Patients With Nonobstructive Coronary Artery Disease and Chest Pain: Impact of Obesity and Depressive Symptoms.

BACKGROUND: Chest pain (CP) in patients with nonobstructive coronary artery disease is a therapeutic challenge affecting morbidity and mortality. We aimed to identify clinical factors associated with CP in this population, hypothesizing that obesity and depressive symptoms are associated with CP. METHODS AND RESULTS: In 814 patients with angiographically confirmed nonobstructive coronary artery disease, we measured sociodemographic variables, clinical risk factors, medications, and Patient Health Questionnaire 9 scores for depressive symptoms. We assessed CP frequency and prevalence by using all items from the Seattle Angina Questionnaire angina frequency domain to generate an angina frequency composite score. In the overall sample (58.8±11.7 years old, 52.6% female), 42.8% had obesity, and 71.5% had CP, with an angina frequency composite score (SD) score of 76.4 (22.1). Compared with individuals without obesity, individuals with obesity had a higher prevalence (77.6% versus 67%, P<0.001) and more frequent CP (angina frequency composite score, 74.9 [SD, 22.2] versus 78.3 [SD, 21.9], P=0.02). Obesity was independently associated with CP occurrence (odds ratio [OR], 1.7 [95% CI, 1-2.9], P=0.04). Obesity's connection with CP was only in men: men with obesity had more frequent CP (angina frequency composite score, 75.8 [SD, 20.1] versus 82.1 [SD, 19.9], P=0.002) and more prevalent CP (79.5% versus 58.2%, P<0.001) than their counterparts insofar as men with obesity had similar CP to women. Patient Health Questionnaire 9 score (OR, 1.07 [95% CI, 1.01-1.13], P=0.03) was independently associated with CP and partly mediated the association between obesity and CP. CONCLUSIONS: Obesity and depressive symptoms were independently associated with CP in individuals with nonobstructive coronary artery disease, particularly in men, and depressive symptoms partly mediated this association.

Epicardial adipose tissue attenuation on computed tomography in women with coronary microvascular dysfunction: A pilot, hypothesis generating study.

BACKGROUND: Patients with myocardial ischemia without obstructive coronary artery disease often have coronary microvascular dysfunction (CMD) and associated increased risk of cardiovascular (CV) events and anginal hospitalizations. Epicardial adipose tissue (EAT) covers much of the myocardium and coronary arteries and when dysfunctional, secretes proinflammatory cytokines and is associated with CV events. While oxidative stress and systemic inflammation are associated with CMD, the relationship between EAT and CMD in women is not well known. METHODS: Women diagnosed with CMD (n = 21) who underwent coronary computed tomography with coronary artery calcium (CAC) scoring were compared to a reference group (RG) of women referred for CAC screening for preventive risk assessment (n = 181). EAT attenuation (Hounsfield units (HU)) was measured adjacent to the proximal right coronary artery, along with subcutaneous adipose tissue (SCAT). Two-sample t-tests with unequal variances were utilized. RESULTS: Mean age of the CMD group was 56 ± 8 years and body mass index (BMI) was 31.6 ± 6.8 kg/m2. CV risk factors in the CMD group were prevalent: 67 % hypertension, 44 % hyperlipidemia, and 33 % diabetes. Both CMD and RG had similar CAC score (25.86 ± 59.54 vs. 24.17 ± 104.6; p = 0.21. In the CMD group, 67 % had a CAC of 0. Minimal atherosclerosis (CAD-RADS 1) was present in 76 % of women with CMD. The CMD group had lower EAT attenuation than RG (-103.3 ± 6.33 HU vs. -97.9 ± 8.3 HU, p = 0.009, respectively). There were no differences in SCAT attenuation. Hypertension, smoking history, age, BMI, and CAC score did not correlate with EAT in either of the groups. CONCLUSIONS: Women with CMD have decreased EAT attenuation compared to RG women. EAT-mediated inflammation and changes in vascular tone may be a mechanistic contributor to abnormal microvascular reactivity. Clinical trials testing therapeutic strategies to decrease EAT may be warranted in the management of CMD.

Coronary microvascular disease in women: epidemiology, mechanisms, evaluation, and treatment.

Coronary microvascular dysfunction (CMD) involves functional or structural abnormalities of the coronary microvasculature resulting in dysregulation of coronary blood flow (CBF) in response to myocardial oxygen demand. This perfusion mismatch causes myocardial ischemia, which manifests in patients as microvascular angina (MVA). CMD can be diagnosed non-invasively via multiple imaging techniques or invasively using coronary function testing (CFT), which assists in determining the specific mechanisms involving endothelium-independent and dependent epicardial and microcirculation domains. Unlike traditional coronary artery disease (CAD), CMD can often occur in patients without obstructive atherosclerotic epicardial disease, which can make the diagnosis of CMD difficult. Moreover, MVA due to CMD is more prevalent in women and carries increased risk of future cardiovascular events. Successful treatment of symptomatic CMD is often patient-specific risk factor and endotype targeted. This article aims to review newly identified mechanisms and novel treatment strategies for managing CMD, and outline sex-specific differences in the presentation and pathophysiology of the disease.

Pericardial fat volume is related to endothelial-mediated coronary blood flow in women with suspected coronary microvascular dysfunction. A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

Background: Coronary microvascular dysfunction is prevalent in women with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) and is associated with an adverse prognosis. Elevated pericardial fat volume predicts adverse cardiac events, but mechanistic pathways of the association are not well understood. Methods: 118 women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study with suspected coronary microvascular dysfunction but no obstructive CAD underwent adenosine stress 1.5 T cardiovascular magnetic resonance imaging (CMR) imaging and invasive coronary reactivity testing. Semi-quantitative myocardial perfusion reserve index (MPR) index was derived from perfusion images. Pericardial fat volume was measured by manually contouring the cardiac margins and adjacent adipose tissue on a single trans-axial HASTE slice at the level of the left main coronary artery origin and indexed to body surface-area. Simple standard deviation analysis obtained for continuous variables and frequency (percent) for categorical variables. The relationships between pericardial fat volume and coronary reactivity testing parameters were examined by correlation and multivariable regression analyses. Results: Women with suspected coronary microvascular dysfunction had a mean age of 55 ± 10 years, body mass index (BMI) of 28 ± 7 kg/m2, 44 % had a history of smoking, 63 % hypertension, 8 % diabetes, and 20 % dyslipidemia. CMR imaging-derived pericardial fat volume and coronary blood flow response to intracoronary acetylcholine (Δ CBF) were negatively correlated (r = -0.32, p = 0.0013). After adjustment for age, number of risk factors, high-density lipoprotein (HDL), and cold pressor diameter response, pericardial fat volume remained a significant predictor of Δ coronary blood flow (p = 0.04). There was no association with other coronary reactivity testing measures or CMRI derived MPR index. Conclusions: Among women with suspected coronary microvascular dysfunction but no obstructive CAD, pericardial fat volume appears to be related in a hypothesized adverse direction to coronary microvascular endothelial function. These results support further work confirming and extending these results to investigate pericardial fat volume as mechanistic pathway and potential treatment target for coronary microvascular dysfunction-related adverse events.Trial registration: clinicaltrials.govNCT00832702.

Supravalvular Aortic Stenosis in Homozygous Familial Hypercholesterolemia: Contemporary Management.

We report a case of a patient diagnosed with homozygous familial hypercholesterolemia and progressive supravalvular aortic stenosis. Treatment with long-term low-density lipoprotein apheresis and management with novel lipid-lowering agents including an angiopoetin-like protein inhibitor led to significant low-density lipoprotein reduction. The case highlights the challenges in managing the manifestations of homozygous familial hypercholesterolemia.

Optimal Medical Therapy for Stable Ischemic Heart Disease: Focus on Anti-anginal Therapy.

Chronic coronary disease (CCD) is a major cause of morbidity and mortality worldwide. The most common symptom of CCD is exertional angina pectoris, a discomfort in the chest that commonly occurs during activities of daily life. Patients are dismayed by recurring episodes of angina and seek medical help in preventing or minimizing episodes. Angina occurs when the coronary arteries are unable to supply sufficient blood flow to the cardiac muscle to meet the metabolic needs of the left ventricular myocardium. While lifestyle changes and aggressive risk factor modification play a critical role in the management of CCD, management of angina usually requires pharmacologic therapy. Medications such as beta-blockers, calcium channel blockers, nitrates, ranolazine, and others ultimately work to improve the mismatch between myocardial blood flow and metabolic demand. This manuscript briefly describes the pathophysiologic basis for symptoms of angina, and how currently available anti-anginal therapies contribute to preventing or minimize the occurrence of angina.

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease.

AIMS: To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels. METHODS AND RESULTS: In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment. CONCLUSION: Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

In patients with coronary artery disease (CAD), we demonstrate that nearly half of the higher risk of all-cause and cardiovascular mortality associated with lower educational attainment as a measure of socioeconomic status is mediated by systemic inflammation and immune dysregulation, which can be estimated by measuring the circulating soluble urokinase plasminogen activator receptor (suPAR) levels. Even after accounting for differences in cardiovascular risk factors, lower educational attainment is associated with higher mortality risk in patients with CAD and there is activation of inflammatory pathways and immune dysregulation in those with lower (≤high school) educational attainment than in those with higher (≥college) educational attainment, estimated as higher circulating suPAR levels.Almost half of the higher risk for adverse outcomes observed in those with lower educational attainment appears to be due to systemic inflammation and immune dysregulation and can be estimated from measuring suPAR levels.

Hemodynamic Reactivity to Mental Stress in Patients With Coronary Artery Disease.

Importance: The clinical significance of hemodynamic reactivity to mental stress in the population with coronary artery disease (CAD) is unclear. Objective: To investigate the association between hemodynamic reactivity to mental stress and the risk of adverse cardiovascular events in patients with stable CAD. Design, Setting, and Participants: This cohort study included individuals with stable CAD from 2 prospective studies from a university-based hospital network: the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Participants were enrolled between June 2011 and March 2016 and followed up for a median of 6.0 (IQR, 5.6-6.0) years in MIPS and 4.6 (IQR, 3.8-5.3) years in MIMS2. Data were analyzed from December 1, 2022, to February 15, 2023. Exposures: The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. Rate-pressure product reactivity was calculated as the maximum RPP during a standardized mental stress test minus the RPP at rest. Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death or nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure. Results: From the total of 938 individuals from the pooled cohort (mean [SD] age, 60.2 [10.1] years; 611 [65.1%] men), 631 participated in MIPS and 307 in MIMS2. A total of 373 individuals (39.8%) were Black, 519 (55.3%) were White, and 46 (4.9%) were of unknown race or ethnicity. The RPP increased by a mean (SD) of 77.1% (23.1%) during mental stress (mean [SD] absolute change, 5651 [2878]). For every SD decrease in RPP reactivity with mental stress, the adjusted hazard ratios for the primary and secondary end points were 1.30 (95% CI, 1.04-1.72) and 1.30 (95% CI, 1.06-1.56), respectively, in MIPS and 1.41 (95% CI, 1.06-1.97) and 1.21 (95% CI, 1.02-1.60), respectively, in MIMS2. In the pooled sample, when RPP reactivity to mental stress was added to a model including traditional clinical risk characteristics, model discrimination for adverse events improved (increase in C statistic of 5% for the primary end point; P = .009). Conclusions and Relevance: In this cohort study of individuals with stable CAD, a blunted cardiovascular reactivity to mental stress was associated with adverse outcomes. Future studies are needed to assess the clinical utility of mental stress reactivity testing in this population.

Psychosocial Factors of Women Presenting With Myocardial Infarction With or Without Obstructive Coronary Arteries.

BACKGROUND: Women with myocardial infarction (MI) are more likely to have elevated stress levels and depression than men with MI. OBJECTIVES: We investigated psychosocial factors in women with myocardial infarction with nonobstructive coronary arteries (MINOCA) and those with MI and obstructive coronary artery disease (CAD). METHODS: Women with MI enrolled in a multicenter study and completed measures of perceived stress (Perceived Stress Scale-4) and depressive symptoms (Patient Health Questionnaire-2) at the time of MI (baseline) and 2 months later. Stress, depression, and changes over time were compared between MI subtypes. RESULTS: We included 172 MINOCA and 314 MI-CAD patients. Women with MINOCA were younger (age 59.4 years vs 64.2 years; P < 0.001) and more diverse than those with MI-CAD. Women with MINOCA were less likely to have high stress (Perceived Stress Scale-4 ≥6) at the time of MI (51.0% vs 63.0%; P = 0.021) and at 2 months post-MI (32.5% vs 46.3%; P = 0.019) than women with MI-CAD. There was no difference in elevated depressive symptoms (Patient Health Questionnaire-2 ≥2) at the time of MI (36% vs 43%; P = 0.229) or at 2 months post-MI (39% vs 40%; P = 0.999). No differences in the rate of 2-month decline in stress and depression scores were observed between groups. CONCLUSIONS: Stress and depression are common among women at the time of and 2 months after MI. MINOCA patients were less likely to report high stress compared with MI-CAD patients, but the frequency of elevated depressive symptoms did not differ between the 2 groups. Stress and depressive symptoms decreased in both MI-CAD and MINOCA patients over time.

Atherosclerosis in Systemic Lupus Erythematosus.

PURPOSE OF THE REVIEW: Systemic lupus erythematosus (SLE) patients are at increased risk of cardiovascular disease (CVD) compared to the general population, despite most patients being young females, who are not classically considered to be at high risk for cardiovascular disease using traditional risk assessment tools. The purpose of this review is to discuss the pathophysiology of atherosclerosis in SLE and raise awareness of the relationship between SLE and CVD. RECENT FINDINGS: The increased risk of CVD in SLE patients is multifactorial, due to proatherogenic lipid profiles, immune dysregulation and inflammation, side effects of lupus treatment, and microvascular dysfunction. Conventional CV risk models often underperform in the identification of SLE patients at high risk of atherosclerosis. The use of non-invasive imaging serves as a strategy to identify patients with evidence of subclinical CVD and in the evaluation of symptomatic patients. Identification of subclinical atherosclerosis allows for aggressive management of CV risk factors. SLE patients experience an increased risk of atherosclerotic CVD, which is not solely explained by traditional CV risk factors. It is imperative that clinicians are aware of this association to implement prompt detection and treatment of atherosclerotic CVD in SLE patients.