Significant Facility-Level Variation in Utilization of and Adherence with Secondary Prevention Therapies Among Patients with Premature Atherosclerotic Cardiovascular Disease: Insights from the VITAL (Veterans wIth premaTure AtheroscLerosis) Registry7.

PURPOSE: We investigated facility-level variation in the use and adherence with antiplatelets and statins among patients with premature and extremely premature ASCVD. METHODS: Using the 2014-2015 nationwide Veterans wIth premaTure AtheroscLerosis (VITAL) registry, we assessed patients with premature (age at first ASCVD event: males < 55 years, females < 65 years) and extremely premature ASCVD (< 40 years). We examined frequency and facility-level variation in any statin, high-intensity statin (HIS), antiplatelet use (aspirin, clopidogrel, ticagrelor, prasugrel, and ticlopidine), and statin adherence (proportion of days covered ≥ 0.8) across 130 nationwide VA healthcare facilities. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of statins or antiplatelets and statin adherence. RESULTS: Our analysis included 135,703 and 7716 patients with premature and extremely premature ASCVD, respectively. Across all facilities, the median (IQR) prescription rate of any statin therapy, HIS therapy, and antiplatelets among patients with premature ASCVD was 0.73 (0.70-0.75), 0.36 (0.32-0.41), and 0.77 (0.73-0.81), respectively. MRR (95% CI) for any statin use, HIS use, and antiplatelet use were 1.53 (1.44-1.60), 1.58 (1.49-1.66), and 1.49 (1.42-1.56), respectively, showing 53, 58, and 49% facility-level variation. The median (IQR) facility-level rate of statin adherence was 0.58 (0.55-0.62) and MRR for statin adherence was 1.13 (1.10-1.15), showing 13% facility-level variation. Similar median facility-level rates and variation were observed among patients with extremely premature ASCVD. CONCLUSIONS: There is suboptimal use and significant facility-level variation in the use of statin and antiplatelet therapy among patients with premature and extremely premature ASCVD. Interventions are needed to optimize care and minimize variation among young ASCVD patients.

CXCL5 polymorphisms are associated with variable blood pressure in cardiovascular disease-free adults.

OBJECTIVE: Leukocyte count has been associated with blood pressure, hypertension, and hypertensive complications. We hypothesized that polymorphisms in the CXCL5 gene, which encodes the neutrophilic chemokine ENA-78, are associated with blood pressure in cardiovascular disease (CVD)-free adults and that these polymorphisms are functional. METHODS AND RESULTS: A total of 192 community-dwelling participants without CVD or risk equivalents were enrolled. Two CXCL5 polymorphisms (-156 G > C (rs352046) and 398 G > A (rs425535)) were tested for associations with blood pressure. Allele-specific mRNA expression in leukocytes was also measured to determine whether heterozygosity was associated with allelic expression imbalance. In -156 C variant carriers, systolic blood pressure (SBP) was 7 mmHg higher than in -156 G/G wild-type homozygotes (131 ± 17 vs. 124 ± 14 mmHg; P = 0.008). Similarly, diastolic blood pressure (DBP) was 4 mmHg higher in -156 C variant carriers (78 ± 11 vs. 74 ± 11 mmHg; P = 0.013). In multivariate analysis of SBP, age, sex, body mass index, and the -156 G > C polymorphism were identified as significant variables. Age, sex, and the -156 G > C SNP were further associated with DBP, along with white blood cells. Allelic expression imbalance and significantly higher circulating ENA-78 concentrations were noted for variant carriers. CONCLUSION: CXCL5 gene polymorphisms are functional and associated with variable blood pressure in CVD-free individuals. The role of CXCL5 as a hypertension- and CVD-susceptibility gene should be further explored.

Does exercise tolerance testing at 60 days poststroke predict rehabilitation performance?

OBJECTIVE: To assess the relationship between exercise tolerance test (ETT) performance at 6 weeks poststroke and subsequent performance in a treadmill and overground locomotor training program (LTP). DESIGN: Prospective cohort study. SETTING: Exercise testing laboratory in either a primary care hospital or outpatient clinic. PARTICIPANTS: Community-dwelling individuals (N=469), 54.9±19.0 days poststroke, enrolled in the Locomotor Experience Applied Post-Stroke randomized controlled trial. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: For participants randomly assigned to LTP, the number of sessions needed to attain the training goal of 20 minutes of treadmill stepping was determined. Regression analyses determined the contribution of ETT performance (cycling duration), age, and 6-minute walk test (6MWT) distance to attainment of the stepping duration goal. RESULTS: Age, 6MWT, and ETT performance individually accounted for 10.74%, 10.82%, and 10.76%, respectively, of the variance in the number of sessions needed to attain 20 minutes of stepping. When age and 6MWT were included in the model, the additional contribution of ETT performance was rendered nonsignificant (P=.150). CONCLUSIONS: To the extent that ETT performance can be viewed as a measure of cardiovascular fitness rather than neurologic impairment, cardiovascular fitness at the time of the ETT did not make a significant unique contribution to the number of sessions needed to achieve 20 minutes of stepping. The 6MWT, which involves less intensive exercise than the ETT and therefore is likely to be predominantly affected by neurologic impairment and muscular condition, appeared to account for as much variance as the ETT.

Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease.

Importance: There is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively. Objective: To evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD. Design, Setting, and Participants: This was a cross-sectional, multicenter, nationwide VA health care system-based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary care visit in the Veterans Affairs (VA) health care system from October 1, 2014, to September 30, 2015. Participants included 147 600 veteran patients with premature ASCVD, encompassing ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD). Exposures: Women vs men with premature and extremely premature ASCVD. Main Outcomes and Measures: Antiplatelet use, any statin use, HIS use, and statin adherence (proportion of days covered [PDC] ≥0.8). Results: We identified 10 413 women and 137 187 men with premature ASCVD (age ≤55 years) and 1340 women and 8145 men with extremely premature (age ≤40 years) ASCVD. Among patients with premature and extremely premature ASCVD, women represented 7.1% and 14.1% of those groups, respectively. When compared with men, women with premature ASCVD had a higher proportion of African American patients (36.1% vs 23.8%) and lower proportions of Asian patients (0.5% vs 0.7%) and White patients (56.1% vs. 68.1%). In the extremely premature ASCVD group, women had a comparatively higher proportion of African American patients (36.8% vs 23.2%) and lower proportion of White patients (55.0% vs 67.8%) and Asian patients (1.3% vs 1.5%) than men. Among patients with premature IHD, women received less antiplatelet (adjusted odds ratio [AOR], 0.47, 95% CI, 0.45-0.50), any statin (AOR, 0.62; 95% CI, 0.59-0.66), and HIS (AOR, 0.63; 95% CI, 0.59-0.66) therapy and were less statin adherent (mean [SD] PDC, 0.68 [0.34] vs 0.73 [0.31]; ß coefficient: -0.02; 95% CI, -0.03 to -0.01) compared with men. Similarly, women with premature ICVD and premature PAD received comparatively less antiplatelet agents, any statin, and HIS. Among patients with extremely premature ASCVD, women also received less antiplatelet therapy (AOR, 0.61; 95% CI, 0.53-0.70), any statin therapy (AOR,0.51; 95% CI, 0.44-0.58), and HIS therapy (AOR, 0.45; 95% CI, 0.37-0.54) than men. There were no sex-associated differences in statin adherence among patients with premature ICVD, premature PAD, or extremely premature ASCVD. Conclusions and Relevance: This cross-sectional study revealed that women veterans with premature ASCVD and extremely premature ASCVD receive less optimal secondary prevention cardiovascular care in comparison with men. Women with premature ASCVD, particularly those with IHD, were also less statin adherent. Multidisciplinary and patient-centered interventions are needed to improve these disparities in women.

Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) guidelines for management of dyslipidemia and cardiovascular disease risk reduction: Putting evidence in context.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the United States (U.S.) and incurs significant cost to the healthcare system. Management of cholesterol remains central for ASCVD prevention and has been the focus of multiple national guidelines. In this review, we compare the American Heart Association (AHA)/American College of Cardiology (ACC) and the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) Cholesterol guidelines. We review the evidence base that was used to generate recommendations focusing on 4 distinct themes: 1) the threshold of absolute 10-year ASCVD risk to start a clinician-patient discussion for the initiation of statin therapy in primary prevention patients; 2) the utility of coronary artery calcium score to guide clinician-patient risk discussion pertaining to the initiation of statin therapy for primary ASCVD prevention; 3) the use of moderate versus high-intensity statin therapy in patients with established ASCVD; and 4) the utility of ordering lipid panels after initiation or intensification of lipid lowering therapy to document efficacy and monitor adherence to lipid lowering therapy. We discuss why the VA/DoD and AHA/ACC may have reached different conclusions on these key issues.

Incidence, predictors, and outcomes of cardiac pacing after cardiac transplantation: an 11-year retrospective analysis.

More than 20% of cardiac transplant patients go on to require permanent pacing. We sought to determine the incidence of cardiac pacing in our cardiac transplant population and identify characteristics that may predict which patients will require permanent pacing. We reviewed medical records of cardiac transplant recipients and compared baseline characteristics of patients who received pacemakers with those of patients who did not receive pacemakers. Of 292 patients included in this analysis, 71 (24%) required permanent posttransplant pacing. Use of amiodarone before transplant was associated with a nonsignificant trend toward needing a pacemaker after transplant (P=0.08). Patients undergoing biatrial anastomosis were more likely to require permanent pacing than patients undergoing bicaval anastomosis (P<0.001). Approximately one fourth of cardiac transplant patients require permanent pacing. Surgical technique is a major predictor of who will require permanent pacing after cardiac transplantation.

Role of heart failure etiology on arterial wave reflection in heart transplant recipients: relation with C-reactive protein.

OBJECTIVES: Aortic augmentation index (AIa), a measure of arterial pressure wave reflection related to central and peripheral arterial stiffness, is elevated in many heart transplant recipients. We investigated whether the increase in wave reflection observed in some heart transplant recipients is influenced by the etiology of antecedent heart failure and circulating pro-inflammatory proteins early in the post-transplantation period. METHODS: Two months after heart transplantation, 20 heart transplant recipients underwent noninvasive measurement of aortic pressure and wave reflection properties and measurement of plasma pro-inflammatory proteins. RESULTS: AIa adjusted to a heart rate of 75 beats/min (AIaHR75) was higher in heart transplant recipients with ischemic (n = 12) compared with nonischemic (n = 8) heart failure (P < 0.01). Similarly, circulating C-reactive protein, a marker of systemic inflammation and an independent predictor of allograft vasculopathy and death in heart transplant recipients, was higher in heart transplant recipients with ischemic than with nonischemic heart failure (log-transformed, P < 0.05). Moreover, there was a significant relation between log C-reactive protein and AIaHR75 (r = 0.68, P < 0.05), augmented pressure (r = 0.60, P < 0.01), roundtrip time of the reflected wave to the peripheral reflecting sites and back (r = -0.62; P < 0.01), and left ventricular wasted energy (r = 0.55, P < 0.01). Multiple regression analysis revealed that log C-reactive protein explained 43% of the variance in AIaHR75 and the difference in AIaHR75 between groups was abolished when adjusted for log C-reactive protein. CONCLUSIONS: Heart transplant recipients with antecedent ischemic heart failure demonstrated increased AIaHR75 compared with nonischemic heart transplant recipients and AIaHR75 was associated with higher circulating C-reactive protein concentration. Whether elevated arterial wave reflection and associated systemic low-grade inflammation early after transplantation have clinical implications in ischemic heart transplant recipients requires further investigation.

Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure.

Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for < or =4 years. Eight polymorphisms in 6 genes were genotyped: beta(1)-adrenergic receptor (ADRB1, S49G, R389G), beta(2)-adrenergic receptor (ADRB2, G16R, Q27E), alpha(2c)-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.

Association of diurnal blood pressure pattern with risk of hospitalization or death in men with heart failure.

BACKGROUND: An altered diurnal blood pressure (BP) pattern has been linked to the risk of developing heart failure (HF). We tested whether an altered diurnal BP pattern is associated with adverse outcomes (death or hospitalization for HF exacerbation) in patients with HF. METHODS AND RESULTS: A total of 118 patients with HF were enrolled from a tertiary care HF clinic and followed for death or HF hospitalization for up to 4 years; 24-hour ambulatory BP was monitored. Forty patients (34%) had a normal BP dipping pattern (night-day ambulatory BP ratio < 0.9), 44 patients (37%) had a nondipping pattern (0.9 < or = night-day ambulatory BP ratio < 1.0), and 34 patients (29%) had a reverse dipping BP pattern (night-day ambulatory BP ratio > or = 1.0). A total of 39 patients had an adverse outcome. Adverse outcome rates were the lowest in dippers and the highest in reverse dippers (log rank P = .052). Predictors of adverse outcomes, selected on the basis of log likelihood contrast, were as follows: New York Heart Association functional class (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.11-3.44), anemia (HR 2.50, 95% CI 1.23-5.08), and dipping status (HR 1.65, 95% CI 1.08-2.50). CONCLUSION: In addition to other traditional predictors, BP dipping status may be an important prognostic factor in HF.

Arterial-wave reflections are increased in heart failure patients with a left-ventricular assist device.

BACKGROUND: Chronic heart failure (HF) is associated with increased central arterial pulse-wave reflections, which may contribute to increased myocardial oxygen demand. Although the treatment of HF via left-ventricular assist device (LVAD) placement has recently become widespread, the effects of LVAD therapy on central arterial pulse-wave reflections are unknown. METHODS: Central aortic pulse-wave analysis was performed on patients with end-stage HF awaiting cardiac transplantation and on healthy age-matched controls using the SphygmoCor (Akor Medical, Sydney, Australia) system. Arterial pulse-wave data were compared between patients receiving LVAD support versus those receiving intravenous inotropic drugs and healthy control patients. RESULTS: Five patients on LVAD support were compared with 10 patients on inotropic drugs and 10 healthy control patients. Aortic augmented pressure and the aortic augmentation index (AI(a)) were higher in LVAD patients compared with inotrope and control patients, despite similar brachial and aortic blood pressures between groups. The AI(a) was significantly higher in LVAD patients than in patients on inotropic drugs (28.2% +/- 10% v 7.9% +/- 9%, P < or = .01). Additionally, there was a significantly higher aortic systolic tension time index, an index of left-ventricular myocardial oxygen demand, in the LVAD group compared with the inotrope group (2655 +/- 298 mm Hg/sec/min v 1748 +/- 303 mm Hg/sec/min, P < .01). CONCLUSIONS: Central arterial pressure-wave reflection is increased in end-stage HF patients on LVAD support compared with those on inotropic drugs, leading to an increase in aortic augmented pressure, AI(a), and systolic tension time index. The AI(a) is also higher in LVAD patients than in healthy controls. This increased central arterial-wave reflection places an additional hemodynamic load on the LVAD device and may have relevance to the medical management of patients after LVAD placement and to the longevity of the LVAD device itself.

Initial heart rate and systolic blood pressure predict outcomes in chronic heart failure patients who are evaluated for cardiac transplant.

BACKGROUND: Heart rate (HR) and systolic blood pressure (SBP) are currently not considered among common clinical indicators of prognosis in patients referred for heart transplant (Htx). We sought to determine whether an initial hemodynamic profile of HR and SBP could be used to predict outcomes in chronic heart failure patients evaluated for Htx. METHODS: We analyzed the medical records of patients evaluated for Htx and obtained demographic and clinical data collected at the initial transplant clinic visit or inpatient encounter. We assigned patients to groups based on their HR and SBP. Groups were compared after follow-up for differences in freedom from death or Htx. RESULTS: From 1999 to 2003, 400 consecutive patients were considered by the local Htx medical review board. The median duration of follow-up was 26 months (interquartile range 1 to 45 months). Patients with initial >or= 90 beats per minute (bpm) and initial SBP < 100 mmHg ((n = 34) had worse New York Heart Association functional class (p=0.02), lower cardiac output ((p =0.02 ), and greater hyponatremia (>0.001;). These patients were more likely to be hospitalized at the time of referral (p >0.001) and more likely to have experienced death or Htx during follow-up than patients with other hemodynamic profiles (p = 0.001). CONCLUSIONS: A hemodynamic profile of HR and SBP can be used with other prognostic indicators to identify high-risk patients at the time of initial evaluation for Htx.

Sustained restoration of autonomic balance with long- but not short-acting metoprolol in patients with heart failure.

BACKGROUND: The purpose of this study was to compare the effects of immediate-release (IR) metoprolol and extended-release (XL) metoprolol on measures of heart rate variability in chronic systolic heart failure patients. METHODS AND RESULTS: Thirteen metoprolol-treated heart failure patients were randomized to a 2-way crossover study of equal daily doses of metoprolol IR and metoprolol XL, each administered for 3 weeks. After each 3-week interval, patients underwent 24-hour Holter and ambulatory blood pressure monitoring. Over the entire 24-hour period, the ratio of high to total variability (normalized measure of parasympathetic activity) was significantly greater (P < .05), the ratio of low to total variability (normalized measure of sympathetic activity) was significantly lower (P < .05), and the ratio of high to low variability (index of parasympathetic to sympathetic balance) was greater (P < .08) for metoprolol XL compared with metoprolol IR. Over the entire 24-hour period, both systolic and diastolic blood pressure were significantly lower for metoprolol XL compared with metoprolol IR (P < .0001, and .0005, respectively). CONCLUSION: These data suggest that with twice daily dosing, metoprolol IR is inferior to metoprolol XL in its effects on heart rate variability, autonomic balance, and blood pressure in patients with heart failure.

Atorvastatin effect on circulating and leukocyte-produced CD40 ligand concentrations in people with normal cholesterol levels: a pilot study.

STUDY OBJECTIVES: To investigate whether atorvastatin decreases serum or leukocyte-produced CD40 ligand (CD40L) levels and whether these effects are dependent on reduction in low-density lipoprotein cholesterol (LDL) levels in people without overt dyslipidemia. DESIGN: Prospective pilot study. SETTING: University research center. SUBJECTS: Twenty-five normocholesterolemic volunteers (mean age 32 +/- 11 yrs; 15 women, 10 men) without cardiovascular disease. INTERVENTION: After a 2-week drug-free run-in period, subjects received atorvastatin 80 mg/day orally for 16 weeks. MEASUREMENTS AND MAIN RESULTS: All lipoprotein level measurements were performed with the subject in the fasting state. The CD40L concentrations were measured by immunofluorescence detection in serum and leukocyte culture supernates after 24-hour incubation, and treatment effect was analyzed. Baseline mean +/- SD total cholesterol, LDL, high-density lipoprotein cholesterol, and triglyceride levels were 179 +/- 33, 97 +/- 29, 62 +/- 20, and 102 +/- 69 mg/dl, respectively. Mean changes in each of these levels, respectively, after 16 weeks of atorvastatin were -34%, -59%, +3%, and -23%. The median serum CD40L level was lower at 16 weeks (2.3 ng/ml, interquartile range [IQR] 1.2-5.0 ng/ml) than at baseline (3.0 ng/ml, IQR 2.1-3.7 ng/ml), but the change was not significant (p=0.24). However, atorvastatin significantly lowered CD40L produced from leukocytes by 57% (21 pg/mg of protein [IQR 10-38 pg/mg] vs 49 pg/mg [IQR 21-149 pg/mg], p=0.045). Effects were independent of reduction in cholesterol levels. CONCLUSION: Although atorvastatin did not significantly lower serum CD40L levels, significant reduction in leukocyte production was seen independent of degree of LDL reduction. These pilot data suggest a potential benefit in normocholesterolemic individuals that should be further investigated, and that leukocyte CD40L concentrations should be considered in the drug response.

Complementary and alternative medicine use among individuals participating in research: implications for research and practice.

STUDY OBJECTIVES: To determine the frequency and type of complementary and alternative medicine (CAM) use among healthy volunteers participating in research, and to investigate the potential for interactions between commonly used CAM modalities and various drugs. DESIGN: Prospective evaluation. SETTING: University general clinical research center. SUBJECTS: Sixty healthy adults participating in an ongoing drug study. MEASUREMENTS AND MAIN RESULTS: The clinical study database was queried to determine the use and type of existing and newly started CAM throughout the study period. Baseline characteristics were compared between users and nonusers of CAM to identify differences between them. Potential CAM-drug interactions were classified based on curated databases and primary literature sources. Of the 60 subjects enrolled, 30 (50%) used CAM during the study. Of these, 26 (87%) were using CAM at study entry. Baseline CAM users were on average 7 years older than nonusers (p=0.03) and had high-density lipoprotein cholesterol concentrations 10 mg/dl higher than those of nonusers (p=0.04). The group using CAM had more women and nonsmokers than the other group. Several potential CAM-drug interactions were identified. CONCLUSION: Because of high rates of CAM use (50% of the subjects were using biologically based CAM) and the many potential CAM-drug interactions, CAM use should be rigorously addressed in clinical practice and research. Failure to capture this information may have clinical repercussions through pharmacokinetic and pharmacodynamic interference of clinical response and clinical trial results. Clinicians and researchers may be able to identify those most likely to use CAM by their baseline characteristics; this would help target those patients and research subjects for more thorough assessment and follow-up.

Modulatory effects of atorvastatin on endothelial cell-derived chemokines, cytokines, and angiogenic factors.

STUDY OBJECTIVE: To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. DESIGN: In vitro study using a multiplexing method for protein measurement. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy. CONCLUSION: By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.

Managing the post-left ventricular assist device patient.

The implantation of ventricular assist devices allows the opportunity for patients with intractable heart failure to have improved quality and quantity of life. The devices may be implanted after failed attempts to wean from bypass, as a bridge to transplantation, or as destination therapy. Key issues following the implantation of assist devices include the prevention of right ventricular failure, appropriate pharmacologic management, prevention and management of infection, and detection and treatment of device dysfunction.

beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure.

OBJECTIVE: beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability. METHODS: Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. RESULTS: The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure. CONCLUSIONS: Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.

Use of cardiac resynchronization therapy to optimize beta-blocker therapy in patients with heart failure and prolonged QRS duration.

A retrospective analysis was performed on 52 patients with heart failure to determine the change in beta-blocker therapy after cardiac resynchronization therapy (CRT). After 6 months of CRT, the number of patients receiving beta-blocker therapy increased from 36 to 44, with improved clinical outcomes and larger beta-blocker doses, indicating that these 2 therapies may work together to improve outcomes by allowing the use of larger doses of beta blockers while correcting ventricular dyssynchrony.

Dilated cardiomyopathy and acute liver injury associated with combined use of ephedra, gamma-hydroxybutyrate, and anabolic steroids.

Anabolic-androgenic steroids are synthetic derivatives of testosterone that some athletes have used to enhance muscle mass and improve their athletic performance. Ephedrine is a potent sympathomimetic agent that can lead to cardiomyopathy similar to that seen with catecholamine excess. Adverse cardiovascular events attributed to anabolic steroid and ephedra use, such as arrhythmias, myocardial infarction, cardiomyopathy, and sudden death, are rarely reported. Bodybuilders have used gamma-hydroxybutyrate, a potent secretagogue of growth hormone, to promote muscle development. Although dilated cardiomyopathy is a known complication of excess growth hormone levels, it has not been associated with use of gamma-hydroxybutyrate. A healthy 40-year-old man was admitted to our hospital for new-onset congestive heart failure and severe acute hepatitis that developed several months after he began using anabolic-androgenic steroids, ephedra, and gamma-hydroxybutyrate supplements. Analysis with an objective causality assessment scale revealed a probable adverse drug reaction between the patient's use of anabolic steroids, ephedra, and gamma-hydroxybutyrate and the development of his cardiomyopathy and acute liver injury.