ABSTRACTBackground and AimsFemoral artery access is widely used despite recent increase in radial access for percutaneous coronary interventions (PCI). Femoral artery closure devices are used to shorten vascular closure time and reduce bleeding. We sought to examine sex‐based outcomes of femoral artery vascular closure devices (VCD) in patients undergoing PCI.MethodsWe identified patients who had undergone PCI (n = 11,415) in the Indiana University Health Multicenter Cardiac Cath registry using femoral artery access. Clinical outcomes were compared between VCD and manual compression and analyzed according to sex. Patients with cardiogenic shock and left ventricular support devices were excluded.ResultsThe use of any vascular closure device as compared to femoral artery manual compression was associated with a reduction in 72‐h bleeding events (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.46–0.87). With manual compression, women had higher rates of 72‐h bleeding as compared to men (4.5% vs. 1.6%, p < 0.001). Women demonstrated greater absolute risk reduction in 72‐h bleeding events with use of VCD as compared to men (2.8% vs. 0.8%, p < 0.001). For women, VCD were associated with lower risk of access site bleeding (OR: 0.43; 95% CI: 0.24–0.8), hematoma (OR: 0.36; 95% CI: 0.2–0.63), and vascular complications (OR: 0.25, 95% CI: 0.09–0.72). Use of VCD was associated with lower risk of in‐hospital death (adjusted OR: 0.4; 95% CI: 0.28–0.58; p < 0.001) in multivariable regression analysis.ConclusionWomen derive more benefit from use of femoral artery VCD during PCI than men with greater reduction in bleeding rates, access site hematoma, and vascular complications.

ABSTRACT:Unfractionated heparin is the most common anticoagulant used during percutaneous coronary intervention. Practice guidelines recommend an initial weight-based heparin bolus dose between 70 and 100 U/kg to achieve target activated clotting time (ACT) of 250-300 seconds. The impact of severe obesity on weight-based heparin dosing is not well studied. We performed a retrospective analysis of 424 patients undergoing percutaneous coronary intervention who received heparin for anticoagulation. We collected detailed data on cumulative heparin administration and measured ACT values in this cohort. We performed separate analyses to identify clinical predictors that may affect dose-response curves. There was significant variability in dosing with mean dose of 103.9 ± 32-U/kg heparin administered to achieve target ACT ≥ 250 seconds. Women received higher initial heparin doses when adjusted for weight than men (97.6 ± 31 vs. 89 ± 28 U/kg, P = 0.004), and only 49% of patients achieved ACT ≥ 250 s with the initial recommended heparin bolus dose (70-100 U/kg). Lower heparin dose (U/kg) was required in obese patients to achieve target ACT. In multivariate linear regression analysis with ACT as dependent variable, after inclusion of weight-based dosing for heparin, body mass index was the only significant covariate. In conclusion, there is significant variability in the therapeutic effect of heparin, with a lower weight-adjusted heparin dose required in obese patients.

Background:Femoral arterial access remains widely used despite recent increase in radial access for cardiac catheterization and percutaneous coronary intervention (PCI). Various femoral artery closure devices have been developed and are commonly used to shorten vascular closure times, with variable rates of vascular complications observed in clinical trials. We sought to examine the rates of contemporary outcomes during diagnostic catheterization and PCI with the most common femoral artery closure devices. Methods:We identified patients who had undergone either diagnostic catheterization alone (n = 14,401) or PCI (n = 11,712) through femoral artery access in the Indiana University Health Multicenter Cardiac Cath registry. We compared outcomes according to closure type: manual compression, Angio-Seal, Perclose, or Mynx. Access complications and bleeding outcomes were measured according to National Cardiovascular Data ​Registry standard definitions. Results:The use of any vascular closure device as compared to manual femoral arterial access hold was associated with a significant reduction in vascular access complications and bleeding events in patients who underwent PCI. No significant difference in access-site complications was observed for diagnostic catheterization alone. Among closure devices, Perclose and Angio-Seal had a lower rate of hematoma than Mynx. Conclusions:The use of femoral artery access closure devices is associated with a reduction in vascular access complication rates as compared to manual femoral artery compression in patients who undergo PCI.

Bioprosthetic tissue valve thrombosis is a rare entity.1Incidence is likely enhanced but unknown in the setting of Protein S Deficiency. 61 year-old male with Protein S Deficiency with recurring venous thromboembolism post bioprosthetic aortic valve (pericardial tissue valve) 13 months prior

Background High plasma fibrin clot strength (MA) measured by thrombelastography (TEG) is associated with increased risk of cardiac events after percutaneous coronary interventions (PCIs). Factor XIIIa (FXIIIa) cross-links soluble fibrin, shortens clot formation time (TEG-K), and increases final clot strength (MA). Methods We analyzed platelet-poor plasma from patients with previous PCI. Kaolin-activated TEG (R, K, MA) in citrate platelet-poor plasma and FXIIIa were measured (n = 257). Combined primary endpoint was defined as recurrent myocardial infarction (MI) or cardiovascular death (CVD). Relationship of FXIIIa and TEG measurements on cardiac risk was explored. Results FXIIIa correlated with TEG-MA (p = 0.002) and inversely with TEG-K (p < 0.001). High MA (≥35.35 mm; p = 0.001), low K (<1.15 min; p = 0.038), and elevated FXIIIa (≥83.51%; p = 0.011) were associated with increased risk of CVD or MI. Inclusion of FXIIIa activity and low TEG-K in risk scores did not improve risk prediction as compared with high TEG-MA alone. Conclusion FXIIIa is associated with higher plasma TEG-MA and low TEG-K. High FXIIIa activity is associated with a modest increase in cardiovascular risk after PCI, but is less sensitive and specific than TEG-MA. Addition of FXIIIa does not provide additional risk stratification beyond risk associated with high fibrin clot strength phenotype measured by TEG.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.

Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16-24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P<0.001) and increasing BMI (P=0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 +/- 623 vs. 2184 +/- 576 dyn/cm(2), P<0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P=0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration. Blood Coagul Fibrinolysis 24:321-326 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

Background The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo- clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent. Methods Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow® P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)*2 and *3 and PON1 (Q192R) polymorphisms was performed. Results Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased-function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose. Conclusion CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on-treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response.

Introduction: Clopidogrel inhibits ADP mediated platelet aggregation through inhibition of the P2Y12 receptor by its active metabolite. Thrombin induces platelet aggregation by binding to protease activated receptor-1 (PAR-1), and inhibition of PAR-1 has been evaluated in patients treated with clopidogrel to reduce ischemic events after acute coronary syndromes. Residual PAR-1 mediated platelet aggregation may be dependent on extent of clopidogrel response.Material and Methods: Platelet aggregation was measured in 55 patients undergoing elective PCI at 16-24 hours after 600 mg clopidogrel loading dose by light transmittance aggregometry using ADP 20 mu M and thrombin receptor agonist peptide (TRAP) at 15 mu M and 25 mu M as agonists. Genomic DNA was genotyped for common CYP2C19 variants.Results: Increasing quartiles of 20 mu M ADP induced platelet aggregation after clopidogrel loading were associated with increasing levels of TRAP mediated platelet aggregation. Patients in the highest quartile (clopidogrel non-responders) of post treatment ADP aggregation had significantly higher TRAP mediated aggregation than the patients in the lowest quartile (clopidogrel responders) [TRAP 15 mu M: 79.6 +/- 5% vs. 69.5 +/- 8%, p<0.001].Conclusions: Non-responders to clopidogrel show increased residual platelet aggregation induced by TRAP, whereas clopidogrel responders exhibit attenuated response to TRAP. Addition of PAR-1 antiplatelet drugs may be most effective in patients with reduced clopidogrel response and high residual TRAP mediated platelet aggregation. (C) 2012 Elsevier Ltd. All rights reserved.

Objective. To compare the incidence of contrast-induced nephropathy (CIN) and vascular complications in patients undergoing cardiac catheterization using traditional manual contrast injection techniques with those in which an automated contrast injector device was used. Background. It has been suggested that use of automated contrast injectors in coronary interventions could reduce complications by reducing contrast volume usage and allowing the use of smaller sheaths. Methods. This was a retrospective cohort study with review of patient's electronic medical charts and the Heartbase registry. Complete data were available for 13107 patients between 1999 and 2009. Of those patients, 5137 procedures were performed with traditional manual contrast injection and 7970 procedures used automated contrast injection. The CIN event rate and vascular complication rates were compared between patients who underwent catheterization using these differing techniques. Results. Overall, the incidence of CIN was comparable in traditional and automated contrast injector assisted catheterizations (9.07% vs 8.73%; P=.5). However, for the subgroup of patients that had a diagnostic cardiac catheterization and went on to have an ad hoc angioplasty, incidence of CIN was much lower in the automated contrast injector group (7.04% vs 5.50%; P=.007). The incidence of vascular complications was lower in the automated contrast injector group vs the traditional method (2.85% vs 2.17%; P=.02), irrespective of an ad hoc angioplasty. Conclusion. Use of automated contrast injectors resulted in a significant decrease in vascular complications across all cardiac catheterizations. Additionally, there was a significant decrease in CIN when the automated contrast injector was used for catheterizations that included a percutaneous coronary intervention. J INVASIVE CARDIOL 2012; 24(12): 628-630

Idiopathic giant cell myocarditis is a rare condition with a poor prognosis. Patients with giant cell myocarditis typically die of refractory ventricular arrhythmias or progressive congestive heart failure in about 3 months. The benefit of immunosuppressive therapy varies among patients with giant cell myocarditis, and no factors that would predict which patients will respond to therapy have been identified. Mechanical circulatory support devices, from intra-aortic balloon pumps to more permanent systems, have been used for ventricular support in cases of acute heart failure.Herein, we describe a case of giant cell myocarditis in a previously healthy 44-year-old woman who presented with cardiogenic shock. She was supported hemodynamically with the Impella Recover LP 2.5 left ventricular assist device until a permanent device could be surgically implanted. To our knowledge, this is the 1st reported case of the successful use of the Impella device for hemodynamic support in a patient with giant cell myocarditis until more definitive treatment could be instituted.

The peri-operative risk for patients with coronary drug-eluting stents (DES) who subsequently have non-cardiac surgery (NCS) is unclear. We performed this retrospective study of all patients in our institution who had coronary intervention and subsequent NCS from 2003 through December 2008 to evaluate the incidence of major adverse cardiac events (MACE) in patients who received DES compared to those who received bare-metal stents (BMS) or had percutaneous transluminal coronary angioplasty (PTCA) during the same time period. The main outcome measures were 30-day post-operative myocardial infarction, stent thrombosis, target vessel revascularization (TVR) and cardiac death. During the 6-year study period, 1,770 coronary interventions were performed and 238 patients subsequently had NCS in 8 days to 49 months. Eighteen patients had PTCA, 79 BMS and 141 DES. Acute myocardial infarction occurred in 1 patient who had PTCA, 2 who had BMS and 14 who had DES (p = 0.10). Stent thrombosis occurred in 6 patients who had DES and none who had BMS (p = 0.09). Seven patients who had DES had TVR compared to 1 patient who had BMS and none who had PTCA (p = 0.41). Cardiac mortality occurred in 2 patients who had DES and none who had PTCA or BMS (p = 0.35). In conclusion, the 30-day MACE in patients who received coronary DES and undergone NCS were not significantly different compared to those who received BMS or had PTCA only, with a trend toward higher stent thrombosis in the DES group.

Study Objective. To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement.Design. Population-based, retrospective cohort study.Data Source. National medical and pharmacy benefit claims database comprising approximately 19 million members.Patients. A total of 16,690 patients who had undergone PCI with stent placement and who were highly adherent to clopidogrel therapy alone (9862 patients) or to clopidogrel with a PPI (6828 patients) between October 1, 2005, and September 30, 2006.Measurements and Main Results. The primary end point was the occurrence of a major adverse cardiovascular event during the 1.2 months after stent placement. These events were defined as hospitalization for a cerebrovascular event (stroke or transient ischemic attack), an acute coronary syndrome (myocardial infarction or unstable angina), coronary revascularization (PCI or coronary artery bypass graft), or cardiovascular death. A composite event rate was compared between patients who received clopidogrel alone and those who received concomitant clopidogrel-PPI therapy. Baseline differences in covariates were adjusted by using Cox proportional hazards models. In the 9862 patients receiving clopidogrel alone, 1766 (17.9%) experienced a major adverse cardiovascular event compared with 1710 patients (25.0%) who received concomitant clopidogrel-PPI therapy (adjusted hazard ratio 1.51, 95% confidence interval 1.39-1.64, p<0.0001). Similar associations of increased risk were observed for each PPI studied (omeprazole, esomeprazole, pantoprazole, and lansoprazole).Conclusion. Concomitant use of a PPI and clopidogrel compared with clopidogrel alone was associated with a higher rate of major adverse cardiovascular events within 1 year after coronary stent placement.

BACKGROUND:The management strategy for hypertrophic obstructive cardiomyopathy generally begins with medical therapy. When this fails to control symptoms, consideration is given to mechanically eliminate the obstruction caused by a thickened and bulging interventricular septum to blood flowing out of the left ventricle. The literature is abundant with data about the safety and efficacy of both surgical myectomy and the newer and now more widely utilized percutaneous alcohol septal ablation procedure. Many cases of successful surgical myectomy performed on patients with recurrent or residual symptoms following percutaneous septal ablation have been published. However, there remains a paucity of information available to the clinician faced with a patient with recurrent or residual symptoms after undergoing surgical myectomy.METHODS:We were faced with a series of 2 such patients who presented to our institution after presumed successful myectomy. Both patients had a recurrence of symptoms and a large gradient across the left ventricular outflow tract. Both patients were offered percutaneous alcohol ablation after failure of medical therapy.RESULTS:Excellent results clinically and echocardiographically were achieved in both patients, with complete symptom relief reported at follow up.CONCLUSION:We offer a review of the literature to date and believe our experience demonstrates that percutaneous alcohol septal ablation is an acceptable option that should be offered to patients who have recurrent or incomplete relief of symptoms following presumed successful surgical myectomy.

Cardiomyopathy is a major cause of death in patients with systemic amyloidosis. There are several forms of systemic amyloidosis which cause cardiomyopathy and determination of the exact type of amyloid in each affected patient is essential for treatment and determination of prognosis. In this study, we tested the feasibility of determining the type of amyloidosis by biochemical analysis of endomyocardial biopsies. Right ventricular endomyocardial biopsies were obtained from 10 patients with restrictive cardiomyopathy. Three patients had monoclonal protein demonstrated in serum or urine and all three had bone marrow findings consistent with monoclonal gammopathy. Seven patients had isolated cardiomyopathy without evidence of monoclonal gammopathy. A portion of each myocardial biopsy was submitted for histologic evaluation and all demonstrated amyloid by Congo red staining. Each biopsy was analysed biochemically by isolation of amyloid fibrils and the protein characterised by amino acid sequence analysis. Four amyloid isolates were characterised as immunoglobulin light chain proteins. Two specimens obtained from patients with transthyretin (TTR) DNA mutations contained TTR peptides proving the hereditary nature of the disease. Biopsies from four patients without a TTR mutation contained TTR and were consistent with the diagnosis of senile cardiac amyloidosis (SCA). All endomyocardial biopsy specimens that were analysed had sufficient amyloid fibril subunit protein to allow characterisation by amino acid sequence analysis. This methodology is particularly useful in differentiating SCA with TTR amyloid fibrils from immunoglobulin light chain amyloidosis which also occurs in the elderly age group.

Background— Stent thrombosis (ST) is an uncommon but serious complication of drug-eluting and bare metal stents. To assess drug-eluting stent ST in contemporary practice, we analyzed 2-year data from the 7492-patient ARRIVE registry. Methods and Results— Patients were enrolled at the initiation of percutaneous coronary intervention with no inclusion/exclusion criteria beyond use of the paclitaxel-eluting TAXUS stent. Two-year follow-up was 94% with independent adjudication of major cardiac events. A second, autonomous committee adjudicated Academic Research Consortium (ARC) definite/probable ST. Cumulative 2-year ARC-defined ST was 2.6% (1.0% early ST [<30 days], 0.7% late ST [31 to 365 days], and 0.8% very late ST [>1 year]). Simple-use (single-vessel and single-stent) cases had lower rates than expanded use (broader patient/lesion characteristics, 2-year cumulative: 1.4% versus 3.3%, P <0.001; early ST: 0.4% versus 1.4%, P <0.001; late ST: 0.5% versus 0.8%, P =0.14; very late ST: 0.4% versus 1.0%, P =0.008). Within 7 days of ST, 23% of patients died; 28% suffered Q-wave myocardial infarction. Mortality was higher with early ST (39%) than late ST (12%, P <0.001) or very late ST (13%, P <0.001). Multivariate analysis showed anatomic factors increased early ST (lesion >28 mm, lesion calcification) and late ST (vessel <3.0 mm); biological factors increased very late ST (renal disease, prior brachytherapy). Although early ST (71.4%) and very late ST (23.1%) patients had dual antiplatelet therapy at the time of ST, premature thienopyridine discontinuation was a strong independent predictor of both. Conclusions— The relative risks of early and late ST differ. Knowledge of ST risk for specific subgroups may guide revascularization options until the completion of randomized trials in these broad populations.