Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure.

BACKGROUND: Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. METHODS AND RESULTS: Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. CONCLUSIONS: The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00454818.

Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2.

BACKGROUND: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter-defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM. METHODS AND RESULTS: An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) ≤0.40 and ≤6 months of symptoms. The mean age was 45 ± 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 ± 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50). CONCLUSIONS: In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery.

Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women.

BACKGROUND: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry. METHODS AND RESULTS: IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002). CONCLUSIONS: Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months.

Association of anti-oxidized LDL and candidate genes with severity of coronary stenosis in the Women's Ischemia Syndrome Evaluation study.

Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (< 20%, 20%-49%, > 50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥ 20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r² = 0.01; P = 0.03) and LDL cholesterol (r² = 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3'UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels.

In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: We investigated the role of the renin-angiotensin system in women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). Although microvascular dysfunction has been suggested to explain this syndrome and recently was found to predict adverse outcomes, the mechanisms and treatments remain unclear. METHODS: In a substudy within the WISE, 78 women with microvascular dysfunction (coronary flow reserve [CFR] <3.0 following adenosine) and no obstructive CAD were randomly assigned to either an angiotensin-converting enzyme inhibition (ACE-I) with quinapril or a placebo treatment group. The primary efficacy parameter was CFR at 16 weeks adjusted for baseline characteristics and clinical site. The secondary response variable was freedom from angina symptoms assessed using the Seattle Angina Questionnaire. RESULTS: A total of 61 women completed the 16-week treatment period with repeat CFR measurements, and treatment was well tolerated. For the primary outcome, at 16 weeks, CFR improved more with ACE-I than placebo (P < .02). For the secondary outcome of symptom improvement, ACE-I treatment (P = .037) and CFR increase (P = .008) both contributed. CONCLUSIONS: Microvascular function improves with ACE-I therapy in women with signs and symptoms of ischemia without obstructive CAD. This improvement is associated with reduction in angina. The beneficial response of the coronary microvasculature was limited to women with lower baseline CFR values, suggesting that the renin-angiotensin system may be more involved among women with more severe microvascular defects.

Renin-angiotensin gene polymorphisms and neurohormonal inhibition.

Analyses of polymorphisms in the renin-angiotensin system may never completely predict responsiveness to pharmacotherapy that blocks angiotensin-converting enzyme or the angiotensin receptor type 1. However, the pharmacogenetic studies that have been conducted to date are intriguing, and they illustrate the potential benefit of designing larger genome-wide clinical studies. Such studies will continue to define the role of renin-angiotensin pharmacogenetics in patients with heart failure due to underlying cardiac dysfunction.

Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.

BACKGROUND: SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF. METHODS AND RESULTS: A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. CONCLUSIONS: Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

Multimarker approach predicts adverse cardiovascular events in women evaluated for suspected ischemia: results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Inflammatory marker and hemoglobin levels (eg biomarkers) considered separately, predict adverse events in selected populations. HYPOTHESIS: A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia. METHODS: We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A, and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE). RESULTS: Among 595 women (mean age 58 years, ejection fraction [EF] 65%, majority without coronary stenosis >or= 50%) followed for 3.6 +/- 1.8 years (mean +/- SD), those without abnormal markers had fewer events (11.6%) compared to those with 1 (18.4%), 2 (20.9%), or 3 (37%) abnormal markers (p < 0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with 1 (6.1%), 2 (9.1%), or 3 (17%) abnormal markers (p < 0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as the number of abnormal biomarkers increased risk increased. Women with 3 or 4 abnormal biomarkers were approximately 10-20 times more likely to die (p < 0.05). Biomarkers added to the predictive information provided by the Framingham Risk Score. CONCLUSIONS: Among women undergoing coronary angiography for suspected ischemia, a multibiomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.

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.

Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure.

BACKGROUND: Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF. METHODS AND RESULTS: We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile. CONCLUSIONS: We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.

Simplified method for determination of clarithromycin in human plasma using protein precipitation in a 96-well format and liquid chromatography-tandem mass spectrometry.

A simplified method to determine clarithromycin concentrations in human plasma using protein precipitation in a 96-well plate and liquid chromatography-tandem mass spectrometry was developed and validated. Plasma proteins were precipitated with acetonitrile and roxithromycin was used as the internal standard. After vortex mixing and centrifugation, the supernatants were directly injected onto a Phenomenex Luna Phenyl-Hexyl column (50 mm x 2.0 mm ID, 3 microm). The mobile phase consisted of water and methanol (30:70, v/v) containing 0.1% formic acid and 5mM ammonium acetate. The flow rate was 0.22 mL/min and the total run time (injection to injection) was less than 3 min. Detection of the analytes was achieved using positive ion electrospray tandem mass spectrometry in selected reaction monitoring (SRM) mode. The linear standard curve ranged from 100 to 5000 ng/mL and the precision and accuracy (inter- and intra-run) were within 7.9% and 4.9%, respectively. The method was successfully used to determine clarithromycin concentrations in human plasma samples obtained from healthy subjects who were given clarithromycin 500 mg for 3 days. The method is rapid, simple, precise and directly applicable to clarithromycin pharmacokinetic studies.

Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.

BACKGROUND: Mild hyponatremia is relatively common in patients hospitalized with heart failure (HF). To our knowledge, the association of hyponatremia with outcomes has not been evaluated in the context of in-hospital clinical course including central hemodynamics and changes in serum sodium level. METHODS: The ESCAPE trial (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) was a randomized, controlled study designed to evaluate the utility of a pulmonary artery catheter plus clinical assessment vs clinical assessment alone in guiding therapy in patients hospitalized with New York Heart Association class IV HF due to systolic dysfunction (left ventricular ejection fraction <30%). A Cox proportional hazards model with baseline serum sodium level as a continuous variable was used to examine the association of serum sodium level with 6-month postdischarge mortality, HF rehospitalization, and death or rehospitalization. A categorical analysis was also performed comparing persistent and corrected hyponatremia. RESULTS: A total of 433 hospitalized patients with HF were enrolled in ESCAPE. Hyponatremia (serum sodium level < or = 134 mEq/L) was present in 103 patients (23.8%). (To convert serum sodium to millimoles per liter, multiply by 1.0.) Of these, 71 had persistent hyponatremia (68.9%). Hyponatremia was associated with higher 6-month mortality after covariate adjustment (hazard ratio [HR] for each 3-mEq/L decrease in sodium level, 1.23; 95% confidence interval [CI], 1.05-1.43) (P = .01). After controlling for baseline variables and clinical response, we found that patients with persistent hyponatremia had an increased risk of all-cause mortality (31% vs 16%; HR, 1.82) (P = .04), HF rehospitalization (62% vs 43%; HR, 1.52) (P = .03), and death or rehospitalization (73% vs 50%; HR, 1.54) (P = .01) compared with normonatremic patients. CONCLUSION: Persistent hyponatremia was an independent predictor of mortality, HF hospitalization, and death or rehospitalization despite clinical and hemodynamic improvements that were similar to those in patients without hyponatremia.

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.

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.

Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. HYPOTHESIS: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. METHODS: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia. RESULTS: Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18. CONCLUSIONS: Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against ß1-Adrenergic Receptors.

BACKGROUND: Among various cardiac autoantibodies (AAbs), those recognizing the ß1-adrenergic receptor (ß1AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by ß-blockers and immunoglobulin G3 (IgG3) immunoadsorption. OBJECTIVES: The goal of this study was to investigate the role of ß1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy. METHODS: Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). The presence of IgG and IgG3-ß1AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months. RESULTS: Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-ß1AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p < 0.01; left ventricular end-systolic diameter, p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis showed that IgG3-ß1AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, ß = 0.20, p = 0.01; change in LVEF, ß = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint. CONCLUSIONS: IgG3-ß1AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

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.

Discordant beta-blocker effects on clinic, ambulatory, resting, and exercise hemodynamics in patients with hypertension.

STUDY OBJECTIVES: To determine the correlation between ambulatory and clinic blood pressure in assessing antihypertensive response to beta-blockade, to test whether blood pressure response to metoprolol is associated with the heart rate response, and to determine whether exercise and resting heart rate responses to metoprolol are correlated. DESIGN: Post hoc analysis of a prospective cohort study. SETTING: University-affiliated general clinical research center. PATIENTS: Fifty-one patients aged 35-65 years with uncomplicated hypertension. Intervention. All patients received metoprolol at a dosage titrated to achieve a diastolic blood pressure below 90 mm Hg. MEASUREMENTS AND MAIN RESULTS: Clinic and 24-hour ambulatory blood pressure measurements were obtained and exercise treadmill testing was performed before and after metoprolol treatment. Based on ambulatory blood pressure data, 24 patients (47%) responded (defined as at least a 10% reduction in diastolic blood pressure) to metoprolol compared with 36 patients (71%) based on clinic blood pressure data (p=0.027). Clinic blood pressure was associated with a 67% false-positive rate (responsive blood pressure by clinic data that was actually nonresponsive by ambulatory data). Blood pressure responders and nonresponders exhibited similar reductions in exercise heart rate (24% and 23%, p=0.74). However, responses to metoprolol measured by exercise heart rate versus resting heart rate were not significantly correlated (r=0.24, p=0.105). CONCLUSION: Reliance on clinic blood pressure or resting heart rate for making beta-blocker treatment decisions may yield less than optimal assessment of the antihypertensive response or degree of beta-blockade.