Sex-Specific Association Between Coronary Artery Disease Severity and Myocardial Ischemia Induced by Mental Stress.

OBJECTIVE: It is unclear whether mental stress-induced myocardial ischemia (MSIMI) is related to obstructive coronary artery disease (CAD). We examined this question and contrasted results with ischemia induced by conventional stress testing (CSIMI). Because women are more susceptible to ischemia without coronary obstruction than men, we examined sex differences. METHODS: We studied 276 patients 61 years and younger with recent myocardial infarction. CAD severity was quantified using the log-transformed Gensini Score (lnGS) and the Sullivan Stenosis Score. Patients underwent myocardial perfusion imaging with mental stress (public speaking) and conventional (exercise or pharmacological) stress testing. MSIMI and CSIMI were defined as a new or worsening perfusion defect. RESULTS: The prevalence of MSIMI was 15% in men and 20% in women. The median GS for patients with MSIMI was 65.0 in men and 28.5 in women. In logistic regression models adjusted for demographic and cardiovascular risk factors, CAD severity was associated with CSIMI in the full sample (odds ratio [OR] = 1.49, 95% [CI], 1.14-1.95, per 1-unit increase in lnGS), with no significant difference by sex. Although CAD severity was not associated with MSIMI in the entire sample, results differed by sex. CAD severity was associated with MSIMI among men (OR = 1.95, 95% CI, 1.13-3.36, per 1-unit increase in lnGS), but not among women (OR = 1.02, 95% CI, 0.74-1.42, p = .042 for interaction). Analysis using Sullivan Stenosis Score yielded similar results. CONCLUSIONS: Findings suggest that CAD severity is related to MSIMI in men but not women. MSIMI in women may therefore be driven by alternative mechanisms such as coronary microvascular disease.

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes.

RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (

Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study.

Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health.

Inflammatory response to mental stress and mental stress induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with increased risk of adverse cardiovascular outcomes, yet the underlying mechanisms are not well understood. We measured the inflammatory response to acute laboratory mental stress in patients with coronary artery disease (CAD) and its association with MSIMI. We hypothesized that patients with MSIMI would have a higher inflammatory response to mental stress in comparison to those without ischemia. METHODS: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during mental stress testing using a public speaking stressor. MSIMI was determined as impaired myocardial perfusion using a 17-segment model. Inflammatory markers including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metallopeptidase 9 (MMP-9) and high-sensitivity C reactive protein (hsCRP) were measured at rest and 90 min after mental stress. Results were validated in an independent sample of 228 post-myocardial infarction patients. RESULTS: Of 607 patients analyzed in this study, (mean age 63 ±â€¯9 years, 76% male), 99 (16.3%) developed MSIMI. Mental stress resulted in a significant increase in IL-6, MCP-1, and MMP-9 (all p <0.0001), but not hsCRP. However, the changes in these markers were similar in those with and without MSIMI. Neither resting levels of these biomarkers, nor their changes with mental stress were significantly associated with MSIMI. Results in the replication sample were similar. CONCLUSION: Mental stress is associated with acute increases in several inflammatory markers. However, neither the baseline inflammatory status nor the magnitude of the inflammatory response to mental stress over 90 min were significantly associated with MSIMI.

The association between acute mental stress and abnormal left atrial electrophysiology.

BACKGROUND: Acute stress may trigger atrial fibrillation (AF), but the underlying mechanisms are unclear. We examined if acute mental stress results in abnormal left atrial electrophysiology as detected by more negative deflection of P-wave terminal force in lead V1 (PTFV1 ), a well-known marker of AF risk. METHODS AND RESULTS: We examined this hypothesis in 422 patients (mean age = 56 ± 10 years; 61% men; 44% white) with stable coronary heart disease who underwent mental (speech task) stress testing. PTFV1 was defined as the duration (milliseconds) times the value of the depth (µV) of the downward deflection (terminal portion) of the P-wave in lead V1 measured on digital electrocardiograms (ECG). Electrocardiographic left atrial abnormality was defined as PTFV1 ≤ -4000 µV*ms. Mean PTFV1 values during stress and recovery were compared with rest. The percentage of participants who developed left atrial abnormality during stress and recovery was compared with the percentage at rest. Compared with rest, PTFV1 became more negative during mental stress (mean change =  -348, 95% CI = [-515, -182]; P < 0.001) and no change was observed at recovery (mean change = 12, 95%CI = [-148, 172]; P = 0.89). A larger percentage of participants showed left atrial abnormality on ECGs obtained at stress (n = 163, 39%) and recovery (n = 142, 34%) compared with rest (n = 127, 30%). CONCLUSION: Acute mental stress alters left atrial electrophysiology, suggesting that stressful situations promote adverse transient electrical changes to provide the necessary substrate for AF.

Recurrent Coronary Artery Fistulae and a Novel Transforming Growth Factor Beta-3 Mutation.

Loeys-Dietz syndrome (LDS) is a rare connective tissue disease associated with mutations in transforming growth factor (TGF) signaling leading to an increased risk of arterial calcification, aneurysms, and/or dissections. We report a case in which genetics evaluation revealed a rare variant E244K in the TGFB3 gene. The variant leads to the substitution of glutamic acid for lysine, two amino acids with dissimilar properties. Analysis from evolutionary data shows the glutamic acid is maintained across species. The clinical significance of the E244K variant in association with LDS was never previously reported as pathologic. This case report aims to report that the significance of the E244K variant in the TGFB3 gene is found to be pathologic in our case. A search on the Genome Aggregation Database (gnomAD) did not reveal any previously identified individuals with this variant, despite being a well-covered region. ClinVar has a few entries for E244K, where most of them are listed as unknown significance. Bringing together the genotype evidence with our patient's clinical picture, we consider the variant to be pathogenic for this family.

Circulating Progenitor Cells and Cognitive Impairment in Men and Women with Coronary Artery Disease.

BACKGROUND: Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). OBJECTIVE: To assess the association between CPCs and memory performance among individuals with CAD. METHODS: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45med/CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations enriched for hematopoietic and endothelial progenitors. RESULTS: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all < 0.05). There was a significant interaction in the magnitude of this association with race (p < 0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. CONCLUSION: Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study.

Longitudinal associations between self-reported experiences of discrimination and depressive symptoms in young women and men post- myocardial infarction.

Objectives: Research suggests that following a myocardial infarction (MI), women under the age of 60 have more elevated depressive symptoms and adverse outcomes than similarly aged men. Identifying risk factors that contribute to gender differences in depressive symptoms among this group may be critical to the development of psychosocial interventions. Experiences of discrimination may be an important correlate of depressive symptoms in this group; however, studies of this relationship have largely been cross-sectional and focused on healthy populations. This study examines longitudinal associations among gender, discrimination, and depressive symptoms in a young post-MI cohort. Methods: Participants were 313 adults from the Myocardial Infarction and Mental Stress Ischemia Study 2 of young (≤60 yrs) post-MI patients. At baseline and 6 month follow-up, depressive symptoms were measured with the Beck Depression Inventory-II and discrimination was assessed with the 10-item version Everyday Discrimination scale. Linear regression models were used to assess the longitudinal association between reports of discrimination and depressive symptoms adjusted for sociodemographic characteristics, psychosocial factors and health status indicators and tested for gender differences. Results: The mean age was 51.2, 49.6% were women, and 69.5% were African-American. Although the discrimination-by-gender interaction was marginally significant (p=.09) in the fully adjusted model, findings suggest that the association between changes in reports of discrimination and depressive symptoms over time may be more pronounced for women (ß=.61, standard error=.15, p<.001) than men (ß=.27, standard error=.13, p=.033). Conclusion: Our findings suggest that discrimination is a risk factor for depressive symptoms in young post-MI populations over time.

Comparison of autonomic stress reactivity in young healthy versus aging subjects with heart disease.

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.

Association Between High-Sensitivity Cardiac Troponin Levels and Myocardial Ischemia During Mental Stress and Conventional Stress.

OBJECTIVES: This study sought to investigate whether patients with mental stress-induced myocardial ischemia will have high resting and post-mental stress high-sensitivity cardiac troponin I (hs-cTnI). BACKGROUND: Hs-cTnI is a marker of myocardial necrosis, and its elevated levels are associated with adverse outcomes. Hs-cTnI levels may increase with exercise in patients with coronary artery disease. Mental stress-induced myocardial ischemia is also linked to adverse outcomes. METHODS: In this study, 587 patients with stable coronary artery disease underwent technetium Tc 99m sestamibi-single-photon emission tomography myocardial perfusion imaging during mental stress testing using a public speaking task and during conventional (pharmacological/exercise) stress testing as a control condition. Ischemia was defined as new/worsening impairment in myocardial perfusion using a 17-segment model. RESULTS: The median hs-cTnI resting level was 4.3 (interquartile range [IQR]: 2.9 to 7.3) pg/ml. Overall, 16% and 34.8% of patients developed myocardial ischemia during mental and conventional stress, respectively. Compared with those without ischemia, median resting hs-cTnI levels were higher in patients who developed ischemia either during mental stress (5.9 [IQR: 3.9 to 8.3] pg/ml vs. 4.1 [IQR: 2.7 to 7.0] pg/ml; p < 0.001) or during conventional stress (5.4 [IQR: 3.9 to 9.3] pg/ml vs. 3.9 [IQR: 2.5 to 6.5] pg/ml; p < 0.001). Patients with high hs-cTnI (cutoff of 4.6 pg/ml for men and 3.9 pg/ml for women) had greater odds of developing mental (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.5 to 3.9; p < 0.001) and conventional (OR: 2.4; 95% CI: 1.7 to 3.4; p < 0.001) stress-induced ischemia. Although there was a significant increase in 45-min post-treadmill exercise hs-cTnI levels in those who developed ischemia, there was no significant increase after mental or pharmacological stress test. CONCLUSIONS: In patients with coronary artery disease, myocardial ischemia during either mental stress or conventional stress is associated with higher resting levels of hs-cTnI. This suggests that hs-cTnI elevation is an indicator of chronic ischemic burden experienced during everyday life. Whether elevated hs-cTnI levels are an indicator of adverse prognosis beyond inducible ischemia or whether it is amenable to intervention requires further investigation.

Myocardial Ischemia and Mobilization of Circulating Progenitor Cells.

BackgroundThe response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise-induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and ResultsA total of 356 patients with stable coronary artery disease underwent 99mTc-sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD34+ and CD34+/chemokine (C-X-C motif) receptor 4 PCs were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal-derived factor-1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of ExMI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with ExMI had a significant decrease in CD34+/chemokine (C-X-C motif) receptor 4 (-18%, P=0.01) after stress that was inversely correlated with the magnitude of ischemia (r=-0.19, P=0.003). In contrast, patients without ExMI had an increase in CD34+/chemokine (C-X-C motif) receptor 4 (14.7%, P=0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P<0.001) in all patients undergoing exercise stress testing regardless of ischemia. However, the change in stromal-derived factor-1α level correlated inversely with the change in PC counts in those with ExMI (P=0.03), suggesting a greater decrease in PCs in those with a greater change in stromal-derived factor-1α level with exercise. ConclusionsExMI is associated with a significant decrease in circulating levels of CD34+/chemokine (C-X-C motif) receptor 4 PCs, likely attributable, at least in part, to stromal-derived factor-1α-mediated homing of PCs to the ischemic myocardium. The physiologic consequences of this uptake of PCs and their therapeutic implications need further investigation.

High-Sensitivity Troponin I Levels and Coronary Artery Disease Severity, Progression, and Long-Term Outcomes.

BACKGROUND: The associations between high-sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. METHODS AND RESULTS: In 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all-cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1-vessel CAD, 20% had 2-vessel CAD, and 26% had 3-vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18-0.44; P<0.001) and with CAD progression (log 2 ß=0.36; 95% confidence interval, 0.14-0.58; P=0.001). hsTnI level was also a significant predictor of incident death, cardiovascular death, myocardial infarction, revascularization, and cardiac hospitalizations, independent of the aforementioned covariates and CAD severity. CONCLUSIONS: Higher hsTnI levels are associated with the underlying burden of coronary atherosclerosis, more rapid progression of CAD, and higher risk of all-cause mortality and incident cardiovascular events. Whether more aggressive treatment aimed at reducing hsTnI levels can modulate disease progression requires further investigation.

Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

BACKGROUND AND AIMS: Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study. METHODS: SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD. RESULTS: Plasma suPAR levels were 22.5% (p < 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (≥2 compared to single site) p < 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p < 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p < 0.001 for all]. CONCLUSIONS: Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation.