Cold Pressor Testing and Sympathetic Nervous System Contribution to Ischemia with No Obstructive Coronary Artery Disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project.

Study Objective: Cold Pressor Testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. Design: Prospective cohort. Setting: Academic hospital. Participants: 107 women with suspected INOCA and 21-age-matched reference women. Interventions: CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n=42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main Outcome Measure: MPRIRPP. Results: Compared to reference women, the INOCA group demonstrated higher resting RPP (p=0.005) and CPT MPRIRPP (1.09±0.36 vs 0.83±0.18, p=0.002). Furthermore, INOCA women with impaired ΔCBF (n=23) had higher CPT MPRIRPP (p=0.044) compared to reference women despite lower left ventricular ejection fraction (64±7 % vs 69±2 %, p=0.005) and mass-to-volume ratio (0.79±0.15 vs 0.62±0.09, p<0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. Conclusions: Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. CPT induced a higher MPRIRPP also in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Further investigation in a larger cohort is needed.

Cardiometabolic health after first pregnancy: Associations with social determinants of health. A nuMoM2b-HHS study.

Study objective: This study sought to evaluate the associations between social determinants of health (SDOH) at the time of first pregnancy and subsequent cardiometabolic health, defined as the development of metabolic syndrome. Design: nuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study- Monitoring Mothers-to-Be-Heart Health Study) is an ongoing prospective cohort study. Setting: Eight academic medical centers enrolled and continue to follow participants. Participants: 4484 participants followed a mean of 3.2 years from the time of their first pregnancy. Interventions: N/a. Main outcome measure: Unadjusted and adjusted Poisson regression models with robust standard errors were used to obtain relative risks and 95% confidence intervals estimating the risk of metabolic syndrome for each baseline SDOH. In secondary analyses we examined the associations between SDOH and incident hypertension, obesity, and diabetes mellitus. Results: Metabolic syndrome developed in 13.6% of participants. Higher socioeconomic position at the time of pregnancy was associated with lower rates of metabolic syndrome [income > 200% poverty level aRR 0.55 (95% CI, 0.42-0.71), attainment of a bachelor's degree aRR 0.62 (0.46-0.84) or higher aRR 0.50 (0.35-0.71)], while being single [aRR 1.45 (95% CI, 1.18-1.77)] and having low health literacy were associated with a greater risk of metabolic syndrome [aRR 1.98 (95% CI, 1.28-3.07)]. Conclusions: Over a short interval following first pregnancy, participants accumulated high proportions of cardiovascular risk factors and metabolic syndrome, with some risk associated with SDOH. The impact of interventions addressing SDOH in pregnant people on cardiometabolic health should be tested as a means of reducing health inequities at the population level.

Oral magnesium therapy improves endothelial function in patients with coronary artery disease.

BACKGROUND: Magnesium blocks many of the physiological actions of calcium. Nevertheless, the impact of magnesium supplementation on endothelial function and exercise tolerance in stable coronary artery disease (CAD) patients has not been assessed. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 50 stable CAD patients (41 men and 9 women, mean+/-SD age 67+/-11 years, age range 42 to 82 years) were randomized to receive either magnesium (n=25) (30 mmol/d Magnosolv-Granulat; Asta Medica Company, Inc) or placebo (n=25) for 6 months. Before and after 6 months, endothelium-dependent brachial artery flow-mediated vasodilation (FMD) and endothelium-independent NTG-mediated vasodilation were assessed with high-resolution (10-MHz) ultrasound. Exercise stress testing was performed with use of the Bruce protocol. Intracellular magnesium concentrations ([Mg(2+)](i)) were assessed from sublingual cells through x-ray dispersion (EXA) (normal mean+/-SD values 37. 9+/-4.0 mEq/L). The magnesium therapy significantly increased postintervention ([Mg(2+)](i) versus placebo (36.2+/-5.0 versus 32.7+/-2.7 mEq/L, P<0.02). There was a significant correlation in the total population between baseline [Mg(2+)](i) and baseline FMD (r=0. 48, P<0.01). The magnesium intervention resulted in a significant improvement in postintervention FMD (15.5+/-12.0%, P=0.02 compared with baseline), which was not evident with placebo (4.4+/-2.5%, P=0.78 compared with baseline). There was better exercise tolerance (9.3+/-2.0 versus 7.3+/-3.1 minutes, P=0.05) and less ischemic ST-segment changes (4 versus 10 patients, P=0.05) in the magnesium versus placebo groups, respectively. CONCLUSIONS: Oral magnesium therapy in CAD patients is associated with significant improvement in brachial artery endothelial function and exercise tolerance, suggesting a potential mechanism by which magnesium could beneficially alter outcomes in CAD patients.

The aggressive low density lipoprotein lowering controversy.

Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.

Changes in heart rate and heart rate variability before ambulatory ischemic events(1).

OBJECTIVES: The aim of this study was to determine the time course of autonomic nervous system activity preceding ambulatory ischemic events. BACKGROUND: Vagal withdrawal can produce myocardial ischemia and may be involved in the genesis of ambulatory ischemic events. We analyzed trajectories of heart rate variability (HRV) 1 h before and after ischemic events, and we examined the role of exercise and mental stress in preischemic autonomic changes. METHODS: Male patients with stable coronary artery disease (n = 19; 62.1 +/- 9.3 years) underwent 48-h ambulatory electrocardiographic monitoring. Frequency domain HRV measures were assessed for 60 min before and after each of 68 ischemic events and during nonischemic heart rate-matched control periods. RESULTS: High-frequency HRV decreased from -60, -20 to -10 min before ischemic events (4.8 +/- 1.3; 4.6 +/- 1.3; 4.4 +/- 1.2 ln [ms(2)], respectively; p = 0.04) and further from -4, -2 min, until ischemia (4.4 +/- 1.3; 4.1 +/- 1.3; 3.7 +/- 1.2 ln [ms(2)]; p's < 0.01). Low frequency HRV decreases started at -4 min (p < 0.05). Ischemic events occurring at high mental activities were preceded by depressed high frequency HRV levels compared with events at low mental activity (p = 0.038 at -4 min, p = 0.045 at -2 min), whereas the effects of mental activities were not observed during nonischemic control periods. Heart rate variability measures remained significantly decreased for 20 min after recovery of ST-segment depression when events were triggered by high activity levels. CONCLUSIONS: Autonomic changes consistent with vagal withdrawal can act as a precipitating factor for daily life ischemia, particularly in episodes triggered by mental activities.

Effect of coronary angiography on use of lipid-lowering agents in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study. For the WISE Investigators.

We sought to assess the impact of coronary angiography results on use of lipid-lowering agents among women enrolled in the Women's Ischemia Syndrome Evaluation [WISE] study. WISE is a multicenter study designed to evaluate new diagnostic modalities among women undergoing angiography for suspected coronary artery disease (CAD). History of atherosclerosis, risk factors for CAD, and low-density lipoprotein (LDL) cholesterol are determined at baseline. The percentage of women at LDL cholesterol goal, use of lipid-lowering agents, and eligibility for lipid-lowering therapy were determined based on National Cholesterol Education Program II guidelines at baseline and 6-week follow-up. Among the 212 women for whom angiographic data were available, 84 had known atherosclerosis, 80 had no history of atherosclerosis but > or =2 risk factors (high risk), and 48 had no history of atherosclerosis and <2 risk factors (low risk). At baseline, LDL cholesterol goals were met in 24% women with atherosclerosis, in 56% high-risk women, and in 88% low-risk women. Angiography revealed previously undiagnosed CAD in 70% of the high-risk and in 42% of the low-risk women. After angiography results were available, 6 women started lipid-lowering therapy and 2 stopped. Based on National Cholesterol Education Program II guidelines, 63 additional women would have been eligible for pharmacologic lipid-lowering therapy. Intensification of lipid-lowering therapy was not apparent 6 weeks after coronary angiography in women with newly diagnosed CAD or among women whose diagnosis was confirmed.

Prognostic value of mental stress testing in coronary artery disease.

This study assesses the prognostic value of mental stress-induced ischemic left ventricular wall motion abnormalities and hemodynamic responses in patients with stable coronary artery disease (CAD). Seventy-nine patients (76 men and 3 women) with prior positive exercise test results were exposed to mental arithmetic and a simulated public speech stress in 2 prior studies. Ischemic wall motion abnormalities were monitored using echocardiography or radionuclide ventriculography (RNV). During mental stress testing, new or worsened ischemic wall motion abnormalities to mental stress and exercise were ascertained, as were peak changes in blood pressure and heart rate to mental stress. The occurrence of subsequent cardiac events (including cardiac death, nonfatal myocardial infarction, or revascularization procedures) was ascertained. New cardiac events were observed in 28 of 79 patients (35%) after a median follow-up duration of 3.5 years (range 2.7 to 7.3). Survival analysis indicated that 20 of 45 patients with mental stress ischemia (44%) experienced new cardiac events more frequently than those without mental stress ischemia (8 of 34; 23%; p = 0.048). Type of cardiac event did not differ between mental stress-positive and stress-negative patients. After controlling for baseline blood pressure and study group status (echocardiography vs RNV), there was a significantly higher relative risk of subsequent events for patients with high versus low peak stress-induced diastolic blood pressure responses (RR = 2.4, confidence interval 1.1 to 5.2; p = 0.03). These results demonstrate that ischemic and hemodynamic measures obtained from mental stress testing may be useful in assessing prognosis in CAD patients with prior positive exercise test results.

Hormone therapy in women after heart transplantation.

BACKGROUND: Hormone therapy (HT) for menopausal women has been controversial regarding cardiac outcomes and adverse effects. Studies suggest that HT may cause increase in heart disease, stroke, and cancer. The use of HT in heart transplantation has not been firmly established. METHODS: The records of 356 female heart transplant recipients, undergoing transplantation from 1994 to 2011, were reviewed. We found 19 patients after age 35 years who were initiated on HT for noncontraceptive purposes. These patients were compared 1:3 with a contemporaneous control group matched for age, sex, era, and time after heart transplantation (paired for time from transplantation to initiation of HT). We assessed for subsequent 5-year survival, freedom from cardiac allograft vasculopathy (CAV; stenosis ≥ 30%), freedom from nonfatal major adverse cardiac events (NF-MACE; myocardial infarction, heart failure, percutaneous cardiac intervention, stroke, and need for pacemaker/defibrillator), and subsequent 1-year freedom from any-treated rejection. Additionally, we compared significant adverse effects of HT between groups. RESULTS: HT patients compared with control subjects revealed no significant difference in subsequent 5-year survival (79% vs 75%; P = .66), freedom from CAV (90% vs 88%; P = .85), or NF-MACE (90% vs 93%; P = .65). There was also no significant difference in subsequent 1-year freedom from any-treated rejection between the groups. Other adverse effects of HT including subsequent 5-year incidence of thrombosis (pulmonary embolus), malignancy, and stroke were also similar to control subjects. CONCLUSIONS: HT is not associated with poor outcome or adverse effects in female heart transplant patients after age 35 years. However, a larger cohort of patients is necessary to confirm these observations.

Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

OBJECTIVES: The beta-adrenergic receptor (betaAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the beta(1)AR (ADRB1), beta(2)AR (ADRB2), beta(3)AR (ADRB3), Gs protein alpha (GNAS1), to which all three beta-receptors couple and the G protein beta3 subunit (GNB3), to which beta(3)ARs couple. DESIGN: A case-control genetic association study. SUBJECTS: A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study. MEASUREMENTS: Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made. RESULTS: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity. CONCLUSIONS: Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the betaARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

Supervised exercise and electrocardiographic monitoring during cardiac rehabilitation. Impact on patient care.

PURPOSE: To determine the frequency of medical problem detection during supervised cardiac rehabilitation exercise, and to assess its impact on patient care alteration. METHODS: Six hundred sixty-six cardiac participants (388 in Phase II and 278 in Phase III) were studied during a 1-year period (1989-1990). The supervisory staff recorded all phone calls made to referring physicians regarding individual patient problems identified during exercise sessions including subsequent alteration in patient care. RESULTS: Overall, 112 of 666 (17%) of the patients had problems detected that prompted calls to referring physicians. There was 0.009 call per patient exercise hour, compared to 0.002 call per patient exercise hour in the Phase II and Phase III patients, respectively, P = .0001. Although Phase II patients had a higher uncorrected arrhythmia call frequency compared to the Phase III patients, arrhythmia call frequency was higher in Phase III patients, when corrected for the number of monitored exercise hours (P = .02). Fifty-five percent of calls resulted in patient care alteration, and telemetry-related calls and nontelemetry-related calls resulted in a similar proportion of patient care alteration. Overall, 11% (73 of 666) of patients had alteration of their care, of which 4% (24 of 666) resulted from telemetry-related calls. Clinical variables between the patients with calls versus the patients with no calls demonstrated that the call group were older, and had a more frequent history of hypertension. CONCLUSION: Medically supervised cardiac rehabilitation with and without telemetry monitoring detects problems that lead to alteration in medical care. Older patients have more problems detected. Medical problem detection may contribute to the beneficial impact of cardiac rehabilitation observed in randomized trials.

Cholesterol awareness and treatment in patients with coronary artery disease participating in cardiac rehabilitation.

OBJECTIVES: To survey cholesterol management practices among patients with coronary artery disease enrolled and not enrolled in cardiac rehabilitation. BACKGROUND: The National Cholesterol Education Program (NCEP) initially established guidelines regarding cholesterol awareness and treatment in 1987. Serum cholesterol reduction is most effective for reducing cardiac events in patients with established coronary artery disease, yet surveys of cholesterol awareness and treatment have not included these patients. METHODS: Three hundred seventy-nine men and women with coronary artery disease were surveyed according to cholesterol awareness, serum cholesterol level, frequency of lipid-lowering medication use, and frequency of achievement of a serum total cholesterol < 5.2 mmol/L (200 mg/dL) corresponding the 1987 NCEP guidelines for coronary artery disease patients, which were in place at the time of the study survey. RESULTS: Overall, 72% of the patients were aware of their cholesterol level, with an average serum total cholesterol of 5 5 +/- 1.0 mmol/L (213 +/- 39 mg/dL). Use of lipid-lowering medication was 26%. Forty-three percent had a total cholesterol < 5.2 mmol/L (200 mg/dL). Patients enrolled in a long-term cardiac rehabilitation program demonstrated enhanced cholesterol awareness (78%), lower total cholesterol values (5.2 +/- 0.9 mmol/L [203 +/- 36 mg/dL]), higher use of lipid-lowering the therapy (34%), and more frequent achievement of total serum cholesterol of < 5.2 mmol/L (200 mg/dL) (48%) compared to the other patient groups (all P < .05). CONCLUSIONS: Patients with coronary artery disease demonstrate relatively low rates of cholesterol awareness, lipid-lowering medication use, and achievement of total serum cholesterol < 5.2 mmol/L (200 mg/dL) corresponding to the 1987 NCEP guidelines. Participation in long-term cardiac rehabilitation is associated with enhancement of these rates. Further efforts to educate physicians and develop programs to optimize cholesterol management in patients with coronary artery disease are needed.

Intracellular magnesium predicts functional capacity in patients with coronary artery disease.

To determine whether increased intracellular levels of magnesium ([Mg]i) are associated with enhanced functional capacity, we performed symptom-limited exercise treadmill testing on 42 stable coronary artery disease (CAD) patients (37 men, 5 women, mean age 68 +/- 9 years). [Mg]i was found to be an independent and significant predictor of exercise duration (R = 0.31, p = 0.02) in a multivariate stepwise regression model. Patients with > normal [Mg]i of 1.23 microg/mg protein (n = 13) had a significantly greater mean functional capacity, measured in higher achieved metabolic equivalents (10.6 +/- 2.5 vs. 8.9 +/- 2.3, p < 0.05) and exercise duration (9.4 +/- 2.3 vs. 7.9 +/- 2.2 min, p < 0.05) compared to patients with [Mg]i

Cardiovascular stress response and coronary artery disease: evidence of an adverse postmenopausal effect in women.

OBJECTIVES: To test the hypothesis that postmenopausal women demonstrate greater vascular instability, measured by enhanced cardiovascular stress responses during mental stress, compared with men and premenopausal women. BACKGROUND: Recent data suggest that estrogen plays a role in regulating vascular tone. The possible consequences of estrogen deficiency during menopause on systemic vascular reactivity is largely unexplored. METHODS: One hundred subjects (84 men and 16 women) underwent mental stress testing with radionuclide ventriculo graphy. Study subjects included 19 normal volunteers, 23 control subjects with chest pain syndromes or hypertension but without coronary artery disease, and 58 coronary artery disease subjects. The subjects performed a series of three mental stress tasks, during which hemodynamic data and radionuclide ventriculograms were obtained. RESULTS: Overall, women demonstrated greater hemodynamic responses during mental stress measured by changes in heart rate, systolic and diastolic blood pressure, and double product compared with those of men (all p < 0.05). Women with coronary artery disease demonstrated greater heart rate, diastolic blood pressure, and double product stress responses than their male counterparts (all p < 0.05). Women of postmenopausal age demonstrated significantly greater systolic blood pressure reactivity than men or premenopausal women (p < 0.05). CONCLUSIONS: Women of postmenopausal age have greater cardiovascular responses to stress than men or premenopausal women. These findings suggest an additional mechanism by which estrogen deficiency conveys a poor prognosis in female patients with coronary artery disease.

Plasma apolipoprotein B levels predict platelet-dependent thrombosis in patients with coronary artery disease.

Elevated plasma apolipoprotein B is a known risk factor for atherosclerotic coronary artery disease (CAD), however its relationship to arterial thrombosis is unexplored. We prospectively assessed apolipoprotein B and platelet-dependent thrombosis (PDT) in 42 CAD patients (37 men, 5 women, mean age 68 +/- 9 years), by exposing porcine aortic media to their flowing unanticoagulated venous blood for 5 min using an ex vivo perfusion (Badimon) chamber. PDT was significantly correlated with apolipoprotein B (r = 0.41, p = 0.009), intracellular magnesium levels (r = -0.46, p = 0.003) fasting blood glucose (r = 0.47, p = 0.002), and total cholesterol (r = 0.43, p = 0.006). PDT did not correlate with serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I or fibrinogen levels. These findings suggest that the positive relationship of elevated apolipoprotein B to CAD may be, in part, related to its prothrombotic effects.

Physical activity and functional capacity measurement in women: a report from the NHLBI-sponsored WISE study.

Physical activity and functional capacity have not been assessed by questionnaire for criterion validity in women. We wished to evaluate the ability of a physical activity and a functional capacity assessment questionnaire to predict functional capacity measured by treadmill exercise stress testing, as well as correlate with cardiac risk factors and angiographic coronary artery disease (CAD) in women. In a National Heart, Lung and Blood Institute (NHLBI)-sponsored cross-sectional population study involving four academic medical centers, 476 women with cardiac risk factors undergoing coronary angiography for evaluation for suspected myocardial ischemia were enrolled in the Women's Ischemia Syndrome Evaluation (WISE). The main outcome measures were functional capacity measured during symptom-limited exercise treadmill testing, cardiac risk factors, and CAD, using core laboratory-determined measures. Physical activity measured by the Postmenopausal Estrogen and Progesterone Intervention physical activity questionnaire (PEPI-Q) and functional capacity measured by the Duke Activity Status Index (DASI) questionnaire, correlated with functional capacity measured in metabolic equivalents (METS), as estimated during symptom-limited exercise treadmill testing (r = 0.27, p = 0.001 and r = 0.31, p = 0. 0002, respectively). The DASI was a significant independent predictor of functional capacity even after adjustment for cardiac risk factors, and the PEPI-Q was not. The DASI and PEPI-Q scores were inversely associated with higher numbers and levels of cardiac risk factors, as well as angiographic CAD. The DASI questionnaire is a reasonable correlate of functional capacity achieved during symptom-limited treadmill exercise testing in women with suspected myocardial ischemia. Lower functional capacity or physical activity measured by the DASI and PEPI-Q, respectively, is associated with more prevalent cardiac risk factors and angiographic CAD. These findings suggest that the DASI and, to a lesser extent, the PEPI-Q have criterion validity for use in health-related research in women.