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1.  Use of Dabigatran for Peri-Procedural Anticoagulation in Patients Undergoing Catheter Ablation for Atrial Fibrillation 
Pulmonary vein isolation (PVI) for atrial fibrillation (AF) is associated with a transient increased risk of thromboembolic and hemorrhagic events. We hypothesized that dabigatran can be safely used as an alternative to continuous warfarin for the peri-procedural anticoagulation in PVI.
Methods and Results
999 consecutive patients undergoing PVI were included; 376 patients were on dabigatran (150 mg) and 623 were on warfarin with therapeutic INR. Dabigatran was held 1 to 2 doses prior to PVI and restarted at the conclusion of the procedure or as soon as patients were transferred to the nursing floor. Propensity score matching was applied to generate a cohort of 344 patients in each group with balanced baseline data. Total hemorrhagic and thromboembolic complications were similar in both groups, before (3.2% vs 3.9%; p = 0.59), and after (3.2% vs 4.1%; p = 0.53) matching. Major hemorrhage occurred in 1.1% vs 1.6% (p = 0.48) before, and 1.2% vs 1.5% (p = 0.74) after matching in the dabigatran vs warfarin group respectively. A single thromboembolic event occurred in each of the dabigatran and warfarin groups. Despite higher doses of intra-procedural heparin, the mean ACT was significantly lower in patients who held dabigatran for 1 or 2 doses than those on warfarin.
Our study found no evidence to suggest a higher risk of thromboembolic or hemorrhagic complications with use of dabigatran for peri-procedural anticoagulation in patients undergoing PVI compared to uninterrupted warfarin therapy.
PMCID: PMC3688655  PMID: 23553523
anticoagulants; fibrillation; ablation; catheter ablation; stroke
2.  Aggregate National Experience with the Wearable Cardioverter-Defibrillator: Event Rates, Compliance and Survival 
To determine patient compliance and effectiveness of antiarrhythmic treatment by the wearable cardioverter-defibrillator (WCD).
Effectiveness of the WCD for prevention of sudden death is dependent on event type, patient compliance and appropriate management of ventricular tachycardia/fibrillation (VT/VF).
Compliance and events were recorded in a nation-wide registry of post-market release WCDs. Survival, using the Social Security Death Index, was compared with survival in implantable cardioverter-defibrillator (ICD) patients.
Of 3569 patients wearing the WCD (age 59.3±14.7, duration 52.6±69.9 days), daily use was 19.9±4.7 hours (>90% of the day) in 52% of patients. More days of use correlated with higher daily use (p<0.001). Eighty sustained VT/VF events occurred in 59 patients (1.7%). First shock success was 76/76 (100%) for unconscious VT/VF and 79/80 (99%) for all VT/VF. Eight patients died after successful conversion of unconscious VT/VF (survival 89.5% of VT/VF events). Asystole occurred in 23 (17 died), pulseless electrical activity in 2 and respiratory arrest in 1 (3 died), representing 24.5% of sudden cardiac arrests. During WCD use, 3541/3569 patients (99.2%) survived overall. Survival occurred in 72/80 (90%) VT/VF events and 78/106 (73.6%) for all events. Long-term mortality was not significantly different from first ICD implant patients but highest among patients with traditional ICD indications.
Compliance was satisfactory with 90% wear time in >50% of patients and low sudden death mortality during usage. Survival was comparable to that of implantable ICD patients. However, asystole was an important cause of mortality in sudden cardiac arrest events.
PMCID: PMC2962668  PMID: 20620738
Wearable cardioverter defibrillator; Implantable cardioverter defibrillator; Outcomes; Compliance
3.  Left Atrial Epicardial Adiposity and Atrial Fibrillation 
Atrial fibrillation (AF) has been linked to inflammatory factors and obesity. Epicardial fat is a source of several inflammatory mediators related to the development of coronary artery disease. We hypothesized that periatrial fat may have a similar role in the development of AF.
Methods and Results
Left atrium (LA) epicardial fat pad thickness was measured in consecutive cardiac CT angiograms performed for coronary artery disease or AF. Patients were grouped by AF burden: no (n=73), paroxysmal (n=60), or persistent (n=36) AF. In a short-axis view at the mid LA, periatrial epicardial fat thickness was measured at the esophagus (LA-ESO), main pulmonary artery, and thoracic aorta; retrosternal fat was measured in axial view (right coronary ostium level). LA area was determined in the 4-chamber view. LA-ESO fat was thicker in patients with persistent AF versus paroxysmal AF (P=0.011) or no AF (P=0.003). LA area was larger in patients with persistent AF than paroxysmal AF (P=0.004) or without AF (P<0.001). LA-ESO was a significant predictor of AF burden even after adjusting for age, body mass index, and LA area (odds ratio, 5.30; 95% confidence interval, 1.39 to 20.24; P=0.015). A propensity score–adjusted multivariable logistic regression that included age, body mass index, LA area, and comorbidities was also performed and the relationship remained statistically significant (P=0.008).
Increased posterior LA fat thickness appears to be associated with AF burden independent of age, body mass index, or LA area. Further studies are necessary to examine cause and effect, and if inflammatory, paracrine mediators explain this association.
PMCID: PMC2974566  PMID: 20504944
atrial fibrillation; inflammation; obesity; pericardium; tomography
4.  Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk 
Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated.
To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans.
Design, Setting, and Participants
The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity.
Main Outcome Measures
Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD.
The PON1 genotype demonstrated significant dose-dependent associations (QQ192>QR192>RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32–3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09–2.03; P=.01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P<.001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1–5.5; P<.001) and for arylesterase, 2.9 (95% CI, 1.8–4.7; P<.001) and remained independent in multivariate analysis.
This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.
PMCID: PMC3014051  PMID: 18349088
5.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
6.  Protection of Mice Against Rotavirus Challenge following Intradermal DNA Immunization by Biojector Needle-Free Injection 
Vaccine  2007;25(16):3215-3218.
Mucosal administration (intranasal or oral) of a VP6 rotavirus vaccine to mice consistently elicits high levels of protection after rotavirus challenge (93 – >99% reductions in fecal rotavirus shedding) but only when co-administered with an effective adjuvant such as LT(R192G). Here, we showed that Biojector needle-free injection of VP6-encoded plasmids also induced protection (85 – 93%) when they were co-administrated with LT(R192G)-encoded plasmids. A reduction in the amount of VP6 plasmid from 50 to 10 μg reduced protection from 93 to 70%, but the immunized mice remained significantly (P<0.05) protected. Intramuscular needle injection of VP6/LT(R192G)-plasmids also induced significant protection (66%).
PMCID: PMC1906844  PMID: 17280754
Rotavirus; DNA vaccine; needle-free injection
7.  Mice Develop Effective but Delayed Protective Immune Responses When Immunized as Neonates either Intranasally with Nonliving VP6/LT(R192G) or Orally with Live Rhesus Rotavirus Vaccine Candidates 
Journal of Virology  2006;80(10):4949-4961.
Rotavirus vaccines are delivered early in life, when the immune system is immature. To determine the effects of immaturity on responses to candidate vaccines, neonatal (7 days old) and adult mice were immunized with single doses of either Escherichia coli-expressed rotavirus VP6 protein and the adjuvant LT(R192G) or live rhesus rotavirus (RRV), and protection against fecal rotavirus shedding following challenge with the murine rotavirus strain EDIM was determined. Neonatal mice immunized intranasally with VP6/LT(R192G) were unprotected at 10 days postimmunization (dpi) and had no detectable rotavirus B-cell (antibody) or CD4+ CD8+ T-cell (rotavirus-inducible, Th1 [gamma interferon and interleukin-2 {IL-2}]-, Th2 [IL-5 and IL-4]-, or ThIL-17 [IL-17]-producing spleen cells) responses. However, by 28 and 42 dpi, these mice were significantly (P ≥ 0.003) protected and contained memory rotavirus-specific T cells but produced no rotavirus antibody. In contrast, adult mice were nearly fully protected by 10 dpi and contained both rotavirus immunoglobulin G and memory T cells. Neonates immunized orally with RRV were also less protected (P = 0.01) than adult mice by 10 dpi and produced correspondingly less rotavirus antibody. Both groups contained few rotavirus-specific memory T cells. Protection levels by 28 dpi for neonates or adults were equal, as were rotavirus antibody levels. This report introduces a neonatal mouse model for active protection studies with rotavirus vaccines. It indicates that, with time, neonatal mice develop full protection after intranasal immunization with VP6/LT(R192G) or oral immunization with a live heterologous rotavirus and supports reports that protection depends on CD4+ T cells or antibody, respectively.
PMCID: PMC1472046  PMID: 16641286

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