ayman alkhoder

Introduction: Microvascular dysfunction during acute mental stress may be an important determinant of major adverse cardiovascular outcomes (MACE) especially among middle-aged women survivors of an acute myocardial infarction (MI). Hypothesis: There are sex differences in the association between microvascular dysfunction and MACE. Methods: The Myocardial Infarction and Mental Stress Study 2 enrolled individuals who had been hospitalized for an MI in the past 8 months at the age of 60 years or younger, with an oversampling of women. Reactive hyperemia index (RHI) was used to measure digital microvascular function before and 30 minutes after a public-speaking mental stress task. This assessment was contrasted with macrovascular endothelial function at the brachial artery through flow-mediated dilation (FMD). Participants were followed for 5-years, and MACE was defined as a composite of cardiovascular death, first/recurring events for nonfatal MI, and hospitalizations for heart failure...

Introduction: Peripheral arterial vasoconstriction during mental stress (MS) has been associated with mental stress-induced myocardial ischemia, which in turn has been linked with worse cardiovascular outcomes. It is unknown whether the magnitude of peripheral vasoconstriction with MS is predictive of long term outcomes. Hypothesis: We hypothesized that greater peripheral arterial vasoconstriction during MS would be associated with adverse events among patients with coronary artery disease (CAD). Methods: Four hundred sixty-three patients with stable CAD and normal left ventricular function, (age 63±9, 75% male, 27% Black, EF 60±8 %) underwent MS testing with a standardized public speaking stressor. Digital pulse wave amplitude was continuously measured at baseline and during MS using peripheral arterial tonometry (PAT), and the PAT ratio of pulse wave amplitude (during mental stress/ baseline) was calculated. Cox proportional hazard models were calculated to examine the association...

Introduction: Previous studies have found that lower resting short-term heart rate variability (HRV), a measure of autonomic dysfunction, predicts adverse cardiac events. Abnormal autonomic function may precipitate myocardial ischemia. Physiologic challenges like Valsalva and deep breathing may also provide important data by modulating preload/afterload and stimulating various autonomic receptors. Methods: We examined autonomic function in 166 patients with CAD using the ANSAR method (ANX 3.0, ANSAR Inc. Philadelphia, PA). HRV was measured in the sitting position, standing position, during deep breathing, and during Valsalva. After ANSAR testing, patients underwent 99m Tc[[Unable to Display Character: ‐]]sestamibi myocardial perfusion imaging at rest and with exercise or pharmacological stress. A summed difference score (SDS) was computed to quantify ischemia using a 17-segment model with observer-independent software. Multivariable models adjusted for CAD risk factors, psychiatric ...

Background: Exposure to psychological stress has been associated with the development of sustained arrhythmias. Acute changes in atrial electrophysiology may serve as intermediate phenotypes for stress-induced arrhythmia. The relationship between atrial electrical changes and stress related changes in heart rate and myocardial ischemia is unknown. We sought to study the effect of altered atrial electrophysiology and stress related rise in HR and myocardial ischemia in females and males. Methods: We examined if acute mental stress was associated with abnormal P-wave axis development in 359 patients (mean age=56 ± 9.9 years; 62% men; 43% white) with stable coronary heart disease and normal baseline P-wave axis (between 0° and 75°) who underwent mental stress testing (speech task). We computed the percentage of patients who had abnormal P-wave axis during stress and recovery. Sex-stratified analyses were performed. A multivariable logistic regression model was used to determine if ment...

Introduction: Depression and posttraumatic stress disorder (PTSD) are associated with impaired baroreflex sensitivity, a risk factor for sudden death. Unlike depression, PTSD is associated with hyperarousal. We hypothesized that, in patients with CAD, depressive and PTSD symptoms associate with different autonomic responses to standing (baroreflex response). Methods: We examined 178 patients with CAD for autonomic dysfunction with the ANSAR test (ANX 3.0, ANSAR Inc. Philadelphia, PA) in which heart rate variability was measured in both sitting (5 minutes) and standing (5 minutes) positions. Sympathetic (SNS) and parasympathetic (PNS) nervous system activity was measured using continuous wavelet transform and log-transformed. PTSD symptoms were assessed using the PTSD checklist scale (PCL), and depressive symptoms were assessed using the Beck Depression Inventory-II (BDI). Both BDI and PCL were examined in multivariate models simultaneously, adjusting for CAD risk factors, beta block...

Background: Circulating progenitor cells (CPCs) are involved in vascular repair and regeneration. Low levels of CPCs in patients with CAD have been linked to adverse cardiovascular outcomes. The response of CPCs to transient myocardial ischemia in patients with CAD has not been studied before. We aimed to investigate the CPC response to exercise provoked myocardial ischemia (demand ischemia), and compare it to myocardial ischemia detected during pharmacological stress test (flow mismatch). Methods: 570 patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during exercise (69%), or pharmacological stress (31%). myocardial ischemia was defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. CD34+ CPCs were enumerated by flow cytometry at rest and 30 min after stress testing. The change in CPC count was compared between patients with and without myocardial ischemia using mixed linear models. Results: Mean age was 63±9 years, ...

Background: Evidence supports that peripheral vasoconstriction during mental stress predicts mental stress induced ischemia (MSIMI). However, whether a dose response relationship exists with ischemia severity has not been evaluated; additionally, whether peripheral vascular function during the recovery phase is also related to MSIMI is not known. Hypothesis: We hypothesized that increased digital microvascular constriction during both mental stress and recovery are predictive of increased severity of mental stress ischemia. Methods: We evaluated 204 patients with stable CAD with high quality vascular data using a standardized mental stress test using a public speaking task. Peripheral artery tonometry (PAT) (Itamar Inc) was used to assess digital microvascular tone. Vasoconstriction was calculated as the ratio of pulse wave amplitude during speech/recovery and the last 3 minutes of baseline, with lower ratio indicating more vasoconstriction. 99mTc sestamibi myocardial perfusion imag...

Introduction: Although mental stress-induced myocardial ischemia (MSIMI) has been linked to adverse cardiovascular outcomes, its underlying mechanisms remain to be elucidated. We assessed whether autonomic dysfunction was important in precipitating MSIMI with the hypothesis that autonomic function, estimated using heart rate variability (HRV), will be associated with MSIMI. Methods: We examined autonomic function at rest in 168 patients with CAD using the ANSAR method (ANX 3.0, ANSAR Inc. Philadelphia, PA). Sympathetic and parasympathetic tone were assessed using low (LFa) and respiratory (RFa) frequency HRV that was adjusted for respiration using continuous wavelet transform. Sympathovagal balance was calculated as the ratio of LFa/RFa. Patients underwent 99mTc sestamibi myocardial perfusion imaging during both mental stress testing using a public speaking task, and, as a control condition, with conventional (pharmacologic or exercise) stress testing. Ischemia was defined as a new ...

Introduction: Reduced functional capacity, assessed by self-reported Duke Activity Status Index (DASI) is associated with adverse outcomes. Peripheral microvascular dysfunction, measured as reduced digital reactive hyperemia index (RHI) is also associated with adverse events. Whether microvascular dysfunction is related to functional capacity is unknown. Hypothesis: We hypothesized that peripheral microvascular dysfunction is associated with diminished functional capacity. Methods: In 531 patients with stable CAD (age 62±9, 75% male, 30% Black, EF 55±13%) enrolled in the Mental Ischemia Prognosis Study, self-reported functional capacity was assessed with the DASI questionnaire with a score of >25 as the cutoff for normal. Pulsatile arterial tonometry (EndoPat, Itamar Inc.) was used to measure digital RHI during 5 minutes of upper arm occlusion with blood pressure cuff followed by reperfusion. Logistic regression was used to model reduced RHI (25 vs ≤ 25). Results: Median RHI was ...

Background: Mental stress-induced myocardial ischemia (MSIMI) in patients with CAD is unrelated to its severity and is associated with adverse cardiovascular outcomes. The impact of vascular function and its response to mental stress (MS) on the development of MSIMI remains unclear. We measured endothelial function and arterial stiffness, and their change with MS, with the hypothesis that abnormalities in the vascular functional responses will contribute to MSIMI. Methods: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during MS testing using a public speaking stressor. MSIMI was defined as impaired myocardial perfusion using a 17-segment model. Endothelial function [endothelium-dependent flow-mediated dilation (FMD)], microvascular reactivity [reactive hyperemia index (RHI, Endo-PAT2000)] and arterial stiffness [pulse wave velocity (PWV), Sphygmocor Inc.] were measured at rest and 30-min after MS. Results: Of 457 patients with CAD aged 63±9 years (7...

Background: Excessive peripheral microvascular constriction during acute psychological stress, measured using peripheral arterial tonometry reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. The ratio of digital pulse wave amplitude during stress compared to rest (sPAT) is used to estimate the degree of microvascular response to stress. We sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. Methods: A total of 642 post-MI and stable CAD subjects from two prospective cohort studies underwent mental stress testing with a standardized public speaking stressor. Digital pulse wave amplitude was continuously measured using PAT and the stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated. Genotyping was performed using Illumina’s Multi-Ethnic Genotyping Array (MEGA) platform and imputed to the 1000 Genome reference panel. Race stra...

Importance Stem and progenitor cells mobilize from the bone marrow in response to myocardial ischemia. However, the association between the change in circulating progenitor cell (CPC) counts and disease prognosis among patients with ischemia is unknown. Objective To investigate the association between the change in CPC counts during stress testing and the risk of adverse cardiovascular events in patients with stable coronary artery disease (CAD). Design, Setting, and Participants This prospective cohort study included a population-based sample of 454 patients with stable CAD who were recruited between June 1, 2011, and August 15, 2014, at Emory University-affiliated hospitals and followed up for 3 years. Data were analyzed from September 15, 2018, to October 15, 2018. Exposures Myocardial perfusion imaging with technetium Tc 99m sestamibi at rest and 30 to 60 minutes after conventional stress testing. Main Outcomes and Measures Circulating progenitor cells were enumerated with flow cytometry as CD34-expressing mononuclear cells (CD45med/CD34+), with additional quantification of subsets coexpressing the chemokine (C-X-C motif) receptor 4 (CD34+/CXCR4+). Changes in CPC counts were calculated as poststress minus resting CPC counts. Cox proportional hazards regression models were used to identify factors associated with the combined end point of cardiovascular death and myocardial infarction after adjusting for clinical covariates, including age, sex, race, smoking history, body mass index, and history of heart failure, hypertension, dyslipidemia, and diabetes. Results Of the 454 patients (mean [SD] age, 63 [9] years; 76% men) with stable CAD enrolled in the study, 142 (31.3%) had stress-induced ischemia and 312 (68.7%) did not, as measured by single-photon emission computed tomography. During stress testing, patients with stress-induced ischemia had a mean decrease of 20.2% (interquartile range [IQR], -45.3 to 5.5; P < .001) in their CD34+/CXCR4+ counts, and patients without stress-induced ischemia had a mean increase of 3.2% (IQR, -20.6 to 35.1; P < .001) in their CD34+/CXCR4+ counts. Twenty-four patients (5.2%) experienced adverse events. After adjustment, baseline CPC counts were associated with worse adverse outcomes, but this association was not present after stress-induced ischemia was included in the model. However, the change in CPC counts during exercise remained significantly associated with adverse events (hazard ratio, 2.59; 95% CI, 1.15-5.32, per 50% CD34+/CXCR4+ count decrease), even after adjustment for clinical variables and the presence of ischemia. The discrimination of risk factors associated with incident adverse events improved (increase in C statistic from 0.72 to 0.77; P = .003) with the addition of the change in CD34+/CXCR4+ counts to a model that included clinical characteristics, baseline CPC count, and ischemia. Conclusions and Relevance In this study of patients with CAD, a decrease in CPC counts during exercise is associated with a worse disease prognosis compared with the presence of stress-induced myocardial ischemia. Further studies are needed to evaluate whether strategies to improve CPC responses during exercise stress will be associated with improvements in the prognosis of patients with CAD.

The influence of acute psychological stress on cardiovascular disease is an emerging public health concern. Identification of brain mechanisms underlying this may aid in the discovery of possible treatments. Acute psychological stress may induce arteriolar vasoconstriction and reduce blood flow to vital organs. We hypothesized that functional changes in brain regions involved with memory and autonomic/emotional regulation are implicated in the vasoconstrictive stress response, including the medial prefrontal cortex (anterior cingulate), insula, and dorsolateral prefrontal cortex. Subjects with a history of coronary artery disease (N = 59) underwent measurement of microvascular vasomotor tone with the EndoPAT device and O-15 positron emission tomography (PET) imaging of the brain during exposure to mental stress and control conditions. The peripheral arterial tonometry (PAT) ratio was calculated as the mean peripheral vasomotor tone during stress divided by the mean tone during rest....

Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress (MS). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow (CBF) responses during MS remains understudied. We hypothesized that coronary vasomotion during MS is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation. In 38 patients aged 59±8 years undergoing coronary angiography, endothelium-dependent and endothelium-independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after MS induced by mental arithmetic testing. Peripheral microvascular tone during MS was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio). MS increased the rate-pressure product by 22% (±23...

To investigate sex-specific vascular mechanisms for mental stress-induced myocardial ischemia (MSIMI). Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 ver...

Mental stress-induced myocardial ischemia (MSIMI) is frequent in patients with coronary artery disease and is associated with worse prognosis. Young women with a previous myocardial infarction (MI), a group with unexplained higher mortality than men of comparable age, have shown elevated rates of MSIMI, but the mechanisms are unknown. We studied 306 patients (150 women and 156 men) ≤61 years of age who were hospitalized for MI in the previous 8 months and 112 community controls (58 women and 54 men) frequency matched for sex and age to the patients with MI. Endothelium-dependent flow-mediated dilation and microvascular reactivity (reactive hyperemia index) were measured at rest and 30 minutes after mental stress. The digital vasomotor response to mental stress was assessed using peripheral arterial tonometry. Patients receivedTc-sestamibi myocardial perfusion imaging at rest, with mental (speech task) and conventional (exercise/pharmacological) stress. The mean age of the sample was...

Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events. We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med(+) blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34(+) and CD34(+)/CXCR(+) cell count remained independently associated with a diagnosis of HF (P<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects ...

Mental stress-induced myocardial ischemia (MSIMI) in patients with coronary artery disease (CAD) is associated with adverse cardiovascular outcomes. We aim to assess hemodynamic, neuro-hormonal, endothelial, vasomotor and vascular predictors of MSIMI. We subjected 660 patients with stable CAD to 99mTc sestamibi myocardial perfusion imaging at rest, with mental (speech task) and with conventional (exercise/pharmacological) stress. Endothelium-dependent flow-mediated dilation (FMD), microvascular reactivity [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] were measured at rest and 30-min after mental stress. The digital microvascular vasomotor response during mental stress was assessed using peripheral arterial tonometry (PAT). A total of 106(16.1%) patients had MSIMI. Mental stress was accompanied by significant increases in rate-pressure-product (heart rate x systolic blood pressure; RPP), epinephrine levels and PWV, and significant decreases in FM...

Leucocyte 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 (PCs) are involved in tissue repair and regeneration. To examine the relationship between LTL and PCs, and their impact on adverse cardiovascular outcomes. We measured LTL by quantitative PCR in 566 outpatients (age 63±9 years, 76% male) with coronary artery disease (CAD). Circulating PCs were enumerated by flow cytometry. After adjustment for age, gender, race, BMI, smoking 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 (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization o...

Background: Angiotensin II plays a key role in the pathogenesis of atherosclerosis at least partly by promoting oxidative stress (OS) and inflammation. Objectives: We investigated the effects of Angiotensin II type-1 receptor (AT 1 R) blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis, OS, and inflammation. Methods: Subjects (n= 120, 60±9 years, 51% male) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan (n=80), titrated up to 320 mg daily, or placebo (n=40) for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging (MRI) was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area (VWA) and wall thickness (WT) were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent brachial artery vasodilation. Statistical comparisons between groups were performed using a linear mixed-effects model to account for multiple measurements within subject. Results: Over 2 years, the carotid bulb VWA decreased with valsartan (p=0.008) but not with placebo (p=0.28); p=0.01 between groups. Similarly, mean WT increased with placebo (p=0.0035) but remained unchanged with Valsartan (p=0.31); p=0.009 between groups. Importantly, plaque thickness decreased with Valsartan (p= 0.014) but was unchanged with placebo (p=0.16); p=0.01 between groups. These findings were independent of statin therapy and changes in blood pressure. Furthermore, there were significant improvements in the aminothiol cysteineglutathione disulfide and fibrinogen levels and in endothelium-independent vasodilation with Valsartan. Conclusions: AT 1 R blockade with Valsartan is associated with significant carotid arterial remodeling manifested as regression in carotid atherosclerosis, changes that may be secondary to improvement in OS, inflammation, and vascular function.

Importance Mental stress-induced myocardial ischemia is a recognized phenomenon in patients with coronary heart disease (CHD), but its clinical significance in the contemporary clinical era has not been investigated. Objective To compare the association of mental stress-induced or conventional stress-induced ischemia with adverse cardiovascular events in patients with CHD. Design, Setting, and Participants Pooled analysis of 2 prospective cohort studies of patients with stable CHD from a university-based hospital network in Atlanta, Georgia: 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 (last follow-up, February 2020). Exposures Provocation of myocardial ischemia with a standardized mental stress test (public speaking task) and with a conventional (exercise or pharmacological) stress test, using single-photon emission computed tomography. Main Outcomes and Measures The primary outcome was a composite of cardiovascular death or first or recurrent nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure. Results Of the 918 patients in the total sample pool (mean age, 60 years; 34% women), 618 participated in MIPS and 300 in MIMS2. Of those, 147 patients (16%) had mental stress-induced ischemia, 281 (31%) conventional stress ischemia, and 96 (10%) had both. Over a 5-year median follow-up, the primary end point occurred in 156 participants. The pooled event rate was 6.9 per 100 patient-years among patients with and 2.6 per 100 patient-years among patients without mental stress-induced ischemia. The multivariable adjusted hazard ratio (HR) for patients with vs those without mental stress-induced ischemia was 2.5 (95% CI, 1.8-3.5). Compared with patients with no ischemia (event rate, 2.3 per 100 patient-years), patients with mental stress-induced ischemia alone had a significantly increased risk (event rate, 4.8 per 100 patient-years; HR, 2.0; 95% CI, 1.1-3.7) as did patients with both mental stress ischemia and conventional stress ischemia (event rate, 8.1 per 100 patient-years; HR, 3.8; 95% CI, 2.6-5.6). Patients with conventional stress ischemia alone did not have a significantly increased risk (event rate, 3.1 per 100 patient-years; HR, 1.4; 95% CI, 0.9-2.1). Patients with both mental stress ischemia and conventional stress ischemia had an elevated risk compared with patients with conventional stress ischemia alone (HR, 2.7; 95% CI, 1.7-4.3). The secondary end point occurred in 319 participants. The event rate was 12.6 per 100 patient-years for patients with and 5.6 per 100 patient-years for patients without mental stress-induced ischemia (adjusted HR, 2.0; 95% CI, 1.5-2.5). Conclusions and Relevance Among patients with stable coronary heart disease, the presence of mental stress-induced ischemia, compared with no mental stress-induced ischemia, was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction. Although these findings may provide insights into mechanisms of myocardial ischemia, further research is needed to assess whether testing for mental stress-induced ischemia has clinical value.