Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

AIMS: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers. METHODS: Study participants were stratified to G143E non-carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*h/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers. CONCLUSIONS: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms.

Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency >0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs, including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), were loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. In addition, A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs, includingL40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), significantly reduced CES1 protein and/or mRNA expression levels in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of the human liver. Neither CES1 expression nor activity was affected by the two haplotypes. In summary, this study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1.

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation.

Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.

Trandolapril, an angiotensin-converting enzyme inhibitor prodrug, needs to be activated by carboxylesterase 1 (CES1) in the liver to exert its intended therapeutic effect. A previous in vitro study demonstrated that the CES1 genetic variant G143E (rs71647871) abolished CES1-mediated trandolapril activation in cells transfected with the variant. This study aimed to determine the effect of the G143E variant on trandolapril activation in human livers and the pharmacokinetics (PKs) and pharmacodynamics (PDs) in human subjects. We performed an in vitro incubation study to assess trandolapril activation in human livers (5 G143E heterozygotes and 97 noncarriers) and conducted a single-dose (1 mg) PK and PD study of trandolapril in healthy volunteers (8 G143E heterozygotes and 11 noncarriers). The incubation study revealed that the mean trandolapril activation rate in G143E heterozygous livers was 42% of those not carrying the variant (p = 0.0015). The clinical study showed that, relative to noncarriers, G143E carriers exhibited 20% and 15% decreases, respectively, in the peak concentration (Cmax ) and area under the curve from 0 to 72 h (AUC0-72 h ) of the active metabolite trandolaprilat, although the differences were not statistically significant. Additionally, the average maximum reductions of systolic blood pressure and diastolic blood pressure in carriers were ~ 22% and 23% less than in noncarriers, respectively, but the differences did not reach a statistically significant level. In summary, the CES1 G143E variant markedly impaired trandolapril activation in the human liver under the in vitro incubation conditions; however, this variant had only a modest impact on the PK and PD of trandolapril in healthy human subjects.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure.

BACKGROUND: Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. METHODS: The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. RESULTS: A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). CONCLUSION: Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

Routine Postprocedure Chest Radiography Is Not Warranted After Right-Heart Catheterization.

PURPOSE: To determine whether routine postprocedure chest radiography is indicated to exclude pneumothorax after outpatient right heart catheterization with or without endomyocardial biopsy. METHODS: This HIPAA-compliant retrospective quality improvement cohort study was approved by the institutional review board. All outpatients from January 1, 2010, to July 1, 2017, who underwent routine postprocedure chest radiography after right heart catheterization with or without endomyocardial biopsy formed the study population (n = 6,036). Subjects were identified by electronic medical record query using Current Procedural Terminology codes. Pneumothorax prevalence was calculated by coded review of chest radiography reports. Size of pneumothorax (if present) and clinical outcome were determined, and 95% confidence intervals (CIs) were calculated. RESULTS: Most (99%) right heart catheterizations were performed using an internal jugular vein approach, as determined by a random sample of 100 subjects. The prevalence of pneumothorax on postprocedure chest radiography reports was 0.1% (7 of 6,036; 95% CI: 0.05%-0.24%). Three of these seven pneumothoraces were confirmed by repeat imaging within 1 hour to be false-positives (ie, no pneumothorax), resulting in a corrected pneumothorax rate of 0.07% (4 of 6,036; 95% CI: 0.00%-0.2%). The remaining four that reported pneumothoraces were less than 1 cm. No chest tubes were placed, and all subjects were discharged home without an unexpected escalation in the level of care. CONCLUSION: In a large cohort of over 6,000 subjects, pneumothorax after right heart catheterization utilizing an internal jugular vein approach was rare and when found was clinically insignificant. False-positives were common. Routine postprocedure chest radiography in this setting is not warranted and is being discontinued at the study institution.

Association of Donor Tricuspid Valve Repair With Outcomes After Cardiac Transplantation.

BACKGROUND: Tricuspid regurgitation after cardiac transplantation is associated with worse clinical outcomes. This study sought to determine the association of donor tricuspid valve repair (dTVR) with outcomes after cardiac transplantation. METHODS: Patients who underwent cardiac transplantation between January 20, 2002, and December 31, 2016, were included. Multivariable Cox regression modeling was performed to determine the association between dTVR and the composite outcome of death, posttransplant TVR, kidney transplant after cardiac transplant, or chronic dialysis, and included propensity scoring to control for baseline differences in likelihood of undergoing dTVR. RESULTS: The analysis included 330 patients, with 173 (52.4%) undergoing dTVR. dTVR performance varied by surgeon and also increased over time, with 71 (83.5%) performed during January 1, 2011, to November 30, 2013. Transplant year and surgeon were significantly associated with the baseline likelihood of undergoing dTVR. Although fewer composite outcomes occurred in the dTVR vs no dTVR group (39 [22.5%] vs 56 [36.4%], p = 0.006), dTVR was not significantly associated with the composite outcome in multivariable modeling. Lower risk for the composite outcome was associated with greater number of biopsies during the first posttransplant year, whereas higher risk was associated with more high-grade biopsy specimens and higher creatinine. CONCLUSIONS: There was no significant benefit or harm with regards to the composite of death, posttransplant TVR, or dialysis associated with dTVR.

Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction.

OBJECTIVES: This study was designed to assess effects of mitral valve annuloplasty (MVA) on mortality in patients with mitral regurgitation (MR) and left ventricular (LV) systolic dysfunction. BACKGROUND: Mitral valve annuloplasty improves hemodynamics and symptoms in these patients, but effects on long-term mortality are not well established. METHODS: We retrospectively analyzed consecutive patients with significant MR and LV systolic dysfunction on echocardiography between 1995 and 2002. Cox regression analysis, including MVA as a time-dependent covariate and propensity scoring to adjust for differing probabilities of undergoing MVA, was used to identify predictors of death, LV assist device implantation, or United Network for Organ Sharing-1 heart transplantation. RESULTS: Of 682 patients identified, 419 were deemed surgical candidates; 126 underwent MVA. Propensity score derivation identified age, ejection fraction, and LV dimension to be associated with undergoing MVA. End points were reached in 120 (41%) non-MVA and 62 (49%) MVA patients. Increased risk of end point was associated with coronary artery disease (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.30 to 2.49), blood urea nitrogen (HR 1.01, 95% CI 1.005 to 1.02), cancer (HR 2.77, 95% CI 1.45 to 5.30), and digoxin (HR 1.66, 95% CI 1.15 to 2.39). Reduced risk was associated with angiotensin-converting enzyme inhibitors (HR 0.65, 95% CI 0.44 to 0.95), beta-blockers (HR 0.59, 95% CI 0.42 to 0.83), mean arterial pressure (HR 0.98, 95% CI 0.97 to 0.99), and serum sodium (HR 0.93, 95% CI 0.90 to 0.96). Mitral valve annuloplasty did not predict clinical outcome. CONCLUSIONS: In this analysis, there is no clearly demonstrable mortality benefit conferred by MVA for significant MR with severe LV dysfunction. A prospective randomized control trial is warranted for further study of mortality with MVA in this population.

Angiotensin-converting enzyme inhibitors and change in aortic valve calcium.

BACKGROUND: Calcium accumulation in the aortic valve is a hallmark of aortic sclerosis and aortic stenosis. Because lipoproteins, angiotensin-converting enzyme, and angiotensin II colocalize with calcium in aortic valve lesions, we hypothesized an association between angiotensin-converting enzyme inhibitor (ACEI) use and lowered aortic valve calcium (AVC) accumulation, as measured by electron beam computed tomography. METHODS: Rates of change in volumetric AVC scores were determined retrospectively for 123 patients who had undergone 2 serial electron beam computed tomographic scans. The mean (+/-SD) interscan interval was 2.5 (+/-1.7) years; 80 patients did not receive ACEIs and 43 received ACEIs. The relationship of ACEI use to median rates of AVC score change (both unadjusted and adjusted for baseline AVC scores and coronary heart disease risk factors) was determined. We also examined the relationship of ACEI use to the likelihood of and adjusted odds ratio for definite progression (AVC change >2 times the median interscan variability). RESULTS: Unadjusted and adjusted median rates of AVC score change were significantly higher in the no-ACEI group than in the ACEI group (adjusted median AVC changes [95% confidence interval]: relative, 28.7%/y [18.9%-38.5%/y] vs 11.0%/y [-1.9% to 24.0%/y], P = .04; absolute: 25.1/y [19.7-30.5/y] vs 12.2/y [4.5-19.9/y], P = .02). The adjusted odds ratio (95% confidence interval) for definite AVC progression was significantly lower for patients who received ACEIs (0.29 [0.11-0.75], P = .01). CONCLUSIONS: This retrospective study finds a significant association between ACEI use and a lower rate of AVC accumulation. The results support the need for prospective, randomized trials of ACEIs in calcific aortic valve disease.

Relation of serum uric acid to cardiovascular disease.

This review summarizes recent published literature on the association between serum uric acid and cardiovascular disease, a relationship which is complex and not fully elucidated. Uric acid may be a marker for risk, a causative agent in cardiovascular disease, or both. Various biologic factors can influence serum uric acid levels, and serum uric acid level itself is closely related to conditions such as hypertension, dyslipidemia, obesity, and impaired glucose metabolism, that contribute to cardiovascular disease pathophysiology. Serum uric acid levels have been found to be associated with adverse outcomes, including mortality, in the general population. In addition, serum uric acid is associated with increased risk for incident coronary heart disease, heart failure, and atrial fibrillation. In the setting of established systolic heart failure, serum uric acid is positively associated with disease severity and mortality risk. Whether targeting treatment based on uric acid levels might affect clinical outcomes is still being studied.

Comparing the Effectiveness of an Axial and a Centrifugal Left Ventricular Assist Device in Ventricular Unloading.

Centrifugal (CFG) and axial flow (AX) left ventricular assist devices have different hydrodynamic properties that may impact the effectiveness of left ventricular unloading. We sought to determine whether patients implanted with the HeartWare HVAD (CFG) and HeartMate II (AX) had a similar degree of hemodynamic support by comparing parameters measured using echocardiography and right heart catheterization. Using our prospectively collected database, we identified 268 patients implanted with the AX and 93 with the CFG. Demographic characteristics were similar between groups. AX patients had a significantly lower INTERMACS score. Baseline ventricular dimension, mitral regurgitation, right ventricular systolic pressure, right atrial pressure, mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance were similar. Wedge pressure was higher, and left ventricular ejection fraction was lower at baseline in the AX. After implantation, there was a greater reduction of right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, and left ventricular internal diameter during diastole in the AX cohort. After implantation, cardiac output by Fick calculation showed a greater improvement in the AX group. These results demonstrate that both AX and CFG devices resulted in left ventricular unloading; however, AX devices may offer advantages in the magnitude of left ventricular unloading, which could have implications in myocardial recovery or reduction in pulmonary vascular resistance before transplantation.

Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2).

OBJECTIVES: The purpose of this study was to examine treatment and outcomes in patients admitted to the hospital with acute myocardial infarction (AMI) complicated by congestive heart failure (CHF). BACKGROUND: Although cardiogenic shock complicating AMI has been studied extensively, the hospital course of patients presenting with CHF is less well established. METHODS: The Second National Registry of Myocardial Infarction (NRMI-2) was analyzed to determine hospital outcomes for patients with ST-elevation AMI admitted with CHF (Killip classes II or III). RESULTS: Of 190,518 patients with AMI, 36,303 (19.1%) had CHF on admission. Patients presenting with CHF were older (72.6 +/- 12.5 vs. 63.2 +/- 13.5 years), more often female (46.8% vs. 32.1%), had longer time to hospital presentation (2.80 +/- 2.6 vs. 2.50 +/- 2.4 h), and had higher prevalence of anterior/septal AMI (38.8% vs. 33.3%), diabetes (33.1% vs. 19.5%), and hypertension (54.6% vs. 46.1%) (all p < 0.0005). Also, they had longer lengths of stay (8.1 +/- 7.1 vs. 6.8 +/- 5.3 days, p < 0.00005) and greater risk for in-hospital death (21.4% vs. 7.2%; p < 0.0005). Patients with CHF were less likely to receive aspirin (75.7% vs. 89.0%), heparin (74.6% vs. 91.1%), oral beta-blockers (27.0% vs. 41.7%), fibrinolytics (33.4% vs. 58.0%), or primary angioplasty (8.6% vs. 14.6%), and more likely to receive angiotensin-converting enzyme inhibitors (25.4% vs. 13.0%). Congestive heart failure on admission was one of the strongest predictors of in-hospital death (adjusted odds ratio 1.68; 95% confidence interval 1.62, 1.75). CONCLUSIONS: Patients with AMI presenting with CHF are at higher risk for adverse in-hospital outcomes. Despite this, they are less likely to be treated with reperfusion therapy and medications with proven mortality benefit.

Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry.

Although small, randomized trials have shown that statin use is associated with decreased risks of mortality and severe rejection, no study has examined statin therapy as used in actual practice in large numbers of heart transplant recipients. We analyzed data from the Heart Transplant Lipid Registry (n = 12 centers). Patients were included if they underwent transplantation between 1995 and 1999, survived >/=30 days after transplantation, and had >/=30 days of Registry follow-up. Multivariable Cox regression models, with propensity scoring performed to adjust for nonrandom allocation of statin therapy, were performed to determine the association of statin therapy with death and fatal rejection. The study included 1,186 patients, with a mean follow-up of 580 +/- 469 days; 937 patients (79%) received statin therapy. Overall, 71 patients (6%) died and 40 (3.4%) had fatal rejection. The statin group had a lower frequency of death (4% vs 13.7%, p <0.0001) and fatal rejection (2.4% vs 7.2%, p = 0.0001). Using multivariable Cox regression, with propensity scoring included to adjust for likelihood of receiving statin therapy, statin use was the only factor associated with lower risk of death (hazard ratio 0.29, 95% confidence interval 0.13 to 0.67) and fatal rejection (hazard ratio 0.27, 95% confidence interval 0.09 to 0.78). This study represents the largest population of heart transplant recipients analyzed for the relation between statin therapy and clinical outcomes in actual practice. Statin therapy was significantly associated with lower risk of death and fatal rejection, benefits that were independent of lipid values.

Brain natriuretic peptide predicts serious cardiac allograft rejection independent of hemodynamic measurements.

BACKGROUND: Serum brain natriuretic peptide (BNP) has been reported to be elevated in heart transplant recipients with both cellular and vascular rejection. Whether BNP can be used to help predict the severity of rejection is not well established. METHODS: We analyzed serial BNP measurements obtained during endomyocardial biopsy procedures in consecutive heart transplant patients occurring >45 days after transplantation. To eliminate potential confounding from prior rejection episodes, we included only observations in which the previous biopsy grade was 0 or 1A. Multivariable linear regression was performed examining the outcome of increasing seriousness of rejection, defined as grade 0 < 1A < 2 < 1B < 3A < vascular rejection. A univariable logistic regression model was performed using log-transformed BNP as a predictor of vascular rejection. RESULTS: There were 77 patients, with 161 separate observations. Median time between transplantation and first assessment was 6.0 months (interquartile range, 2.1, 31.6). Using multivariable linear regression, 3 factors were significantly associated with biopsy score: pulmonary capillary wedge pressure (p < 0.0001), BNP (p = 0.003), and heart rate (p = 0.01). Even after other significant univariable predictors (including pulmonary capillary wedge pressure) were forced into the model, BNP remained a significant predictor of biopsy score (p = 0.02). Log BNP was a significant univariable predictor of vascular rejection, with an odds ratio of 12.55 (per 1 unit increase, 95% confidence interval 3.43-45.84; p = 0.0001) and a model c-statistic of 0.91. CONCLUSIONS: BNP predicts new episodes of serious cardiac allograft rejection, particularly vascular rejection, independent of hemodynamic measurements, and may be a useful part of rejection surveillance.

Gallbladder disease in cardiac transplant patients: a survey study.

HYPOTHESIS: Preemptive cholecystectomy in cardiac transplant patients with radiographic biliary pathology reduces the morbidity and mortality of biliary tract disease following heart transplantation compared with expectant management. DESIGN AND SETTING: Institutional survey at the University of Washington, Seattle. PATIENTS: Cardiac transplant recipients between January 1, 1992, and January 1, 2001. Main Outcome Measure Clinical course of patients who were diagnosed as having biliary tract disease following heart transplantation and were managed expectantly (observed) compared with the course of patients whose conditions were diagnosed and who underwent an operation. RESULTS: Sixty (35.7%) of 168 cardiac transplant patients were evaluated for biliary tract pathologic condition. Of the 71.7% (43 of 60 patients) who had an abnormal radiographic evaluation, 46.5% (20 patients) had surgery on their biliary tract while the other patients were observed. Nine of the 23 patients who were followed up expectantly had cholelithiasis, 7 patients had gallbladder wall thickening, 5 patients had sludge in their gallbladder, and 2 had biliary dilatation. These patients were followed up for a mean +/- SD of 3.7 +/- 1.3 years; none developed biliary tract symptoms during this period. Cholecystectomies were completed for both emergent (7) and elective (14) indications. The mean +/- SD length of stay for patients who had emergent operations was 24.3 +/- 11.2 days, compared with 3.2 +/- 2.8 days for the patients who had elective operations. Seven (33%) of the 21 patients who had an operation had a significant complication and 1 patient died. CONCLUSIONS: These data suggest that the morbidity of an elective cholecystectomy in cardiac transplant patients is significant and equivalent to the morbidity associated with emergent procedures. Expectant management of patients with radiographic evidence of biliary tract pathology discovered after transplantation was safe in this series.

Predictors of repeat revascularization after nonemergent, first percutaneous coronary intervention in the community.

BACKGROUND: We sought to determine the incidence of and risk factors for repeat revascularization after nonemergent, first percutaneous coronary intervention (PCI) performed in contemporary community practice. METHODS: We analyzed a prospective registry of consecutive patients undergoing isolated PCI in the state of Washington. Multivariate Cox regression analysis was used to determine predictors of repeat revascularization (by PCI or bypass surgery) within 1 year after first PCI. RESULTS: Between January 1, 1999, and December 31, 1999, there were 3571 nonemergent first PCIs, 87.7% of which involved stent placement. Repeat revascularization occurred in 577 (16.2%) patients. Repeat revascularization was predicted by multivessel disease (hazard ratio [HR] 1.36, 95% CI 1.12-1.66), stable versus no angina (HR 1.27, 95% CI 1.03-1.57), and maximum stent length used (per 1 mm longer: HR 1.01, 95% CI 1.002-1.02), while prior myocardial infarction (HR 0.77, 95% CI 0.62-0.96) and creatinine >1.2 mg/dL (HR 0.74, 95% CI 0.56-0.98) were associated with lower risk of repeat revascularization. Diabetes was a significant predictor only when the outcome was limited to revascularization by coronary artery bypass surgery (HR 1.52, 95% CI 1.03-2.23). Although glycoprotein IIb/IIIa inhibitor use was a significant univariate predictor of freedom from early repeat revascularization (within 60 days after first PCI), after controlling for potential confounders, it was no longer significant. CONCLUSIONS: In this contemporary, community-based registry of patients undergoing nonemergent first PCI, clinical practice and outcomes are consistent with evidence from clinical trials and previous controlled studies. Results from controlled studies may reasonably be extrapolated to such a community setting.

Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis.

This study was undertaken to determine whether aortic valve calcium (AVC) scores measured by electron beam tomography can identify patients with echocardiographically defined aortic stenosis. Electron beam tomography is increasingly being used to detect coronary artery calcium. AVC can also be measured on electron beam tomographic (EBT) scans obtained to screen for coronary calcium. Whether EBT AVC scores correlate with the presence of aortic stenosis, as assessed by echocardiography, is unknown. Results of this study suggest that AVC scores should be calculated routinely for coronary calcium screening EBT scans, and that patients with Agatston AVC scores above a certain level (e.g., >150) should be referred for echocardiography.

Vitamin D receptor genetics on extracellular matrix biomarkers and hemodynamics in systolic heart failure.

INTRODUCTION: Vitamin D deficiency has been associated with the development of myocardial hypertrophy and inflammation. These findings suggest that vitamin D status and vitamin D receptor (VDR) genomics may play a role in myocardial fibrosis. The aim of this pilot study was to determine the association between vitamin D levels, VDR polymorphisms, and biomarkers of left ventricular remodeling and hemodynamics. METHODS: In a cross-sectional pilot study, patients with ejection fraction (EF) <40% (and New York Heart Association ≥ II) undergoing right heart catheterization were included in the study. Blood was collected for determination of 25-hydroxyvitamin D level (antibody competitive immunoassay), VDR genotypes (BsmI, ApaI, TaqI, and FokI), and biomarkers (N-terminal propeptide of collagen type III [PIIINP], matrix metalloproteinase 2, and galectin 3). The vitamin D genotypes were determined through the use of pyrosequencing. RESULTS: A total of 30 patients with a mean EF of 17% ± 8% were enrolled. There was a significant association between the BsmI C allele, ApaI G allele, and TaqI A allele, which formed a haplotype block (CGA) for analysis. There were no differences in baseline parameters between patients with the VDR haplotype block (n = 20) and those without (n = 10). Individual genotypes were not associated with any biomarker or hemodynamics. Patients with the CGA haplotype demonstrated significantly higher log PIIINP values (1.74 ± 0.32 mcg/mL vs 1.36 ± 0.31 mcg/mL, P = .0041). When evaluating vitamin D levels below and above the median level (19 ng/mL), there was no significant difference between these 2 groups in regard to biomarker levels for left ventricular remodeling. CONCLUSION: This study has shown that a biomarker for collagen type III synthesis, PIIINP, was associated with the CGA haplotype of BsmI, ApaI, and TaqI single nucleotide polymorphisms on the VDR. These findings suggest that VDR genetics may play a role in myocardial fibrosis in patients with systolic heart failure.

The effect of continuous infusion loop diuretics in patients with acute decompensated heart failure with hypoalbuminemia.

PURPOSE: Hypoalbuminemia is believed to decrease diuretic effectiveness and contribute to diuretic resistance that is observed in patients with nephrotic syndrome. Hypoalbuminemia is also seen in patients with acute decompensated heart failure (ADHF). However, the role of hypoalbuminemia on the effectiveness of continuous infusion diuretics in patients with ADHF is not known. METHODS: To evaluate hypoalbuminemia (albumin ≤ 3 g/dL) and diuretic effectiveness, we performed a retrospective study in 162 patients admitted to a tertiary care center for treatment of ADHF over a 3-year period. All patients received continuous infusion diuretic for at least a 2-day time period. RESULTS: A total of 33 patients were determined to have hypoalbuminemia. Average net urine output over a 2-day study period was similar between patients with and without hypoalbuminemia (-1462 ± 1734 vs -1233 ± 1560 mL, P = .46, respectively). In addition, diuretic doses (furosemide equivalent/24 hours) were similar between the 2 groups (788 ± 671 vs 778 ± 713 mg, P = .91, respectively) as was baseline serum creatinine (1.6 ± 0.6 vs 1.6 ± 0.6 mg/dL, P = .5, respectively). CONCLUSION: Overall, hypoalbuminemia did not decrease the diuretic effectiveness when measured by the net urine output in patients receiving continuous infusion diuretics for the treatment of ADHF.

Effect of obesity on in-hospital treatment for acute coronary syndrome complicated by new-onset heart failure.

OBJECTIVE: Obesity has been associated with superior outcomes in heart failure (HF) and acute coronary syndrome (ACS). Although patients with new-onset HF after ACS are at a high risk, they may receive less aggressive treatment. It is unknown whether treatment practices are biased by BMI. METHODS AND RESULTS: Consecutive patients without previous HF, who were hospitalized with ACS, and had left ventricular ejection fraction less than 40% or clinical HF were analyzed to assess the utilization of evidence-based treatment by BMI. BMI was categorized into normal (18.5 to <25 kg/m), overweight (25 to <30 kg/m), and obese (≥30 kg/m) groups. Multivariable logistic regression models were performed to examine the association of BMI with undergoing cardiac catheterization, and discharge on ß-blocker or angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Analysis included 461 patients. There were no significant differences among BMI groups in performance of cardiac catheterization or discharge on ACE inhibitor/ARB or ß-blocker. Compared with normal, neither overweight nor obese BMI was significantly associated with cardiac catheterization [overweight: odds ratio (OR) 1.49, 95% confidence interval (CI) 0.82-2.72, P=0.2; obese: OR 1.75, 95% CI 0.92-3.33, P=0.09], or discharge on ACE inhibitor/ARB (overweight: OR 0.70, 95% CI 0.40-1.21, P=0.7; obese: OR 0.69, 95% CI 0.39-1.23, P=0.2), or ß-blocker (overweight: OR 1.24, 95% CI 0.69-2.21, P=0.5; obese: OR 1.13, 95% CI 0.62-2.07, P=0.7). CONCLUSION: Among patients with new-onset HF complicating ACS, there were no significant differences in evidence-based treatment practices by BMI.