Mingyuan Shao

Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

CONTEXT 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. OBJECTIVE 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. RESULTS 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. CONCLUSION 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.

Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol: A Randomized Controlled Trial

CONTEXT Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins. OBJECTIVE To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. INTERVENTIONS Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. MAIN OUTCOME MEASURES The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment. RESULTS The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed. CONCLUSIONS Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01105975.

Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival.

OBJECTIVES The purpose of this study was to determine patient compliance and effectiveness of antiarrhythmic treatment by the wearable cardioverter-defibrillator (WCD). BACKGROUND Effectiveness of the WCD for prevention of sudden death is dependent on event type, patient compliance, and appropriate management of ventricular tachycardia/ventricular fibrillation (VT/VF). METHODS Compliance and events were recorded in a nationwide registry of post-market release WCDs. Survival, using the Social Security Death Index, was compared with survival in implantable cardioverter-defibrillator (ICD) patients. RESULTS Of 3,569 patients wearing the WCD (age 59.3+/-14.7 years, duration 52.6+/-69.9 days), daily use was 19.9+/-4.7 h (>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 of 76 (100%) for unconscious VT/VF and 79 of 80 (99%) for all VT/VF. Eight patients died after successful conversion of unconscious VT/VF (89.5% survival 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, 3,541 of 3,569 patients (99.2%) survived overall. Survival occurred in 72 of 80 (90%) VT/VF events and 78 of 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. CONCLUSIONS Compliance was satisfactory with 90% wear time in >50% of patients and low sudden death mortality during use. Survival was comparable to that of ICD patients. However, asystole was an important cause of mortality in sudden cardiac arrest events.

Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial

Background— Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality. Methods and Results— We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001). Conclusions— In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation

Background—Pulmonary vein isolation (PVI) for atrial fibrillation 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 periprocedural anticoagulation in PVI. Methods and Results—A total of 999 consecutive patients undergoing PVI were included; 376 patients were on dabigatran (150 mg), and 623 patients were on warfarin with therapeutic international normalized ratio. Dabigatran was held 1 to 2 doses before 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% versus 3.9%; P=0.59) and after (3.2% versus 4.1%; P=0.53) matching. Major hemorrhage occurred in 1.1% versus 1.6% (P=0.48) before and 1.2% versus 1.5% (P=0.74) after matching in the dabigatran versus warfarin group, respectively. A single thromboembolic event occurred in each of the dabigatran and warfarin groups. Despite higher doses of intraprocedural heparin, the mean activated clotting time was significantly lower in patients who held dabigatran for 1 or 2 doses than those on warfarin. Conclusions—Our study found no evidence to suggest a higher risk of thromboembolic or hemorrhagic complications with use of dabigatran for periprocedural anticoagulation in patients undergoing PVI compared with uninterrupted warfarin therapy.

Left atrial epicardial adiposity and atrial fibrillation.

Background—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). Conclusions—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.

Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease

Background— 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, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 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 appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15). Conclusions— Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.

Clinical Outcomes of Patients With Diabetic Nephropathy Randomized to Clopidogrel Plus Aspirin Versus Aspirin Alone (A post hoc Analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA] Trial)

No prospective randomized trial has specifically examined the long-term outcomes of clopidogrel use in patients with chronic kidney disease. This study aimed to determine the risks and benefits of long-term clopidogrel administration in patients with diabetic nephropathy, the most common form of chronic kidney disease. We performed a post hoc analysis of the CHARISMA trial, which randomly assigned patients without active acute coronary syndrome, but with established atherosclerotic disease (symptomatic) or multiple risk factors for atherosclerotic disease (asymptomatic), to clopidogrel plus aspirin versus placebo plus aspirin. All CHARISMA patients (n = 15,603) were separated into the 3 groups: nondiabetic patients, diabetic patients without nephropathy, and diabetic patients with nephropathy. Within each group, outcomes of patients randomly assigned to clopidogrel were compared with those of patients randomly assigned to placebo. Outcomes in the prespecified CHARISMA subgroups of asymptomatic and symptomatic patients were also compared with respect to study drug assignment and nephropathy status. Patients with nephropathy who received clopidogrel had no difference in bleeding, but experienced significantly increased cardiovascular (CV) and overall mortality compared with those randomly assigned to placebo. There were no differences in bleeding, overall mortality, or CV mortality for nondiabetic or diabetic patients without nephropathy who received clopidogrel versus placebo. In the asymptomatic cohort, patients with nephropathy randomly assigned to clopidogrel had significantly increased overall and CV mortality compared with placebo, whereas asymptomatic patients without nephropathy randomly assigned to clopidogrel had no significant mortality difference compared with placebo. In conclusion, this post hoc analysis suggested that clopidogrel may be harmful in patients with diabetic nephropathy. Additional studies are needed to investigate this possible interaction.

Clinical Predictors of Plaque Progression Despite Very Low Levels of Low-Density Lipoprotein Cholesterol

OBJECTIVES The purpose of this study was to characterize the determinants of plaque progression despite achieving very low levels of low-density lipoprotein cholesterol (LDL-C). BACKGROUND Despite achieving very low levels of LDL-C, many patients continue to demonstrate disease progression and have clinical events. METHODS A total of 3,437 patients with coronary artery disease underwent serial intravascular ultrasound examination in 7 clinical trials. Patients who achieved an on-treatment LDL-C level of <or=70 mg/dl (n = 951) were stratified as progressors (n = 200) and nonprogressors (n = 751) and compared. RESULTS Despite achieving LDL-C <or=70 mg/dl, >20% of patients continued to progress. There were no demographic differences between groups. Progressors demonstrated higher baseline levels of glucose (117.1 +/- 42.5 mg/dl vs. 112.1 +/- 40.0 mg/dl, p = 0.02), triglycerides (157.5 mg/dl vs. 133.0 mg/dl, p = 0.004), and a smaller decrease of apolipoprotein B (-25.1 +/- 3.4 mg/dl vs. -27.4 +/- 3.35 mg/dl, p = 0.01) at follow-up. Multivariable analysis revealed that independently associated risk factors of progression in patients with LDL-C <or=70 mg/dl included baseline percent atheroma volume (p = 0.001), presence of diabetes mellitus (p = 0.02), increase in systolic blood pressure (p = 0.001), less increase in high-density lipoprotein cholesterol (p = 0.01), and a smaller decrease in apolipoprotein B levels (p = 0.001), but not changes in C-reactive protein (p = 0.78) or LDL-C (p = 0.84). CONCLUSIONS Residual risk factors are associated with the likelihood of disease progression in patients who achieve very low LDL-C levels. In addition, the association between apolipoprotein B and atheroma progression highlights the potential importance of LDL particle concentration in patients with optimal LDL-C control. This finding highlights the need for intensive modification of global risk in patients with coronary artery disease.

C-Reactive Protein, but not Low-Density Lipoprotein Cholesterol Levels, Associate With Coronary Atheroma Regression and Cardiovascular Events After Maximally Intensive Statin Therapy

Background— Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina). The association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy is unknown. Methods and Results— The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in the change from baseline of percent atheroma volume on intravascular ultrasound, CRP-modulating effects, or MACE rates, thus allowing for a (prespecified) post hoc analysis to test associations between the changes in CRP levels with coronary disease progression and MACE. Patients with nonincreasing CRP levels (n=621) had higher baseline (2.3 [1.1–4.7] versus 1.1 [0.5–1.8] mg/L; P<0.001) and lower follow-up CRP levels (0.8 [0.5–1.7] versus 1.6 [0.7–4.1] mg/L; P<0.001) versus those with increasing CRP levels (n=364). Multivariable analysis revealed a nonincreasing CRP level to independently associate with greater percent atheroma volume regression (P=0.01). Although the (log) change in CRP did not associate with MACE (hazard ratio, 1.18; 95% confidence interval, 0.93–1.50; P=0.17), the (log) on-treatment CRP associated significantly with MACE (hazard ratio, 1.28; 95% confidence interval, 1.04–1.56; P=0.02). On-treatment low-density lipoprotein cholesterol levels did not correlate with MACE (hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.45). Conclusions— Following 24 months of potent statin therapy, on-treatment CRP levels associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT000620542.