Vera Bittner

Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND Women with polycystic ovary syndrome (PCOS) have a greater clustering of cardiac risk factors. However, the link between PCOS and cardiovascular (CV) disease is incompletely described. OBJECTIVE The aim of this analysis was to evaluate the risk of CV events in 390 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Womens Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. METHODS A total of 104 women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of androstenedione (> or = 701 pg/ml), testosterone (> or = 30.9 ng/dl), or free testosterone (> or = 4.5 pg/ml). Cox proportional hazard model was fit to estimate CV death or myocardial infarction (n = 55). RESULTS Women with clinical features of PCOS were more often diabetic (P < 0.0001), obese (P = 0.005), had the metabolic syndrome (P < 0.0001), and had more angiographic coronary artery disease (CAD) (P = 0.04) compared to women without clinical features of PCOS. Cumulative 5-yr CV event-free survival was 78.9% for women with clinical features of PCOS (n = 104) vs. 88.7% for women without clinical features of PCOS (n = 286) (P = 0.006). PCOS remained a significant predictor (P < 0.01) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD as covariates. CONCLUSION Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.

OBJECTIVES This subanalysis of the TNT (Treating to New Targets) study investigates the effects of intensive lipid lowering with atorvastatin in patients with coronary heart disease (CHD) with and without pre-existing chronic kidney disease (CKD). BACKGROUND Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD. METHODS A total of 10,001 patients with CHD were randomized to double-blind therapy with atorvastatin 80 mg/day or 10 mg/day. Patients with CKD were identified at baseline on the basis of an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) using the Modification of Diet in Renal Disease equation. The primary efficacy outcome was time to first major cardiovascular event. RESULTS Of 9,656 patients with complete renal data, 3,107 had CKD at baseline and demonstrated greater cardiovascular comorbidity than those with normal eGFR (n = 6,549). After a median follow-up of 5.0 years, 351 patients with CKD (11.3%) experienced a major cardiovascular event, compared with 561 patients with normal eGFR (8.6%) (hazard ratio [HR] = 1.35; 95% confidence interval [CI] 1.18 to 1.54; p < 0.0001). Compared with atorvastatin 10 mg, atorvastatin 80 mg reduced the relative risk of major cardiovascular events by 32% in patients with CKD (HR = 0.68; 95% CI 0.55 to 0.84; p = 0.0003) and 15% in patients with normal eGFR (HR = 0.85; 95% CI 0.72 to 1.00; p = 0.049). Both doses of atorvastatin were well tolerated in patients with CKD. CONCLUSIONS Aggressive lipid lowering with atorvastatin 80 mg was both safe and effective in reducing the excess of cardiovascular events in a high-risk population with CKD and CHD.

Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial

BACKGROUND Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. DESIGN This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. SUMMARY ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: A report from the registry of studies of left ventricular dysfunction☆

OBJECTIVES This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Hypoestrogenemia of hypothalamic origin and Coronary artery disease in Premenopausal women: A report from the NHLBI-sponsored WISE study

OBJECTIVES We sought to evaluate hypoestrogenemia of hypothalamic origin and its association with angiographic coronary artery disease (CAD) in premenopausal women. BACKGROUND Coronary artery disease in premenopausal women appears to have a particularly poor prognosis. Primate animal data suggest that premenopausal CAD is strongly determined by psychosocial stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia. METHODS We assessed reproductive hormone blood levels and angiographic CAD using core laboratories in 95 premenopausal women with coronary risk factors who were enrolled in the National Heart, Lung, and Blood Institute-sponsored Womens Ischemia Syndrome Evaluation and were undergoing coronary angiography for evaluation for suspected ischemia. RESULTS Premenopausal women with angiographic CAD (n = 13) had significantly lower estradiol, bioavailable estradiol, and follicle-stimulating hormone (FSH) (all p < 0.05) than women without angiographic CAD (n = 82), even after controlling for age. Hypoestrogenemia of hypothalamic origin, defined as estradiol <184 pmol/l (50 pg/ml), FSH <10 IU/l, and luteinizing hormone <10 IU/l, was significantly more prevalent among the women with CAD than those without CAD (9/13 [69%] vs. 24/82 [29%], respectively, p = 0.01). Hypoestrogenemia of hypothalamic origin was the most powerful predictor of angiographic CAD in a multivariate model (odds ratio [OR] 7.4 [confidence interval (CI) 1.7 to 33.3], p = 0.008). Anxiolytic/sedative/hypnotic and antidepressant medication use were independent predictors of hypoestrogenemia of hypothalamic origin in a multivariate model (OR 4.6 [CI 1.3 to 15.7], p = 0.02, OR 0.10 [CI 0.01 to 0.92], p = 0.04, respectively). CONCLUSIONS Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, disruption of ovulatory cycling characterized by hypoestrogenemia of hypothalamic origin appears to be associated with angiographic CAD.

Predictors of cardiac rehabilitation referral in coronary artery disease patients: findings from the American Heart Association's Get With The Guidelines Program.

OBJECTIVES Our purpose was to determine factors independently associated with cardiac rehabilitation referral, which are currently not well described at a national level. BACKGROUND Substantial numbers of eligible patients are not referred to cardiac rehabilitation at hospital discharge despite proven reductions in mortality and national guideline recommendations. METHODS We used data from the American Heart Associations Get With The Guidelines program, analyzing 72,817 patients discharged alive after a myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft surgery between January 2000 and September 2007 from 156 hospitals. We identified factors associated with cardiac rehabilitation referral at discharge and performed multivariable logistic regression, adjusted for clustering, to identify which factors were independently associated with cardiac rehabilitation referral. RESULTS Mean age was 64.1 +/- 13.0 years, 68% were men, 79% were white, and 30% had diabetes, 66% hypertension, and 52% dyslipidemia; mean body mass index was 29.1 +/- 6.3 kg/m(2), and mean ejection fraction 49.0 +/- 13.6%. All patients were admitted for coronary artery disease (CAD), with 71% admitted for myocardial infarction. Overall, only 40,974 (56%) were referred to cardiac rehabilitation at discharge, ranging from 53% for myocardial infarction to 58% for percutaneous coronary intervention and to 74% for coronary artery bypass graft patients. Older age, non-ST-segment elevation myocardial infarction, and the presence of most comorbidities were associated with decreased odds of cardiac rehabilitation referral. CONCLUSIONS Despite strong evidence for benefit, only 56% of eligible CAD patients discharged from these hospitals were referred to cardiac rehabilitation. Increased physician awareness about the benefits of cardiac rehabilitation and initiatives to overcome barriers to referral are critical to improve the quality of care of patients with CAD.

Age and sex differences in presentation of symptoms among patients with acute coronary disease: the REACT Trial. Rapid Early Action for Coronary Treatment

BACKGROUND There are few data on possible age and sex differences in presentation of symptoms for patients with acute coronary disease. OBJECTIVE To investigate demographic differences in presentation of symptoms at the time of hospital presentation for acute myocardial infarction (AMI) and unstable angina. METHODS The medical records of patients who presented with chest pain and who also had diagnoses of AMI (n = 889) or unstable angina (n = 893) on discharge from 43 hospitals were reviewed as part of data collection activities of the Rapid Early Action for Coronary Treatment trial based in 10 pair-matched communities throughout the USA. RESULTS Dyspnea (49%), arm pain (46%), sweating (35%), and nausea (33%) were commonly reported by men and women of all ages in addition to the presenting complaint of chest pain. After we had controlled for various characteristics through regression modeling, older persons with AMI were significantly less likely than were younger persons to complain of arm pain and sweating, and men were significantly less likely to report vomiting than were women. Among persons with unstable angina, arm pain and sweating were reported significantly less often by elderly patients. Nausea and back, neck, and jaw pain were more common complaints of women. CONCLUSIONS Results of this study suggest that there are differences between symptoms at presentation of men and women, and those in various age groups, hospitalized with acute coronary disease. Clinicians should be aware of these differences when diagnosing and managing patients suspected to have coronary heart disease.

The 6-minute walk test: how important is the learning effect?

BACKGROUND The 6-minute walk test is a submaximal exercise test that is widely used as an outcomes measure in clinical trials and cardiopulmonary rehabilitation. An initial learning effect with repeated administration is well documented, but it is unknown whether this learning effect persists with time. METHODS This study was designed to determine whether the learning effect persists after 2 months. Fifty healthy adults (mean age, 30.6 years; 48% men, 82% white) unfamiliar with the 6-minute walk test completed 3 walks at baseline (walks 1-3) and 3 walks at follow-up (walks 4-6). Height, weight, and self-reported physical activity were assessed at both points. Distances walked during the 6 walks were compared with a general linear model for repeated measures with post-hoc pairwise comparisons corrected by the Bonferroni method. A P value <.05 was considered to be significant. RESULTS The distance walked increased significantly between walks 1 and 3 (2046 +/- 228 ft to 2194 +/- 266 ft, P <.05). There was no difference in distance walked between walks 3 and 4, which were conducted 2 months apart. The distance walked increased significantly between walks 4 and 6 (2201 +/- 233 ft to 2285 +/- 257 ft, P <.05). The overall learning effect was inversely correlated with distance walked at walk 1, but was unrelated to age, sex, height, weight, or physical activity level. CONCLUSION The initial learning effect is maintained during a 2-month period. A more modest additional learning effect occurs during the follow-up walks. Both learning effects should be taken into account when using the 6-minute walk test as an outcomes measure.

Coronary artery disease and coronary artery bypass grafting in diabetic patients aged ≥65 years (report from the Coronary Artery Surgery Study [CASS] registry)

A cohort of 317 diabetic patients, aged > or = 65 years, with angiographically proven coronary artery disease, was analyzed and followed for a mean of 12.8 years. Compared with 1,843 age-matched nondiabetic patients, diabetic patients were more likely to (1) have a higher number of coronary occlusions, (2) not be current smokers, (3) have higher systolic but lower diastolic blood pressures, (4) have evidence of peripheral vascular disease, and (5) be women. They did not differ significantly with respect to total cholesterol, family history of coronary artery disease, history of hypertension, or left ventricular hypertrophy. In the total elderly cohort, diabetes was found to be an independent predictor of mortality, conferring a 57.0% increased risk of death. Survival analysis showed that diabetic subjects consistently had higher mortality than nondiabetics. However, the relative survival benefit of coronary artery bypass graft surgery versus medical therapy was comparable in diabetic and nondiabetic patients. Surgical therapy conferred a reduction in mortality of 44%.

The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE).

UNLABELLED High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women. METHODS We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Womens Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. RESULTS Mean age was 57 +/- 11 years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% CI 1.05-3.64, P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% CI 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but became nonsignificant when angiographic results were included. CONCLUSION Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events.