Fitness attenuates long-term cardiovascular outcomes in women with ischemic heart disease and metabolic syndrome.

Background: The prevalence of metabolic syndrome continues to increase steadily while fitness remains relatively low. The contribution of fitness on longer-term cardiovascular outcomes and mortality in individuals with cardiovascular disease and metabolic syndrome remains unknown. Design: Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1996-2001) of women undergoing invasive coronary angiography with signs/symptoms of ischemic heart disease. Methods: Investigated the association of fitness, defined as >7METs measured by self-reported Duke Activity Status Index (DASI), and both metabolic syndrome (ATPIII criteria) and dysmetabolism (ATPIII criteria and/or treated diabetes) with long-term cardiovascular outcomes and all-cause mortality risk. Results: Among the 492 women followed for a median of 8.6 years (range 0-11 years), 19.5% were fit-metabolically healthy (reference), 14.4% fit-metabolic syndrome, 29.9% unfit-metabolically healthy, and 36.2% unfit-metabolic syndrome. Compared to reference, MACE risk was 1.52-fold higher in fit-metabolic syndrome women (HR 1.52, 95% CI 1.03-2.26) and 2.42-fold higher in unfit-metabolic syndrome women (HR 2.42, 95% CI 1.30-4.48). Compared to reference, mortality risk was 1.96-fold higher in fit-dysmetabolism (HR 1.96, 95% CI 1.29-3.00) and 3-fold higher in unfit-dysmetabolism women (HR 3.0, 95% CI 1.66-5.43). Conclusions: In a high risk cohort of women with signs/symptoms of ischemic heart disease, unfit-metabolically healthy and fit-metabolically unhealthy women were at higher risk of long-term MACE and mortality compared to fit-metabolically healthy women; and women who were unfit and metabolically unhealthy were at the highest risk. Our study demonstrates that metabolic health and fitness play an important role in long term outcomes that warrants further investigation. Registration: https://www.clinicaltrials.gov/ct2/show/NCT00000554 (NCT00000554).

Prognostic association of plasma NT-proBNP levels in patients with microvascular angina -A report from the international cohort study by COVADIS.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) with clinical outcomes of patients with microvascular angina (MVA). Methods: In this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. Results: We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e' 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365-482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14-8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P < 0.03). Finally, a significant positive correlation was observed between plasma NT-proBNP levels and E/e' (R = 0.445, P < 0.0001). Conclusions: These results indicate that plasma NT-proBNP levels may represent a novel prognostic biomarker for MVA patients.

Trans-myocardial omega-3 fatty acid gradient in coronary microvascular dysfunction.

Background: Cardiac remodeling is a process mediated, in part, by 18-hydroxyeicosapentaenoic acid (HEPE), a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). We hypothesized that trans-myocardial levels of 18-HEPE could inform the pathophysiologic processes involved in heart failure with preserved ejection fraction (HFpEF). Methods: We measured the concentration of 18-HEPE and EPA in trans-myocardial plasma samples from 10 subjects enrolled in The Women's Ischemia Syndrome Evaluation [WISE] Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-HFpEF project. Results: Concentrations of 18-HEPE were significantly lower in coronary venous compared to the aortic plasma (270.5 pg/mL [212.8-480.8] vs. 430.5 pg/mL [299.5-655.8], p = 0.0039). There was a significant correlation between the concentrations of coronary venous EPA and aortic 18-HEPE (r = 0.94, p = 0.0002), and aortic EPA and aortic 18-HEPE (r = 0.82, p = 0.0058). Conclusions: Results of this small pilot study support the suggestion that 18-HEPE is synthesized outside the heart and utilized within the myocardial bed.

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

BACKGROUND/OBJECTIVES: Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia. SUBJECTS/METHODS: We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use. RESULTS: The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes. CONCLUSIONS: Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.

International prospective cohort study of microvascular angina - Rationale and design.

BACKGROUND: Patients with signs and symptoms of myocardial ischemia and non-obstructive coronary artery disease (CAD) frequently have coronary functional abnormalities, including coronary microvascular dysfunction. Those with the latter are grouped under the term "microvascular angina" (MVA). Although diagnostic criteria exist for MVA, as recently proposed by our COVADIS (COronary VAsomotor Disorders International Study) group and the condition has been increasingly recognized in clinical practice, the clinical characteristics and long-term prognosis of MVA patients in the current era remain to be fully elucidated. AIMS: In the present study, we aimed to prospectively assess the clinical characteristics and long-term prognosis of MVA subjects in the current era in an international, multicenter, observational, and prospective registry study. METHODS: A total of 15 medical centers across 7 countries (USA, UK, Germany, Spain, Italy, Australia, and Japan) enrolled subjects fulfilling the COVADIS diagnostic criteria for MVA as follows; (1) signs and/or symptoms of myocardial ischemia, (2) absence of obstructive CAD, and (3) objective evidence of myocardial ischemia and/or coronary microvascular dysfunction. The primary endpoint was the composite of major cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to heart failure or unstable angina. Between July 2015 and December 2018, a total of 706 subjects with MVA (M/F 256/450, 61.1 ± 11.8 [SD] yrs.) were registered. Subjects will be followed for at least 1 year. SUMMARY: The present study will provide important information regarding the clinical characteristics, management, and long-term prognosis of MVA patients in the current era.

Not typical angina and mortality in women with obstructive coronary artery disease: Results from the Women's Ischemic Syndrome Evaluation study (WISE).

BACKGROUND: Women frequently present with symptoms not typical of angina (NTA) making ischemic heart disease recognition, diagnosis and treatment challenging. We compared mortality in women with obstructive coronary artery disease (CAD) with NTA vs typical angina (TA). METHODS: We studied 326 Women's Ischemia Syndrome Evaluation (WISE) participants undergoing coronary angiography for suspected myocardial ischemia with core-lab measured obstructive CAD. TA was defined as sub-sternal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin; NTA did not meet criteria for TA. The women were followed for non-fatal events and death for a median of 5.9 and 9.6 years respectively. Multivariate cox proportional hazards regression determined relations to events. RESULTS: Overall, 115 (35%) of the women had TA. Baseline demographics, risk factors or additional symptom characteristics were similar between the two angina groups. Non-fatal events did not differ between groups. Women with NTA had a higher mortality compared to TA women (36% vs 26%, respectively, p = 0.047). Despite adjustment for additional major risk variables, NTA was an independent predictor of mortality compared to TA with a hazard ratio of 1.73 (95% Confidence interval: 1.04, 2.89). CONCLUSIONS: Among women with suspected ischemia undergoing coronary angiography with obstructive CAD, NTA was more common than TA, and predicted a higher longer-term mortality. Further investigation is needed to confirm these results, and investigate potential explanations for the higher mortality observed in women with NTA women, including lower recognition or action in the setting of obstructive CAD.

Sex differences in ischemic heart disease and heart failure biomarkers.

Since 1984, each year, more women than men die of ischemic heart disease (IHD) and heart failure (HF), yet more men are diagnosed. Because biomarker assessment is often the first diagnostic employed in such patients, understanding biomarker differences in men vs. women may improve female morbidity and mortality rates.Some key examples of cardiac biomarker utility based on sex include contemporary use of "unisex" troponin reference intervals under-diagnosing myocardial necrosis in women; greater use of hsCRP in the setting of acute coronary syndrome (ACS) could lead to better stratification in women; and greater use of BNP with sex-specific thresholds in ACS could also lead to more timely risk stratification in women.Accurate diagnosis, appropriate risk management, and monitoring are key in the prevention and treatment of cardiovascular diseases; however, the assessment tools used must also be useful or at least assessed for utility in both sexes. In other words, going forward, we need to evaluate sex-specific reference intervals or cutoffs for laboratory tests used to assess cardiovascular disease to help close the diagnostic gap between men and women.

Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease).

The syndromes of myocardial infarction/myocardial ischemia with No Obstructive Coronary Artery Disease (MINOCA/INOCA) are increasingly evident. A majority of these patients have coronary microvascular dysfunction. These patients have elevated risk for a cardiovascular event (including acute coronary syndrome, myocardial infarction, stroke, and repeated cardiovascular procedures) and appear to be at higher risk for development of heart failure with preserved ejection fraction. Terminology such as coronary artery disease or coronary heart disease is often synonymous with obstructive atherosclerosis in the clinician's mind, leaving one at a loss to recognize or explain the phenomenon of MINOCA and INOCA with elevated risk. We review the available literature regarding stable and unstable ischemic heart disease that suggests that use of the ischemic heart disease (IHD) terminology matters for women, and should facilitate recognition of risk to provide potential treatment targets and optimized health.

Mental stress peripheral vascular reactivity is elevated in women with coronary vascular dysfunction: Results from the NHLBI-sponsored Cardiac Autonomic Nervous System (CANS) study.

BACKGROUND: Women with chest pain, ischemia, and no obstructive coronary artery disease often have coronary vascular dysfunction (CVaD). Peripheral vascular reactivity to mental stress may contribute mechanistic understanding of stress-induced ischemia in women with CVaD. METHODS: 62 women (41 CVaD and 21 controls) underwent mental stress testing (MST) with anger recall, mental arithmetic, and forehead cold pressor (COP) challenge. Emotional arousal was measured (Likert scale). Reactive hyperemia index (RHI) was calculated before and after MST by peripheral arterial tonometry (PAT). Stress PAT ratio (SPR) of pulse amplitude during stress to rest was obtained to measure vasoconstriction. Wilcoxson rank sum test was used for analysis. RESULTS: Mean age of CVaD and control groups was 58±9 and 55±10years (p=0.73). Baseline RHI correlated with coronary endothelial function (r=0.36, p=0.03) and inversely with RHI change post-MST (r=-0.51, p<0.001). During MST, 10% of controls reported chest pain vs. 41% of CVaD subjects (p=0.01). RHI did not change significantly after MST in either group. CVaD subjects had lower SPR vs. controls during mental arithmetic (0.54 [0.15, 1.46] vs. 0.67 [0.36, 1.8], p=0.039), not evident in the other tasks. Vasoconstriction inversely correlated with anxiety (r=-3.4, p=0.03), frustration (r=-0.37, p=0.02), and feeling challenged (r=-0.37, p=0.02) in CVaD but not controls. CONCLUSIONS: Mental stress peripheral vascular reactivity is elevated in women with CVaD compared to controls. Elevated vascular reactivity may be one contributor to stress-induced chest pain in CVaD. Interventions that modulate vasoconstrictive responses may be of benefit and should be tested in clinical trials in women with CVaD.

Do women with statin-related myalgias have low vitamin D levels?

BACKGROUND: Statin intolerance is often due to myalgias. Severe vitamin D deficiency is characterized by musculoskeletal pain. We hypothesized that statin-intolerance is associated with vitamin D deficiency. OBJECTIVES: To determine whether there is an association between statin-intolerance and vitamin D deficiency in a retrospective observational analysis. METHODS: We evaluated 20 female patients with prior myalgia-related daily dose statin intolerance on an alternative day statin dosing protocol of twice weekly for 4 weeks followed by advancement to daily dosing, as tolerated. Fasting baseline and follow-up lipid and 25-hydroxy-vitamin D (25-OHD) levels were obtained by chart review. RESULTS: The group median age was 61 ± 13 years old and BMI was 27 ± 7 kg/m(2). Women who remained on alternative day statin dosing (n = 16) compared to women on daily dosing (n = 4) had a significantly lower group mean 25-OHD (mean 29 ± 11.23 vs. 47.5 ± 23.53 ng/ml p = 0.0307 respectively). CONCLUSIONS: In women with prior myalgia-related statin intolerance, vitamin D levels were significantly lower in women who remained on alternative day dosing compared to those who were tolerant of daily dosing.

Cardiovascular and mortality risk of apparent resistant hypertension in women with suspected myocardial ischemia: a report from the NHLBI-sponsored WISE Study.

BACKGROUND: Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (WISE) analysis, we assessed long-term adverse outcomes associated with apparent treatment-resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography. METHODS AND RESULTS: Women (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow-up. Apparent treatment-resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow-up. Risk of all-cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension. CONCLUSIONS: In this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long-term risk of major adverse events, including death, that emerged early during follow-up.

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.