Myocardial ischemia with no obstructive coronary arteries (INOCA) is a chronic coronary syndrome condition that is increasingly being recognized as a substantial contributor to adverse cardiovascular mortality and outcomes, including myocardial infarction and heart failure with preserved ejection fraction (HFpEF). While INOCA occurs in both women and men, women are more likely to have the finding of INOCA and are more adversely impacted by angina, with recurrent hospitalizations and a lower quality of life with this condition. Abnormal epicardial coronary vascular function and coronary microvascular dysfunction (CMD) have been identified in a majority of INOCA patients on invasive coronary function testing. CMD can co-exist with obstructive epicardial CAD, diffuse non-obstructive epicardial CAD, and with coronary vasospasm. Epicardial vasospasm can also occur with normal coronary arteries that have no atherosclerotic plaque on intravascular imaging. While all predisposing factors are not clearly understood, cardiometabolic risk factors, and endothelium dependent and independent mechanisms that increase oxidative stress and inflammation are associated with microvascular injury, CMD and INOCA. Cardiac autonomic dysfunction has also been implicated in abnormal vasoreactivity and persistent symptoms. INOCA is under-recognized and under-diagnosed, partly due to the heterogenous patient populations and mechanisms. However, diagnostic testing methods are available to guide INOCA management. Treatment of INOCA is evolving, and focuses on cardiac risk factor control, improving ischemia, reducing atherosclerosis progression, and improving angina and quality of life. This review focuses on INOCA, relations to HFpEF, available diagnostics, current and investigational therapeutic strategies, and knowledge gaps in this condition.

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).

Background The autonomic response to acute emotional stress can be highly variable, and pathological responses are associated with increased risk of adverse cardiovascular events. We evaluated the autonomic response to stress reactivity of young healthy subjects and aging subjects with coronary artery disease to understand how the autonomic stress response differs with aging. Methods Physiologic reactivity to arithmetic stress in a cohort of 25 young, healthy subjects (< 30 years) and another cohort of 25 older subjects (> 55 years) with CAD was evaluated using electrocardiography, impedance cardiography, and arterial pressure recordings. Stress-related changes in the pre-ejection period (PEP), which measures sympathetic activity, and high frequency heart rate variability (HF HRV), which measures parasympathetic activity, were analyzed as primary outcomes. Results Mental stress reduced PEP in both groups (p<0.01), although the decrease was 50% greater in the healthy group. Mean HF HRV decreased significantly in the aging group only (p = 0.01). Discussion PEP decreases with stress regardless of health and age status, implying increased sympathetic function. Its decline with stress may be attenuated in CAD. The HF HRV (parasympathetic) stress reactivity is more variable and attenuated in younger individuals; perhaps this is related to a protective parasympathetic reflex. Trial registration ClinicalTrials.gov Identifier: NCT02657382.

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.

Background: Mental stress–induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease. Women with coronary artery disease tend to have more mental stress–induced myocardial ischemia and more chest pain/anginal symptoms than men, but whether the association between mental stress–induced myocardial ischemia and angina burden differs in women and men is unknown. Methods: This was a cross-sectional study with experimental manipulation of 950 individuals with stable coronary artery disease. Chest pain/angina frequency in the previous 4 weeks was assessed with the Seattle Angina Questionnaire's angina-frequency subscale. Mental stress–induced myocardial ischemia was assessed with myocardial perfusion imaging during mental stress (standardized public speaking task). Presence of mental stress–induced myocardial ischemia was based on expert readers and established criteria. A conventional (exercise or pharmacologic) stress test was used as a control condition. Results: Overall, 338 individuals (37%) reported angina; 112 (12%) developed mental stress–induced myocardial ischemia, and 256 (29%) developed conventional stress ischemia. Women who reported angina had almost double the probability to develop mental stress–induced myocardial ischemia (19% vs 10%, adjusted prevalence rate ratio, 1.90; 95% confidence interval, 1.04-3.46), whereas there was no such difference in men (11% vs 11%, adjusted prevalence rate ratio, 1.09; 95% confidence interval, 0.66-1.82). No association was found between angina symptoms and conventional stress ischemia for women or men. Results for ischemia as a continuous variable were similar. Conclusions: In women, but not in men, anginal symptoms may be a marker of vulnerability toward ischemia induced by psychologic stress. These results highlight the psychosocial origins of angina in women and may have important implications for the management and prognosis of women with angina.

Takotsubo syndrome (TTS) is caused by catecholamine surge, which is also observed in COVID-19 disease due to the cytokine storm. We performed a systematic literature search using PubMed/Medline, SCOPUS, Web of Science, and Google Scholar databases to identify COVID-19-associated TTS case reports and evaluated patient-level demographics, clinical attributes, and outcomes. There are 12 cases reported of TTS associated with COVID-19 infection with mean age of 70.8 ± 15.2 years (range 43-87 years) with elderly (66.6% > 60 years) female (66.6%) majority. The time interval from the first symptom to TTS was 8.3 ± 3.6 days (range 3-14 days). Out of 12 cases, 7 reported apical ballooning, 4 reported basal segment hypo/akinesia, and 1 reported median TTS. Out of 12 cases, during hospitalization, data on left ventricular ejection fraction (LVEF) was reported in only 9 of the cases. The mean LVEF was 40.6 ± 9.9% (male, 46.7 ± 5.7%, and female, 37.7 ± 10.6%). Troponin was measured in all 12 cases and was elevated in 11 (91.6%) without stenosis on coronary angiography except one. Out of 11 cases, 6 developed cardiac complications with 1 case each of cardiac tamponade, heart failure, myocarditis, hypertensive crisis, and cardiogenic shock in 2. Five patients required intubation, 1 patient required continuous positive airway pressure, and 1 patient required venovenous extracorporeal membrane oxygenation. The outcome was reported in terms of recovery in 11 (91.6%) out of 12 cases, and a successful recovery was noted in 10 (90.9%) cases. COVID-19-related TTS has a higher prevalence in older women. Despite a lower prevalence of cardiac comorbidities in COVID-19 patients, direct myocardial injury, inflammation, and stress may contribute to TTS with a high complication rate.

Clinical Cardiology published by Wiley Periodicals, Inc. Background: 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). Hypothesis: To further understand this, we performed subgroup analysis comparing subjects who presented with TA vs nontypical angina (NTA) using baseline data of patients with nonobstructive CAD and coronary microvascular dysfunction (CMD) enrolled in a clinical trial. Methods: 155 subjects from the RWISE study were divided into 2 groups based on angina characteristics: TA (defined as above) and NTA (angina that does not meet criteria for TA). Coronary reactivity testing (responses to adenosine, acetylcholine, and nitroglycerin), cardiac magnetic resonance–determined myocardial perfusion reserve index (MPRI), baseline Seattle Angina Questionnaire (SAQ), and Duke Activity Status Index (DASI) scores were evaluated. Results: The mean age was 55 ± 10 years; Overall, 30% of subjects had TA. Baseline shortness of breath, invasively assessed acetylcholine-mediated coronary endothelial function, and SAQ score were worse in the TA group (all P < 0.05), whereas adenosine-mediated coronary flow reserve, MPRI, and DASI score were similar to the NTA group. Conclusions: Among subjects with CMD and no obstructive CAD, those with TA had more angina pectoris, shortness of breath, and worse quality of life, as well as more severe coronary endothelial dysfunction. Typical angina in the setting of CMD is associated with worse symptom burden and coronary endothelial dysfunction. These results indicate that TA CMD subjects represent a relatively new CAD phenotype for future study and treatment trials.

Symptomatic individuals suspected of having myocardial ischemia often have no obstructive atherosclerotic narrowing of epicardial coronary arteries. Abnormal coronary vascular reactivity and, in particular, coronary artery vasospasm (CAS) may be an explanation in a subset of these patients. Psychological factors play an important role in ischemic heart disease, but their role in CAS is not clear; autonomic dysfunction and increased inflammation are two prevailing pathophysiological mechanisms implicated in abnormal coronary reactivity resulting from mental health conditions. Interrelationships between psychological factors, abnormal coronary reactivity, and sex/gender differences are poorly defined in the etiology of CAS. In this issue of Psychosomatic Medicine (2019;81:237-245), Hung et al. report a frequency of less than 0.1% of new-onset CAS in the Taiwanese population, with higher occurrence in women and younger individuals. Patients with CAS had a higher prevalence of previous anxiety and depression compared with those with coronary artery disease and controls, with no sex differences. In this editorial comment, we discuss the potential reasons for underreporting of CAS and the challenges regarding the use of administrative health records for psychosomatic research. In this editorial, a model is presented to explain the association between emotional stressors and mental health factors with CAS, including the role of sympathetic nervous system activation, inflammation, oxidative stress, endothelial dysfunction, and smooth muscle cell dysregulation.

Background: Recurrent hospitalization is prevalent in women with signs and symptoms of ischemia and no obstructive coronary artery disease. We hypothesized that rates of angina hospitalization might have changed over time, given advances in diagnostic and therapeutic approaches. Methods and Results: We evaluated 551 women enrolled in the WISE (Women's Ischemia Syndrome Evaluation) study with no obstructive coronary artery disease (CAD) for a follow-up period of 9.1 years. We analyzed angina hospitalization rates using the Kaplan-Meier method. Univariate analysis and multivariable Cox proportional hazard models were developed for prediction of angina hospitalization in women with signs and symptoms of angina and no CAD. A total of 223 women had nonobstructive CAD (>20–50% <stenosis) and 328 had no CAD (<20% stenosis). Among women with either no or nonobstructive CAD, the mean age was 56±11 years, 56% had hypertension, 46% dyslipidemia, 51% were smokers, and 10% had prior myocardial infarction. The rates of angina hospitalization for a maximum of 9.1 years showed near-linear increases in both groups (P=0.03). Hypertension, dyslipidemia, nonobstructive CAD, use of nitrates, statins, and angiotensin-converting enzyme inhibitors were univariate predictors of angina hospitalization. Adjusted multivariate hazard ratios for angina hospitalization were significant for use of nitrates 2.58 (1.80–3.69, P<0.0001), statins 1.80 (1.20–2.70, P=0.004), and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 1.81 (1.22–2.68, P=0.003). Conclusions: Angina hospitalization rates continued at a relatively constant rate in all women with no obstructive CAD despite medical advances. Clinical trials aimed at reducing angina hospitalization rates and identifying the pathophysiological mechanisms contributing to angina symptoms in women with no CAD and women with no obstructive CAD.

Background: Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found. Objectives: The authors prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute–sponsored WISE (Women's Ischemia Syndrome Evaluation) study. Methods: Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years. Results: The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes. Conclusions: On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554)