Phosphatase regulatory subunit MYPT2 knockout partially compensates for the cardiac dysfunction in mice caused by lack of myosin light chain kinase 3.

Cardiac contraction is modulated by the phosphorylation state of myosin regulatory light chain 2 (MLC-2v). The level of MLC-2v phosphorylation is dependent on the opposing activities of MLC kinases and phosphatases. The predominant MLC phosphatase found in cardiac myocytes contains Myosin Phosphatase Targeting Subunit 2 (MYPT2). Overexpression of MYPT2 in cardiac myocytes results in a decreased level of MLC phosphorylation, reduced left ventricular contraction, and induction of hypertrophy; however, the effect of knocking out MYPT2 on cardiac function is unknown. We obtained heterozygous mice containing a MYPT2 null allele from the Mutant Mouse Resource Center. These mice were produced in a C57BL/6N background which lack MLCK3, the main regulatory light chain kinase in cardiac myocytes. We found that mice null for MYPT2 were viable and had no obvious phenotypic abnormality when compared to WT mice. Additionally, we determined that WT C57BL/6N mice had a low basal level of MLC-2v phosphorylation, which was significantly increased when MYPT2 was absent. At 12-weeks, MYPT2 KO mice had smaller hearts and showed downregulation of genes involved in cardiac remodeling. Using cardiac echo, we found that 24-week-old male MYPT2 KO mice had decreased heart size with increased fractional shortening compared to their MYPT2 WT littermates. Collectively, these studies highlight the important role that MYPT2 plays in cardiac function in vivo and demonstrate that its deletion can partially compensate for the lack of MLCK3.

PKGIα is activated by metal-dependent oxidation in vitro but not in intact cells.

Type I cGMP-dependent protein kinases (PKGIs) are important components of various signaling pathways and are canonically activated by nitric oxide- and natriuretic peptide-induced cGMP generation. However, some reports have shown that PKGIα can also be activated in vitro by oxidizing agents. Using in vitro kinase assays, here, we found that purified PKGIα stored in PBS with Flag peptide became oxidized and activated even in the absence of oxidizing agent; furthermore, once established, this activation could not be reversed by reduction with DTT. We demonstrate that activation was enhanced by addition of Cu2+ before storage, indicating it was driven by oxidation and mediated by trace metals present during storage. Previous reports suggested that PKGIα Cys43, Cys118, and Cys196 play key roles in oxidation-induced kinase activation; we show that activation was reduced by C118A or C196V mutations, although C43S PKGIα activation was not reduced. In contrast, under the same conditions, purified PKGIß activity only slightly increased with storage. Using PKGIα/PKGIß chimeras, we found that residues throughout the PKGIα-specific autoinhibitory loop were responsible for this activation. To explore whether oxidants activate PKGIα in H9c2 and C2C12 cells, we monitored vasodilator-stimulated phosphoprotein phosphorylation downstream of PKGIα. While we observed PKGIα Cys43 crosslinking in response to H2O2 (indicating an oxidizing environment in the cells), we were unable to detect increased vasodilator-stimulated phosphoprotein phosphorylation under these conditions. Taken together, we conclude that while PKGIα can be readily activated by oxidation in vitro, there is currently no direct evidence of oxidation-induced PKGIα activation in vivo.

[Effects of economic fruit forest planting on the stability of red soil aggregates in the subtropical hilly area]. / 亚热带丘岗区经果林种植对红壤团聚体稳定性的影响.

The stability of aggregates is of great significance to evaluate water and soil environment in regions plan-ting economic fruit forest. We explored the effects of economic fruit forest types on the structure and stability of soil aggregates in the 0-50 cm soil layer from 5-year-old Amygdalus persica, Pyrus sorotina, Citrus reticulata, Camellia oleifera and Actinidia chinensis forests in the hilly area in northern Hunan. The content, distribution characteristics and stability indices of soil aggregates from each economic fruit forest were quantitatively analyzed by the Shavinov method. The results showed that most soil aggregates were mechanically stable, with a minimum content of 92.3%. After wet sieving, the size of water-stable aggregates in the soil from Camellia oleifera forest was mainly >2 mm, accounting for 55.9% of the total aggregates. The 0.25-2 mm aggregates were the dominant particles in the A. persica, P. sorotina, C. reticulata and A. chinensis forest soils, with contributions higher than 43.6%. The mean weight diameter (MWD) and the geometric mean diameter (GMD) of soil aggregates for the five economic fruit forest types ranged from 1.10 to 3.19 mm and 0.61 to 2.28 mm, respectively. Furthermore, the percentages of soil aggregate destruction (PAD) and fractal dimension (D) were in the range of 2.9%-37.3% and 2.30-2.68, respectively. With the increases of soil depth, the stability of soil aggregates from A. persica, C. oleifera and A. chinensis forest soils became worse; MWD and GMD decreased by 1.7%-57.7% and 4.5%-65.8%, respectively; PAD and D increased by 0.4%-17.3% and 1.6%-11.1%, respectively. The effects of economic fruit forest types on the stability of soil aggregates decreased with increasing soil depth. Based on the stability indices, aggregate stability from five economic fruit forests followed the order of C. oleifera > A. chinensis > P. sorotina > C. reticulata > A. persica. The type of economic fruit forest improved the stability of soil structure mainly by affecting the content of large-size aggregates. In terms of improving the distribution and stability of soil aggregates, it was suggested that C. oleifera should be given the top priority as the economic fruit forest in the subtropical hilly area, followed by A. chinensis. Whereas A. persica planting might reduce the degree of soil agglomeration, thus, the protective measures of soil loss should be considered during planting. Our results could provide theoretical basis and application guidance for the development, utilization, and ecological management of economic fruit forests in subtropical hilly areas.

A substitution in cGMP-dependent protein kinase 1 associated with aortic disease induces an active conformation in the absence of cGMP.

Type 1 cGMP-dependent protein kinases (PKGs) play important roles in human cardiovascular physiology, regulating vascular tone and smooth-muscle cell phenotype. A mutation in the human PRKG1 gene encoding cGMP-dependent protein kinase 1 (PKG1) leads to thoracic aortic aneurysms and dissections. The mutation causes an arginine-to-glutamine (RQ) substitution within the first cGMP-binding pocket in PKG1. This substitution disrupts cGMP binding to the pocket, but it also unexpectedly causes PKG1 to have high activity in the absence of cGMP via an unknown mechanism. Here, we identified the molecular mechanism whereby the RQ mutation increases basal kinase activity in the human PKG1α and PKG1ß isoforms. Although we found that the RQ substitution (R177Q in PKG1α and R192Q in PKG1ß) increases PKG1α and PKG1ß autophosphorylation in vitro, we did not detect increased autophosphorylation of the PKG1α or PKG1ß RQ variant isolated from transiently transfected 293T cells, indicating that increased basal activity of the RQ variants in cells was not driven by PKG1 autophosphorylation. Replacement of Arg-177 in PKG1α with alanine or methionine also increased basal activity. PKG1 exists as a parallel homodimer linked by an N-terminal leucine zipper, and we show that the WT chain in WT-RQ heterodimers partly reduces basal activity of the RQ chain. Using hydrogen/deuterium-exchange MS, we found that the RQ substitution causes PKG1ß to adopt an active conformation in the absence of cGMP, similar to that of cGMP-bound WT enzyme. We conclude that the RQ substitution in PKG1 increases its basal activity by disrupting the formation of an inactive conformation.

Long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias after cardiac transplantation: analysis of the UNOS/OPTN cardiac transplant database.

BACKGROUND: Pacemaker-requiring bradyarrhythmias after cardiac transplantation are common, and rarely can lead to sudden cardiac death. Prior outcomes studies have been limited to single-center data. OBJECTIVE: This study sought to define the long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias in the cardiac transplant population. METHODS: This study used multivariable analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database of sequential U.S. cardiac transplant recipients from 1997 to 2007 stratified by postoperative bradyarrhythmias requiring a pacemaker. The primary end point was all-cause mortality. RESULTS: Among 35,987 cardiac transplant recipients (age 46.1 ± 18.3 years, 76% male, 22% bicaval technique) with a follow-up of 6.3 ± 4.7 years, pacemaker-requiring bradyarrhythmias occurred in 3,940 patients (10.9%). Pacemaker recipients demonstrated improved survival (median 8.0 years vs. 5.2 years, P < .001), decreased 5-year mortality (13.8% vs. 17.7%, P < .001), and overall crude mortality (42.9% vs. 45.9%, P < .001). Multivariable propensity-score-adjusted analysis demonstrated improved survival among pacemaker recipients (adjusted hazard ratio 0.84, 95% confidence interval [CI] 0.80 to 0.88, P < .001) after adjustment for donor/recipient age, UNOS listing status, donor heart ischemic time, surgical technique, graft rejection, and other common comorbidities. The bicaval surgical technique was strongly protective against a postoperative pacemaker requirement (odds ratio [OR] 0.33, 95% CI 0.29 to 0.36, P < .001) in multivariable analysis. Among the other variables studied, only increasing donor age (OR 1.04, 95% CI 1.00 to 1.09, P < .001) and recipient age (OR 1.09, 95% CI 1.0 to 1.12, P < .001) were associated with a permanent pacemaker requirement. CONCLUSION: Cardiac transplant recipients with pacemaker-requiring bradyarrhythmias have an excellent long-term prognosis. Increased mortality in the nonpacemaker group merits further investigation. Biatrial surgical technique and increasing donor/recipient age are associated with postoperative pacemaker requirement.

Comparison of rates of progression of coronary atherosclerosis in patients with diabetes mellitus versus those with the metabolic syndrome.

Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 +/- 9.0%, 37.6 +/- 8.9%, and 38.1 +/- 9.1%, p <0.001) and total atheroma volume (198.3 +/- 85.9, 190.7 +/- 85.0, and 186.3 +/- 79.1 mm(3), p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 +/- 174.3 vs 484.4 +/- 160.7 mm(3), p = 0.02), whereas DM was associated with lumen constriction (290.6 +/- 111.7 vs 298.1 +/- 105.5 mm(3), p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 +/- 0.3, +0.3 +/- 0.2, and +0.1 +/- 0.2%, p <0.0001) and total atheroma volume (-1.0 +/- 1.8, -3.3 +/- 1.8, and -4.0 +/- 1.8 mm(3), p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.

Cardiac implantable electronic device infections: presentation, management, and patient outcomes.

BACKGROUND: Indications for cardiac implantable electronic devices (CIEDs) are increasing. Although CIED infections occur infrequently, the impact of this outcome is expected to be substantial. OBJECTIVE: The purpose of this study was to the evaluate the outcome of patients undergoing removal of infected CIEDs. METHODS: A retrospective study was conducted of all patients with proven or suspected infected CIEDs who were referred to the Cleveland Clinic for system removal from January 2002 through March 2007. RESULTS: A total of 412 patients (age 68 +/- 15 years) were included in the study. The majority of patients (241 [59%]) presented with localized infection involving the device pocket. The remaining 171 patients (41%) presented with endovascular infection but no evidence of inflammation of the device pocket. Of the total 414 pathogens isolated, 366 (88%) were aerobic gram-positive organisms, of which 90% were Staphylococcus species, and almost half of these were methicillin resistant. In-hospital mortality was 4.6% (19 patients). Only 2 deaths were extraction related. One-year mortality was 17%. Among the total cohort, 8 (1.9%) patients had relapsing infection within the first year. Among patients who had device replacement during the same hospitalization, 6 (2.6%) had relapsing infections within 1 year of reimplantation; 5 of these patients had systemic symptoms and were bacteremic upon initial presentation. CONCLUSION: CIED infections are most often caused by Staphylococcus species, half of which are methicillin resistant. Percutaneous lead and device removal along with antibiotic therapy are effective as primary interventions. The overall relapse rate is 1.9%, and the relapse rate among patients who had reimplantation during the same hospitalization is 2.6%.

The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis.

BACKGROUND: The mechanism that confers adverse cardiovascular prognosis in patients with the metabolic syndrome (MetS) remains unclear. We sought to investigate the association of MetS and its component risk factors with progression of coronary atherosclerosis. METHODS: We performed a systematic review of 3459 patients who participated in 7 clinical trials that monitored coronary atheroma progression with intravascular ultrasonography. Patients with or without MetS were compared with regard to clinical characteristics, coronary atheroma burden at baseline, and change on serial evaluation. Relationships between plaque progression (> or =5% increase in percent atheroma volume [PAV]), MetS, and its component risk factors were investigated. RESULTS: The metabolic syndrome was highly prevalent and was associated with greater progression of PAV (+0.51% +/- 0.23% vs +0.23% +/- 0.24%; P = .003). Multivariable analysis showed that MetS was associated with a greater likelihood of undergoing progression of PAV (adjusted odds ratio [OR], 1.25; 95% confidence interval [CI], 1.05-1.48; P = .01). When the individual components were used in the model instead of MetS, hypertriglyceridemia (OR, 1.26; 95% CI, 1.06-1.49; P = .008) and a body mass index of 30 or higher (1.18, 1.00-1.40; P = .05) predicted progression of PAV. However, after adjusting for its individual components, MetS was no longer an independent predictor (OR, 1.04; 95% CI, 0.79-1.37; P = .79). CONCLUSION: Although accelerated disease progression is observed in the setting of MetS, this is owing to the presence of individual component risk factors rather than to the presence of the syndrome itself.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk.

BACKGROUND: Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk. METHODS AND RESULTS: Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels. CONCLUSIONS: In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.

The relation between extent of coronary artery disease measured by quantitative coronary angiography and changes in lipid profile: insights from trials of atherosclerosis regression.

BACKGROUND: While favorable changes in atherogenic lipids are indisputably associated with improved clinical outcomes, a similar correlation with quantitative coronary angiography (QCA) parameters is more difficult to document. OBJECTIVE: To assess the relation between changes in lipid profile and parameters of coronary artery disease (CAD) extent measured by QCA. METHODS: We evaluated 1,315 patients enrolled in trials of atherosclerosis regression and correlated their lipid profile with annualized changes in CAD score (average minimal lumen diameter for all segments evaluated), cumulative stenosis score (sum of stenoses for all segments evaluated) and average plaque area for all segments evaluated. RESULTS: During the study, average low-density lipoprotein (LDL) decreased by 28% (p < 0.001), and average high-density lipoprotein (HDL) increased by 8% (p < 0.001). There was no statistical correlation between annualized changes in CAD score and change in LDL (p = 0.31) or % change in LDL (p = 0.53). There was also no statistically significant correlation between change in cumulative stenosis score and change in LDL (p = 0.20) or % change in LDL (p = 0.10). Neither of these parameters of CAD extent correlated with the summation of % changes in LDL and HDL (p = 0.80 and p = 0.34, respectively). Patients with CAD regression (i.e., greater average MLD at follow up, n = 756) had similar LDL, HDL and C-reactive protein levels while on therapy as patients with CAD progression (n = 555). CONCLUSIONS: Detailed analysis of CAD extent by QCA did not reveal a significant association with changes in lipid profile. These findings challenge the use of QCA as a surrogate endpoint for the effect of antiatherosclerotic therapy.

Prognostic value of electrocardiographic measurements before and after cardiac resynchronization device implantation in patients with heart failure due to ischemic or nonischemic cardiomyopathy.

Postimplant QRS narrowing may predict clinical response after cardiac resynchronization therapy (CRT), but identification of nonresponders remains difficult. We studied the predictive value of electrocardiographic characteristics for mortality or cardiac transplantation in patients after CRT. Patients who had electrocardiograms available for review from before and after CRT device implantation were identified from a clinical database. Bivariate and multivariate Cox regression analyses were performed for the end point of death or transplantation. Of 337 patients (age 65+/-12 years, 76% men, left ventricular ejection fraction 22+/-12%, pre-QRS 175+/-30 ms), 84 died and 7 underwent transplantation during a follow-up of 27+/-15 months. Variables predictive of death or transplantation included QRS increase after CRT (45% vs 32%, p=0.03), older age, higher New York Heart Association class, lower left ventricular ejection fraction, and higher tertile of postimplant QRS (p=0.04), but not preimplant rhythm, QRS duration, or QRS morphology. After adjusting for confounding variables, independent predictors of mortality were older age (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.00 to 1.05, p=0.04), lack of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (HR 2.17, 95% CI 1.16 to 4.08, p<0.02), and longer postimplant QRS by tertile (HR 1.50, 95% CI 1.09 to 2.05, p=0.01). In conclusion, wider QRS after CRT device implantation is an independent predictor of mortality or transplantation. In patients with increased QRS durations despite CRT, closer follow-up or reassessment for alternative management strategies may be warranted.

Clopidogrel and aspirin versus aspirin alone for the prevention of stroke in patients with a history of atrial fibrillation: subgroup analysis of the CHARISMA randomized trial.

BACKGROUND: Aspirin offers modest reduction in stroke in patients with atrial fibrillation. Whether combination of aspirin with clopidogrel offers additional protection is unclear. METHODS: Post-hoc subgroup analysis of 593 participants with a history of atrial fibrillation in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) randomized trial testing clopidogrel 75 mg per day plus aspirin (75-162 mg per day) vs. aspirin alone in patients with stable cardiovascular disease or multiple cardiovascular risk factors. RESULTS: Mean patient age was 70 years, 78% were men, and hypertension, heart failure and diabetes were present in 78, 20 and 44%, respectively. During a median follow-up of 2.3 years, stroke (ischemic and hemorrhagic) occurred in 15 of 298 assigned to clopidogrel plus aspirin and in 14 of 285 given aspirin alone (hazard ratio, HR, 1.03, 95% CI 0.49-2.1). There was no difference in all-cause mortality (HR 1.1, 95% CI 0.6-1.9) or in the composite of stroke, myocardial infarction, or vascular death (HR = 1.2, 95% CI 0.7-2.0). Severe/fatal extracranial hemorrhage occurred in 6 patients with combination vs. 3 with aspirin alone. CONCLUSIONS: This post-hoc subgroup analysis does not support the use of this combination over aspirin alone in patients with a history of atrial fibrillation pending results of ongoing larger randomized trials.

Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.

OBJECTIVES: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD). BACKGROUND: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied. METHODS: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD. RESULTS: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004). CONCLUSIONS: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1; NCT00050817).

Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.

CONTEXT: Statins reduce low-density lipoprotein cholesterol (LDL-C) levels and slow progression of coronary atherosclerosis. However, no data exist describing the relationship between statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and disease progression. OBJECTIVE: To investigate the relationship between changes in LDL-C and HDL-C levels and atheroma burden. DESIGN, SETTING, AND PATIENTS: Post-hoc analysis combining raw data from 4 prospective randomized trials (performed in the United States, North America, Europe, and Australia between 1999 and 2005), in which 1455 patients with angiographic coronary disease underwent serial intravascular ultrasonography while receiving statin treatment for 18 months or for 24 months. Ultrasound analysis was performed in the same core laboratory for all of the studies. MAIN OUTCOME MEASURE: Relationship between changes in lipoprotein levels and coronary artery atheroma volume. RESULTS: During statin therapy, mean (SD) LDL-C levels were reduced from 124.0 (38.3) mg/dL (3.2 [0.99] mmol/L) to 87.5 (28.8) mg/dL (2.3 [0.75] mmol/L) (a 23.5% decrease; P<.001), and HDL-C levels increased from 42.5 (11.0) mg/dL (1.1 [0.28] mmol/L) to 45.1 (11.4) mg/dL (1.2 [0.29] mmol/L) (a 7.5% increase; P<.001). The ratio of LDL-C to HDL-C was reduced from a mean (SD) of 3.0 (1.1) to 2.1 (0.9) (a 26.7% decrease; P<.001). These changes were accompanied by a mean (SD) increase in percent atheroma volume from 39.7% (9.8%) to 40.1% (9.7%) (a 0.5% [3.9%] increase; P = .001) and a mean (SD) decrease in total atheroma volume of 2.4 (23.6) mm3 (P<.001). In univariate analysis, mean levels and treatment-mediated changes in LDL-C, total cholesterol, non-HDL cholesterol, apolipoprotein B, and ratio of apolipoprotein B to apolipoprotein A-I were significantly correlated with the rate of atherosclerotic progression, whereas treatment-mediated changes in HDL-C were inversely correlated with atheroma progression. In multivariate analysis, mean levels of LDL-C (beta coefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (beta coefficient, -0.26 [95% confidence interval, -0.41 to -0.10]) remained independent predictors of atheroma regression. Substantial atheroma regression (> or =5% reduction in atheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-C greater than the mean (7.5%; P<.001). No significant differences were found with regard to clinical events. CONCLUSIONS: Statin therapy is associated with regression of coronary atherosclerosis when LDL-C is substantially reduced and HDL-C is increased by more than 7.5%. These findings suggest that statin benefits are derived from both reductions in atherogenic lipoprotein levels and increases in HDL-C, although it remains to be determined whether the atherosclerotic regression associated with these changes in lipid levels will translate to meaningful reductions in clinical events and improved clinical outcomes.

Antihypertensive therapy and regression of coronary artery disease: insights from the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) and Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation (NORMALISE) trials.

BACKGROUND: In patients with coronary artery disease (CAD), therapies designed to prevent clinical events are not always associated with significant reduction in coronary obstruction, as measured by quantitative coronary angiography. We set out to explore the relationship between quantitative coronary angiography parameters, baseline characteristics, and clinical events in a large trial of CAD regression with antihypertensive agents. METHODS AND RESULTS: Patients randomized to amlodipine, enalapril, or placebo in the CAMELOT trial were followed for 24 months for major ischemic events. Among 431 patients participating in the angiographic and intravascular ultrasound substudy NORMALISE, 298 (99 amlodipine, 96 enalapril, and 103 placebo) had complete angiographic and intravascular ultrasound data. The patients did not differ significantly with respect to baseline characteristics (except for diabetes) or extent of CAD. After 24 months, the change in minimal lumen diameter (MLD) was -0.02 +/- 0.13 for amlodipine, -0.03 +/- 0.12 for enalapril, and -0.03 +/- 0.17 mm for placebo (P = .40). Major ischemic events occurred in 20.2%, 24%, and 25.2%, respectively (P = .68). There was no significant correlation between change in MLD and age, sex, statin therapy, or systolic blood pressure at baseline. The change in MLD did not differ in patients with and without cardiovascular events, regardless of treatment assignment (P = .54). Only the extent of CAD was independently predictive of ischemic events. CONCLUSION: As compared to placebo, amlodipine treatment resulted in fewer ischemic events after 24 months of therapy, but the clinical benefit was not associated with a commensurate improvement in arterial lumen dimensions.

The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.

OBJECTIVES: We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI). BACKGROUND: A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes. METHODS: We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events. RESULTS: In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013). CONCLUSIONS: The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.

Outcomes of patients with acute coronary syndromes who are treated with bivalirudin during percutaneous coronary intervention: an analysis from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial.

BACKGROUND: The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition is not inferior to heparin plus GPIIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. The extent to which this applies to patients with acute coronary syndromes (ACS) is unclear. Therefore, we sought to determine if bivalirudin has similar efficacy in ACS patients as compared with "stable" patients in the REPLACE-2 trial. METHODS: We analyzed the outcomes of ACS patients compared with stable patients and the outcomes of ACS patients according to whether or not they had received bivalirudin, including the economic costs. The trial enrolled 1351 ACS patients (myocardial infarction within 7 days or unstable angina within 48 hours, but not on ongoing GPIIb/IIIa or heparin therapy) and 4554 stable patients. RESULTS: Patients with ACS had a similar rate of death or myocardial infarction at 30 days compared to stable patients (7.2% vs 6.7%, P = .51) and death at 1 year (1.6% vs 2.2%, P = .169), but a higher rate of urgent coronary artery bypass graft at 30 days (1.0% vs 0.3%, P = .002). Patients with ACS treated with bivalirudin had a similar rate of 30-day death, myocardial infarction, or urgent revascularization compared with ACS patients treated with heparin and GPIIb/IIIa inhibitors (8.7% vs 8.0%, P = .616) and death at 1 year (1.5% vs 1.8%, P = .701), but a higher rate of revascularization at 6 months (12% vs 8.4%, P = .04). Patients with ACS treated with bivalirudin had less major bleeding than ACS patients treated with heparin and GPIIb/IIIa inhibitors, although this was not statistically significant (2.7% vs 4.5%, P = .07). Mean 30-day costs for patients with ACS were dollar 12415 for those treated with bivalirudin and dollar 12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022). CONCLUSION: Bivalirudin with provisional GPIIb/IIIa inhibitor use in low-risk ACS patients (not receiving preprocedural GPIIb/IIIa blockade) appears to provide similar protection against death and myocardial infarction as the combination of heparin and GPIIb/IIIa inhibitors, although we observed a higher rate of revascularization at 6 months.

Outcome of multivessel coronary intervention in the contemporary percutaneous revascularization era.

Clinical outcomes after multivessel versus single-vessel percutaneous coronary intervention (PCI) in the era of stents, glycoprotein IIb/IIIa inhibitors, and clopidogrel pretreatment have not been well studied. Thus, we compared outcomes from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET) for patients who underwent multivessel versus single-vessel PCI and separately considered the effect of acute coronary syndromes on the results. Composite clinical outcomes (death, myocardial infarction, and target vessel revascularization) were evaluated at 30 days and 6 months and mortality at 1 year. Safety analysis included in-patient major and minor bleeding. Despite similar baseline characteristics, patients who underwent multivessel PCI (n = 775) had significantly higher 30-day and 6-month composite event rates than did those who were treated in a single coronary artery territory (n = 3,969). This association remained significant at 30 days (hazard ratio 1.57, 95% confidence interval 1.06 to 2.33, p = 0.025) after using propensity matching to minimize confounding factors. The higher event rate was primarily due to an increase in periprocedural myocardial infarction. However, there were no significant differences in propensity-matched ischemic outcomes at 6 months and 1 year or in bleeding. In addition, in a propensity-matched analysis that included 810 patients with acute coronary syndrome, multivessel stenting resulted in numerically more ischemic events than did single-vessel stenting, although this did not reach statistical significance (hazard ratio 1.32, 95% confidence interval 0.85 to 2.05, p = 0.221). In conclusion, multivessel PCI was more often associated with periprocedural myocardial infarction than single-vessel intervention, although this did not translate into higher 1-year mortality. A randomized trial comparing multivessel PCI with staged or surgical revascularization is warranted.

Angiographic adverse events, creatine kinase-MB elevation, and ischemic end points complicating percutaneous coronary intervention (a REPLACE-2 substudy).

Several angiographic adverse events during coronary balloon angioplasty have been associated with increased creatine kinase-MB (CK-MB) enzymes and adverse clinical outcomes. The significance of angiographic adverse events in the stent era has not been widely studied. We analyzed 10 types of angiographic adverse events that were reported in the 6,010-patient Second Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial to determine their relation to CK-MB elevation and clinical ischemic end points after percutaneous coronary intervention (PCI). Angiographic adverse events occurred in 9.1% of REPLACE-2 patients. Most (8 of 10) types of angiographic adverse events were associated with an increased risk of increased CK-MB (p <0.001 for each), and 47% of all patients with an angiographic adverse event developed increased CK-MB. Logistic regression analysis showed that the strongest predictor of death, myocardial infarction, or revascularization at 6 months was the occurrence of an angiographic adverse event during PCI (odds ratio 1.9, 95% confidence interval 1.6 to 2.4, p <0.001). Side branch closure, abrupt closure, any decreased flow during the procedure, angiographic distal embolization, and perforation or tamponade were individual predictors of the occurrence of the combined clinical ischemic end point at 6-month follow-up (p <0.005 for each). In conclusion, most angiographic adverse events during PCI are associated with increased CK-MB and are powerful predictors of adverse clinical events within 6 months.

Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study.

OBJECTIVES: Unfractionated heparin has many shortcomings, including indirect and partial inhibition of thrombin, antibody formation, and platelet activation. Bivalirudin, a short-acting direct thrombin inhibitor, avoids these limitations and has superior outcomes during percutaneous revascularization. This trial was performed to evaluate the safety and efficacy of bivalirudin in off-pump coronary artery bypass grafting. METHODS: An open-label, multicenter randomized trial compared heparin with protamine reversal to bivalirudin in patients undergoing off-pump coronary artery bypass. The primary objective was safety as demonstrated by similar rates of procedural success defined as freedom from a composite of death, myocardial infarction, stroke, and repeat revascularization. Twenty-one institutions randomized 105 patients to receive bivalirudin and 52 patients to receive heparin. RESULTS: The mean age was 65 years for both groups. The bivalirudin group had more grafts: 3.0 +/- 1 versus 2.5 +/- 1. Procedural success rates at 30 days were identical in bivalirudin- and heparin-treated patients (93%). Operative times, total blood loss, reoperations for bleeding, and major adverse events were not significantly different. Strokes were more frequent in the heparin group: 5.5% versus 0; P = .05. Mortality was 2% in each group. Repeat revascularization was required in 3% of bivalirudin- and 2% of the heparin-treated patients. CONCLUSIONS: For patients undergoing off-pump coronary artery bypass grafting, bivalirudin was an effective anticoagulant, without excessive bleeding and with a safety profile similar to that of heparin. Further trials are warranted to assess whether anticoagulation with bivalirudin improves clinical outcomes.