans Administration Medical Center. All patients were followed prospectively for the development of death and MI, and follow-up data were available for all patients at 24 months. After controlling for different baseline clinical, laboratory, and angiographic variables, baseline plasma MPO values were a strong and independent predictor of MI at 24 months by multivariate analysis. Using the median MPO value of the entire cohort of patients (i.e., 20.34 ng/ml) as a prespecified cutoff, the MI-free survival at 24 months for the group whose baseline MPO values were < or =20.34 ng/ml was 88% compared with 74% in those whose values were >20.34 ng/ml (p = 0.0249 by log-rank test). In conclusion, these data demonstrate that baseline MPO levels independently predict MI at 2 years in patients with ACS.

Relation of baseline plasma phospholipid levels to cardiovascular outcomes at two years in men with acute coronary syndrome referred for coronary angiography.

In addition to cholesterol and triglycerides, plasma also contains phospholipids. The choline-containing phospholipids constitute >90% of total plasma phospholipids. To date, no studies have looked specifically at the prognostic significance of total phospholipids in patients with known or suspected coronary artery disease. The present study investigated the long-term prognostic significance of total choline-containing phospholipid levels in a well-characterized cohort of 193 men with acute coronary syndromes who were referred for coronary angiography at a Department of Veterans Affairs Medical Center. All patients were followed prospectively for the development of vascular outcomes. After controlling for a variety of baseline variables (including established biomarkers such high-sensitivity C-reactive protein and fibrinogen), plasma phospholipid values (analyzed as a continuous variable) were a strong and independent predictor of each of the individual end points of all-cause mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41 to 0.90, p = 0.0126), cardiac mortality (HR 0.49, 95% CI 0.29 to 0.81, p = 0.0057), and myocardial infarction (HR 0.71, 95% CI 0.52 to 0.98, p = 0.0342) when using a Cox proportional-hazards model. In addition, baseline phospholipid values were also an independent predictor of the composite outcome of all-cause mortality, fatal or nonfatal myocardial infarction, or stroke (HR 0.66, 95% CI 0.49 to 0.90, p = 0.0075). In conclusion, these data demonstrate that low baseline levels of total choline-containing phospholipid are a strong and independent predictor of cardiovascular outcomes (including mortality) in patients with acute coronary syndromes.

Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin.

We hypothesized that direct thrombin inhibition could attenuate platelet activation and release of soluble CD40 ligand (sCD40L), a marker of inflammation, during percutaneous coronary intervention (PCI). To assess platelet function under flow conditions with bivalirudin versus unfractionated heparin (UFH), we employed the cone and plate(let) analyzer (CPA) assay in drug-spiked blood samples from volunteers (n = 3) in vitro, and then in PCI patients who received bivalirudin alone (n = 20), UFH alone (n = 15), and clopidogrel pretreatment plus bivalirudin (n = 15). Scanning electron microscopy was employed to image bivalirudin or UFH-treated platelets to determine whether platelet function observations had a morphologic explanation. Enzyme immunoassay was used to measure sCD40L levels in PCI patients. In vitro, bivalirudin decreased platelet surface coverage; UFH increased platelet surface coverage. In PCI patients, bivalirudin alone decreased platelet surface coverage, UFH alone increased platelet surface coverage, and clopidogrel pretreatment plus bivalirudin additively reduced platelet surface coverage. Unlike UFH, bivalirudin did not activate platelets in SEM studies. Bivalirudin alone or coupled with clopidogrel significantly reduced plasma sCD40L in PCI patients. In conclusion, our findings suggest that under flow conditions, bivalirudin alone or coupled with clopidogrel may have an antiplatelet effect versus UFH alone during PCI. These data suggest that bivalirudin and UFH may confer an anti-inflammatory effect by reducing sCD40L during PCI.

Fibrinolytic agents for the management of ST-segment elevation myocardial infarction.

Rapid reperfusion is the key treatment goal in patients with ST-segment elevation myocardial infarction (STEMI). The American College of Cardiology-American Heart Association (ACC-AHA) 2004 guidelines for the management of STEMI include recommendations for pharmacologic reperfusion with use of fibrinolytic agents. Fibrinolytic agents are the preferred pharmacologic class for the management of STEMI because of their ability to achieve reperfusion and to restore blood flow when administered within 12 hours of symptom onset. Four fibrinolytic agents are approved for the treatment of STEMI in the United States-streptokinase, alteplase, reteplase, and tenecteplase. Several clinical trials have demonstrated the beneficial effects of these therapies in reducing mortality rates in patients with suspected acute myocardial infarction. Alteplase is administered as an intravenous infusion. However, the relatively long half-lives of reteplase and tenecteplase enable bolus administration, which may be more convenient and less time consuming. Reteplase is administered as a double bolus, and dosing does not depend on the patient's weight; tenecteplase is administered as a single bolus, and dosing is weight based. Adherence to the ACC-AHA guidelines, as well as knowledge about the available fibrinolytic agents, is essential for physicians and pharmacists to make informed decisions regarding appropriate pharmacologic reperfusion strategies.

Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

To evaluate the efficacy and safety of long-duration dual antiplatelet therapy (L-DAPT) compared to short-duration dual antiplatelet therapy (S-DAPT) after drug-eluting stent implantation. We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials assessing the clinical effect of L-DAPT vs S-DAPT after drug-eluting stent. Efficacy end points were all-cause mortality, cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), and target vessel revascularization (TVR). Safety end points were TIMI major bleeding and stroke. Event rates were compared using a random-effects model. We identified 11 randomized controlled trials in which 33,520 patients were randomized to S-DAPT (N = 16,687) and L-DAPT (n = 16,833), respectively. Compared with L-DAPT, S-DAPT was associated with higher rate of MI and lower rate of TIMI major bleeding (1.40 [1.08-1.81] and 0.60 [0.41-0.89], respectively), without any significant differences in the rate of all-cause mortality, cardiac mortality, ST, TVR, and stroke (0.88 [0.75-1.04], 0.98 [0.79-1.22], 1.54 [0.95-2.50], 0.99 [0.73-1.34], and 1.01 [0.78-1.32], respectively). Our results showed that compared with L-DAPT, S-DAPT was associated with higher rate of MI and lower rate of major bleeding without any significant difference in the rates of all-cause mortality, cardiac mortality, ST, TVR, and stroke.

Usefulness of Plasma Tissue Inhibitor of Matrix Metalloproteinase-4 to Predict Death and Myocardial Infarction in Patients With Diabetes Mellitus Referred for Coronary Angiography.

TIMP-4 is the newest member of a family of secreted proteins known as the tissue inhibitors of metalloproteases that selectively inhibit matrix metalloproteases. TIMP-4 is abundantly expressed in human cardiovascular structures and has been implicated in cardiovascular disease. Furthermore, it has also been shown to be a novel target of peroxisome proliferator-activated receptor gamma in rat smooth muscle cells, suggesting a potential role in diabetes mellitus as well. However, there have been no studies that have specifically examined the utility of baseline plasma TIMP-4 levels for the prediction of long-term adverse cardiovascular outcomes. In this study, baseline plasma TIMP-4 levels were measured in 162 male patients with diabetes mellitus who were referred for coronary angiography and followed prospectively for the development of all-cause mortality and enzymatically confirmed myocardial infarction (MI) out to 5 years. After adjustment for a variety of baseline clinical, angiographic and laboratory parameters, plasma TIMP-4 levels were an independent predictor of all-cause mortality (hazard ratio 1.60, 95% CI 1.13 to 2.26; p = 0.0082) and MI (hazard ratio 1.61, 95% CI 1.19 to 2.18; p = 0.0021) at 5 years. Furthermore, in additional multivariate models that adjusted for a variety of biomarkers with established prognostic efficacy, TIMP-4 remained an independent predictor of adverse outcomes. In conclusion, elevated levels of TIMP-4 are associated with an increased risk of long-term all-cause mortality and MI in patients with diabetes mellitus referred for coronary angiography. Moreover, this association is independent of a variety of clinical, angiographic, and laboratory variables, including biomarkers with established prognostic efficacy in the prediction of adverse cardiovascular outcomes.