C. Noel Bairey Merz

Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function.

Diastolic dysfunction measured by cardiac magnetic resonance imaging in women with signs and symptoms of ischemia but no obstructive coronary artery disease

BACKGROUNDnWomen with chest pain and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). The relationship between CMD and diastolic function measured by cardiac magnetic resonance imaging (CMR) is not well described.nnnMETHODSn41 women with suspected CMD underwent CRT and CMR. Left ventricular end-diastolic pressure (LVEDP), coronary flow reserve (CFR) and coronary blood flow (CBF) were measured invasively. Resting CMR of these women and 20 reference controls was assessed for LV mass, septal wall thickness, ejection fraction (LVEF), end-diastolic volume (EDV), peak filling rate (PFR) and time-to-peak-filling rate (tPFR). Pearson correlations and linear regression models were made.nnnRESULTSnMean age was 55±9, all had LVEF≥50%, and 16/41 (40%) had LVEDP>15mmHg. CMD (CFR<2.5 or CBF<50%) was present in 34/41 (83%) women. tPFR (mean 178±110ms) and PFR (mean 3.2±0.64 EDV/s) were not significantly different in women with or without CMD. tPFR increased with age (r=0.37, p=0.017) and septal wall thickness (r=0.47, p=0.002), while PFR decreased with age (r=-0.45, p=0.003). There was an inverse relationship between CFR and tPFR (r=-0.3, p=0.058). Increasing mass was associated with decreasing CBF (p=0.02). Compared to controls, cases had lower LVEF (p=0.049) and lower EDV (p=0.0002).nnnCONCLUSIONnIn women with signs and symptoms of ischemia but no obstructive coronary artery disease, CMD and elevated LVEDP are prevalent. While non-endothelial dependent CMD may be related to diastolic dysfunction, further investigation is needed regarding links between CMD, diastolic dysfunction and the development of heart failure with preserved LVEF.

Migraine Headache and Long Term Cardiovascular Outcomes: An extended follow-up of the Women's Ischemia Syndrome Evaluation.

BACKGROUNDnThe association between migraine headache and cardiovascular events has been inconsistent. This study determines the long-term risk of cardiovascular events among women with and without a history of migraine headache who were under evaluation for suspected myocardial ischemia in the Womens Ischemia Syndrome Evaluation (WISE).nnnMETHODSnThe WISE is a National Heart, Lung and Blood Institute-sponsored prospective, multicenter study that aims to improve myocardial ischemia evaluation in women. A total of 936 women presenting with symptoms of myocardial ischemia underwent structured data collection and coronary angiography. Information pertaining to migraine headache was available in 917 women. All-cause mortality data were available on all women for a median of 9.5 years, and nonfatal cardiovascular event data were available on 888 women for a median of 6.5 years.nnnRESULTSnA total of 224 (24.4%) women reported a history of migraine headache. Compared with women who did not report a history of migraine headache, women with a history of migraine headache had an increased adjusted risk of cardiovascular event (cardiovascular death, nonfatal myocardial infarction, heart failure, or stroke) (hazard ratio 1.83; 95% confidence interval, 1.22-2.75) at a median follow-up of 6.5 years. This result was driven mainly by a twofold increase in the risk of stroke (hazard ratio 2.33; 95% confidence interval, 1.16-4.68).nnnCONCLUSIONnAmong women being evaluated for ischemic heart disease, those reporting a history of migraine headache had increased risk of future cardiovascular events on long-term follow-up. This risk was primarily driven by a more-than twofold increase in the risk of stroke.

Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE)

Background Women with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women. Methods We performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes. Results Among 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2–5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1–3.0], p = 0.01) (1.5 [1.0–2.1], p = 0.04), respectively. Conclusion In women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.

Myocardial tissue deformation is reduced in subjects with coronary microvascular dysfunction but not rescued by treatment with ranolazine.

Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine—a late sodium current inhibitor—improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD).

Ten-Year Mortality in the WISE Study (Women’s Ischemia Syndrome Evaluation)

Background— The WISE study (Women’s Ischemia Syndrome Evaluation) was a prospective cohort study of 936 clinically stable symptomatic women who underwent coronary angiography to evaluate symptoms and signs of ischemia. Long-term mortality data for such women are limited. Methods and Results— Obstructive coronary artery disease (CAD) was defined as ≥50% stenosis on angiography by core laboratory. We conducted a National Death Index search to assess the mortality of women who were alive at their final WISE contact date. Death certificates were obtained. All deaths were adjudicated as cardiovascular or noncardiovascular by a panel of WISE cardiologists masked to angiographic data. Multivariate Cox proportional hazards regression was used to identify significant independent predictors of mortality. At baseline, mean age was 58±12 years; 176 (19%) were non-white, primarily black; 25% had a history of diabetes mellitus, 59% hypertension, 55% dyslipidemia, and 59% had a body mass index ≥30. During a median follow-up of 9.5 years (range, 0.2–11.5 years), a total of 184 (20%) died. Of these, 115 (62%) were cardiovascular deaths; 31% of all cardiovascular deaths occurred in women without obstructive CAD (<50% stenosis). Independent predictors of mortality were obstructive CAD, age, baseline systolic blood pressure, history of diabetes mellitus, history of smoking, elevated triglycerides, and estimated glomerular filtration rate. Conclusions— Among women referred for coronary angiography for signs and symptoms of ischemia, 1 in 5 died from predominantly cardiac pathogeneses within 9 years of angiographic evaluation. A majority of the factors contributing to the risk of death seem to be modifiable by existing therapies. Of note, 1 in 3 of the deaths in this cohort occurred in women without obstructive CAD, a condition often considered benign and without guideline-recommended treatments. Clinical trials are needed to provide treatment guidance for the group without obstructive CAD.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

Background Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Womens Ischemia Syndrome Evaluation) study. Methods and Results Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non‐SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person‐hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). Conclusions SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial

Background Digital wearable devices provide a “real-world” assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown. Objective Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial. Methods We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and coronary microvascular dysfunction (CMD) with no obstructive coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function. Results A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed. Conclusions We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research. Trial Registration Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO)

Phosphodiesterase type 5 inhibition may reduce diastolic function in women with ischemia but no obstructive coronary artery disease

BackgroundIschemia, in the absence of obstructive coronary artery disease, is prevalent in women, and associated with increased risk for major cardiovascular events. Coronary microvascular dysfunction is prevalent in these patients, and associated with impaired diastolic function. Despite our general understanding, however, optimal treatment of this cohort remains elusive.MethodsTo address this knowledge gap, we performed an open-label treatment trial to assess whether phosphodiesterase type 5 inhibition improves coronary microvascular perfusion and diastolic function in women with signs and symptoms of ischemia but no evidence of obstructive coronary artery disease. Left ventricular morphology and function, along with myocardial perfusion reserve index, were assessed by contrast-enhanced cardiac magnetic resonance imaging.ResultsA total of five women enrolled of which four completed the trial, while one was withdrawn by the investigators after developing dyspnea 1xa0week after treatment. Her symptoms resolved after cessation of the study medication. In contrast to our hypothesis, phosphodiesterase type 5 inhibition reduced the rate of circumferential strain in diastole in all four women who completed the trial (that is, diastolic dysfunction). This impairment could not be explained by changes in heart rate, contractility, blood pressure, or preload, and was not associated with a change in myocardial perfusion reserve index. Frequency of angina also tended to increase with treatment, with the greatest increase occurring in the patient with the greatest impairment in diastolic strain.ConclusionsTaken together, these data question the efficacy of phosphodiesterase type 5 inhibition to treat women with ischemic heart disease, and highlight the need for further investigation.

Typical angina is associated with greater coronary endothelial dysfunction but not abnormal vasodilatory reserve

Typical angina (TA) is defined as substernal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin. Women and elderly patients are usually have atypical symptoms both at rest and during stress, often in the setting of nonobstructive coronary artery disease (CAD).