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BACKGROUND. The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive due to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise. METHODS. We performed positron emission tomography (PET) in 275 twins who participated in two examinations approximately 12 years apart. At both visits we obtained a clinical diagnosis of PTSD which was classified as longstanding (both visit 1 and visit 2), late onset (only visit 2) and no PTSD (no PTSD at both visits). With PET we assessed myocardial flow reserve (MFR) which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared PET data at Visit 2 across the 3 categories of longitudinally-assessed PTSD, and examined changes between the two visits. RESULTS. Overall 80% of twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD, and was progressively lower across groups of no PTSD (2.13), late-onset PTSD (1.97), and longstanding PTSD (1.93), p=0.01. A low MFR (a ratio

BackgroundThe COVID-19 pandemic has led to an explosion of research publications spanning epidemiology, basic and clinical science. While a digital revolution has allowed for open access to large datasets enabling real-time tracking of the epidemic, detailed, locally-specific clinical data has been less readily accessible to a broad range of academic faculty and their trainees. This perpetuates the separation of the primary missions of clinically-focused and primary research faculty resulting in lost opportunities for improved understanding of the local epidemic; expansion of the scope of scholarship; limitation of the diversity of the research pool; lack of creation of initiatives for growth and dissemination of research skills needed for the training of the next generation of clinicians and faculty.ObjectivesCreate a common, easily accessible and up-to-date database that would promote access to local COVID-19 clinical data, thereby increasing efficiency, streamlining and democratizing the research enterprise. By providing a robust dataset, a broad range of researchers (faculty, trainees) and clinicians are encouraged to explore and collaborate on novel clinically relevant research questions.MethodsWe constructed a research platform called the Yale Department of Medicine COVID-19 Explorer and Repository (DOM-CovX), to house cleaned, highly granular, de-identified, continually-updated data from over 7,000 patients hospitalized with COVID-19 (1/2020-present) across the Yale New Haven Health System. This included a front-end user interface for simple data visualization of aggregate data and more detailed clinical datasets for researchers after a review board process. The goal is to promote access to local COVID-19 clinical data, thereby increasing efficiency, streamlining and democratizing the research enterprise.Expected OutcomesAccelerate generation of new knowledge and increase scholarly productivity with particular local relevanceImprove the institutional academic climate by:Broadening research scopeExpanding research capability to more diverse group of stakeholders including clinical and research-based faculty and traineesEnhancing interdepartmental collaborationsConclusionsThe DOM-CovX Data Explorer and Repository have great potential to increase academic productivity. By providing an accessible tool for simple data analysis and access to a consistently updated, standardized and large-scale dataset, it overcomes barriers for a wide variety of researchers. Beyond academic productivity, this innovative approach represents an opportunity to improve the institutional climate by fostering collaboration, diversity of scholarly pursuits and expanding medical education. It provides a novel approach that can be expanded to other diseases beyond COVID 19.

Anger and stress can trigger episodes of atrial fibrillation (AF) in patients with a history of AF.The purpose of this study was to determine whether β-blockers can protect against emotionally triggered AF.In this prospective, controlled, electronic diary-based study of emotions preceding AF, patients with a history of paroxysmal or persistent AF (N = 91) recorded their rhythm on event monitors at the time of AF symptoms and completed a diary entry querying mood states (eg, anger and stress) for the preceding 30 minutes (pre-AF "case period") for 1 year. Also, patients underwent monthly 24-hour Holter monitoring during which they were prompted to complete a diary entry twice per hour. Diaries recorded during sinus rhythm comprise controls. Patients' exposure to each emotion was compared between the pre-AF case period and control periods by using generalized estimating equation modeling, as well as interactions between β-blocker use and emotion tested.Sixty percent were prescribed β-blockers. A total of 163 symptomatic AF episodes (in 34 patients) and 11,563 Holter-confirmed sinus rhythm control periods had associated diary data. Overall, the likelihood of an AF episode was significantly higher during anger or stress. This effect, however, was significantly attenuated in patients on β-blockers (odds ratio 22.5; 95% confidence interval 6.7-75.4, P.0001 for patients not prescribed β-blockers vs odds ratio 4.0, 95% confidence interval 1.7-9.5, P = .002 for those prescribed β-blockers; P = .02 for the interaction). Exclusion of patients on sotalol did not affect findings.Anger or stress can trigger AF, but use of β-blockers greatly attenuates this deleterious physiological response.

This review describes the effects of psychological stress on the physiology of the entire vascular system, from individual cellular components to macrovascular and microvascular responses, and highlights the importance of the vascular system in the context of current limitations in cardiac imaging for evaluation of the cardiovascular response to mental stress. The physiological responses that mediate vascular changes are based on evolutionary needs, but there is increasing evidence that the long-term consequences of psychological stress can precipitate the development and progression of cardiovascular disease (CVD). While there is an extensive body of literature describing localized physiological responses or overt cardiovascular manifestations, often framed within the organ-specific scope of cardiovascular imaging, there has not been a comprehensive description of the global vascular effects of psychological stress. Given the global nature of these processes, targeted cardiovascular imaging modalities may be insufficient. Here we approach the vascular response to mental stress systematically, describing the effects on the endothelium, vascular smooth muscle, and adventitia. We then address the mental stress effects on large vessels and the microvascular compartment, with a discussion of the role of microvascular resistance in the pathophysiology of mental stress-induced myocardial ischemia. Vascular responses to psychological stress involve complex physiological processes that are not fully characterized by routine cardiovascular imaging assessments. Future research incorporating standardized psychological assessments targeted toward vascular mechanisms of stress responses is required to guide the development of behavioral and therapeutic interventions.

Mental stress–provoked myocardial ischemia (MSIMI) is an ischemic phenomenon provoked by the experience of psychologically stressful circumstances. While MSIMI was initially identified 50 years ago during activities of daily living through the use of wearable Holter monitor, subsequent research utilized the technologies of cardiac imaging—ventriculography and myocardial perfusion—under controlled conditions to pursue an understanding of pathophysiology and prognosis. This work revealed that MSIMI occurs in almost half of patients with stable coronary artery disease (CAD) and is associated with cardiac events and early mortality. We provide a focused review of the instrumental role that cardiac imaging has played in elucidating how stress affects cardiac physiology and how emerging diagnostic techniques will allow for further research on stress-mediated changes in the coronary macro- and microvasculature. Observations about the cardiac response to mental stress diverge from underlying cornerstones of the traditional CAD paradigm which is based upon myocardial oxygen demand and the degree of epicardial coronary stenosis. Evidence from studies utilizing non-invasive and invasive studies of coronary perfusion indicates perturbations in the microvascular compartment in response to mental stress. Cardiovascular imaging enjoined with mental stress provocation may be a commanding tool to advance our understanding of non-obstructive CAD and the coronary microvasculature. This further understanding will facilitate incorporation of mental stress testing in the clinical care of patients with discrepant diagnostic work-up of CAD and in patients who experience anginal symptoms due to non-exertional and/or emotional triggers. Such algorithms will be crucial to identify treatment targets to modify the risk associated with mental stress–associated ischemia and adverse prognosis.

Background The association of depressive symptoms with health status in peripheral artery disease (PAD) is understudied. No reports of differential impact on women have been described. Methods and Results The PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Artery Disease Investigating Trajectories) registry enrolled 1243 patients from vascular specialty clinics with new or worsening PAD symptoms. Depressive symptoms were assessed at baseline and 3 months using the 8‐Item Patient Health Questionnaire (score ≥10 indicating clinically relevant depressive symptoms). Disease‐specific and generic health status were measured by Peripheral Artery Questionnaire and EQ‐5D Visual Analogue Scale at baseline and 3, 6, and 12 months. An adjusted general linear model for repeated measures was constructed for baseline and 3‐, 6‐, and 12‐month health status outcomes by depressive symptoms at baseline. Differences by sex were tested with interaction effects. The mean age was 67.6±9.4 years with 38% (n=470) women. More women than men (21.1% versus 12.9%; P P Conclusions Women with PAD have a high burden of depressive symptoms. Depressive symptoms were associated with a strikingly worse disease‐specific health status recovery path over the year following PAD diagnosis in men and women. Developing and testing interventions to address depressive symptoms in PAD are urgently needed. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01419080.

Central activation in response to emotion and cognitive stress induces perturbations in the heart and the peripheral vasculature that differ in physiology and clinical manifestations when compared with exercise-induced changes. While our conventional framework of epicardial coronary artery disease is foundational in cardiology, an expanded paradigm is required to address the cardiovascular response to mental stress (MS) and its associated risks, thus addressing the intersection of the patient’s ecological and psychosocial experience with cardiovascular biology. To advance the field of MS in cardiovascular health, certain core challenges must be addressed. These include differences in the trigger activation between exercise and emotion, identification and interpretation of imaging cues as measures of pathophysiologic changes, characterization of the vascular response, and identification of central and peripheral treatment targets. Sex and psychosocial determinants of health are important in understanding the emerging overlap of MS–induced myocardial ischemia with microvascular dysfunction and symptoms in the absence of obstructive disease. In overcoming these critical knowledge gaps, integration of the field of MS will require implementation studies to guide use of MS testing, to support diagnosis of MS induced cardiac and vascular pathophysiology, to assess prognosis, and understand the role of endotying to direct therapy.

Objective— The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Approach and Results— Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1β (IL-1β) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1β expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1β levels. Moreover, we found that elevated IL-1β was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden. Conclusions— Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1β expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

Acute emotionally reactive mental stress (MS) can provoke prognostically relevant deficits in cardiac function and myocardial perfusion, and chronic inflammation increases risk for this ischemic phenomenon. We have described parasympathetic withdrawal and generation of inflammatory factors in MS. Adiposity is also associated with elevated markers of chronic inflammation. High body mass index (BMI) is frequently used as a surrogate for assessment of excess adiposity, and associated with traditional CAD risk factors, and CAD mortality. BMI is also associated with autonomic dysregulation, adipose tissue derived proinflammatory cytokines, which are also attendant to emotion provoked myocardial ischemia. Thus, we sought to determine if body mass index (BMI) contributes to risk of developing myocardial ischemia provoked by mental stress. We performed a prospective interventional study in a cohort of 161 patients with stable CAD. They completed an assessment of myocardial blood flow with single photon emission computed tomography (SPECT) simultaneously during 2 conditions: laboratory mental stress and at rest. Multivariate logistic regression determined the independent contribution of BMI to the occurrence of mental-stress induced ischemia. Mean age was 65.6 ±9.0 years; 87.0% had a history of hypertension, and 28.6% had diabetes. Mean BMI was 30.4 ± 4.7. Prevalence of mental stress ischemia was 39.8%. BMI was an independent predictor of mental stress ischemia, OR=1.10, 95% CI [1.01-1.18] for one-point increase in BMI and OR=1.53, 95% CI [1.06-2.21] for a 4.7 point increase in BMI (one standard deviation beyond the cohort BMI mean), p=0.025 for all. These data suggest that BMI may serve as an independent risk marker for mental stress ischemia. The factors attendant with greater BMI, which include autonomic dysregulation and inflammation, may represent pathways by which high BMI contribute to this risk and serve as a conceptual construct to replicate these findings in larger CAD populations.

Post-traumatic stress disorder (PTSD) is a disabling condition that develops consequent to trauma exposure such as natural disasters, sexual assault, automobile accidents, and combat that independently increases risk for early incident cardiovascular disease (CVD) and cardiovascular (CV) mortality by over 50 % and incident hypertension risk by over 30 %. While the majority of research on PTSD and CVD has concerned initially healthy civilian and military veteran samples, emerging research is also demonstrating that PTSD consequent to the trauma of an acute cardiac event significantly increases risk for early recurrence and mortality and that patient experiences in the clinical pathway that are related to the emergency department environment may provide an opportunity to prevent PTSD onset and thus improve outcomes. Future directions for clinical and implementation science concern broad PTSD and trauma screening in the context of primary care medical environments and the testing of PTSD treatments with CVD-related surrogates and endpoints.

The calcium composition of atherosclerotic plaque has predictive value for increased risk of cardiovascular events. Inflammation is associated with atherosclerotic calcification, but the immune signaling that regulates calcium mineralization in plaque is minimally understood. The hematopoietic Rac family member, Rac2, modulates the activation of immune cells and has potential to influence plaque osteogenesis. Both aortic plaque from ApoE -/- mice fed a high fat diet and coronary plaque from patients revealed increased Rac1:Rac2 expression ratios, driven by dynamic Rac2 expression, to be associated with calcified plaque. On high fat diet, Rac2 -/- ApoE -/- mice demonstrated comparable serum cholesterol and plaque burden relative to ApoE -/- mice, but histology identified differences in plaque structure and cellularity. MicroCT and calcium-targeted imaging identified increased atherosclerotic calcification, which was associated with elevated expression of osteogenic transcription factors and was dependent on the hematopoietic compartment. Calcified plaque expressed higher IL-1β mRNA levels, and serum revealed increased IL-1β protein concentrations. Rac2 -/- ApoE -/- macrophages demonstrated increased activation of Rac1 and consequent Rac1-dependent IL-1β secretion. Downstream of Rac1, NF-κB and reactive oxygen species (ROS) signaling drove IL-1β production by increasing IL-1β mRNA expression and caspase1 activation. Cultured mouse aorta smooth muscle cells mineralized calcium in an IL-1β dose-dependent manner, and the enhanced atherosclerotic calcification in vivo was inhibited by IL-1 receptor antagonist, confirming a cause-and-effect relationship. In patients with stable coronary artery disease, high coronary calcium burden was associated with increased serum IL-1β, and patients with combined elevations in calcium and IL-1β had more events driven by higher mortality, reinforcing the relevance of this inflammatory calcification signaling axis to human disease. Therapeutic targeting of IL-1β expression through the balance of Rac activation has potential to impact patient care by modulating atherosclerotic calcification and consequent cardiovascular events.

In coronary artery disease (CAD), endothelin-1 (ET-1) is released by activated macrophages and thereby contributes to coronary plaque rupture and triggered cardiac events. The multifactorial regulation of ET-1 includes stimulated release by cytokines and autonomic factors. Laboratory stress provokes alteration in autonomic tone and prolonged ET-1 mediated endothelial dysfunction. The objective of the study is to determine the autonomic contribution to an increase in ET-1 in response to laboratory stress in patients with CAD. Patients (n = 88) with chronic stable CAD instrumented with hemodynamic monitor, digital electrocardiogram (ECG) monitor and indwelling catheter for blood sampling completed a laboratory protocol that included initial rest (30 min), baseline (BL: 10 min), and anger recall stress (AR: 8 min). Change from BL to AR was determined for (a) parasympathetic activity (by spectral analysis of ECG); (b) sympathetic activity (by circulating catecholamines); and (c) ET-1. AR provoked increases from BL in catecholamines, and a decrease in parasympathetic activity. Multivariate analysis with change in parasympathetic activity and catecholamines, while controlling for age and use of β-blockers, revealed a significant odds ratio (OR = 3.27, 95% CI 1.03, 10.41 P = 0.04) for an increase in ET-1 associated with parasympathetic withdrawal; no other variables were significant. The predominant influence of parasympathetic activity on anger/stress-provoked increase in ET-1 is consistent with the cholinergic antiinflammatory pathway. Future examination of autonomic influences on atherosclerotic leukocytes, endothelial cell function and the dynamics of ET-1 are warranted.

Objectives—Depression carries an independent 2- to 4-fold increased risk of early morbidity and mortality after acute coronary syndrome (ACS). The pathway(s) linking depression to eventfree survival remain to be determined. We examined the relationship of depression severity to circulating endothelin-1 (ET-1), which has previously been linked to plaque rupture and post-ACS survival. Methods—Patients with documented history of coronary artery disease (n=101) provided a resting morning blood sample that was assayed for ET-1, and completed the Beck Depression Inventory (BDI). ET-1 was treated as a log transformed continuous variable (logET-1), and as a dichotomous variable using a post-ACS risk threshold previously reported (≥1.16 fmol/ml). Results—BDI score was related to logET-1 in both unadjusted and adjusted models. In addition, unadjusted and adjusted logistic regression models with dichotomous ET-1 revealed that for each point increase in BDI score there was approximately a 14% increased likelihood of being at or above ET-1 risk threshold. Secondary logistic regression models demonstrated a greater than 3.5fold likelihood of being at or above this risk threshold in association with a BDI score ≥10. Conclusions—Depression symptom severity predicts ET-1 elevation that has previously been linked to post-ACS survival, with the greatest risk of elevation among those with worse depression symptoms. This link may identify a vulnerability to triggered ACS and poorer survival associated with depression. Future research should establish whether the observed relationship of depressive symptoms to ET-1 level mediates the link between depression and survival.

Objective: To determine whether a tendency to angry rumination predicts anger recall (AR) stress-provoked increase in endothelin (ET)-1 among patients with coronary heart disease (CHD). Methods: Patients with chronic stable CHD (n = 105) completed a five-item measure of tendency to angry rumination (DAB-VR) and underwent a laboratory AR stress protocol (15-minute resting baseline [BL], 8-minute AR). Blood samples drawn at end of BL and AR were assayed for ET-1. Change in ET-1 from BL to AR (increase versus decrease/no change) was treated dichotomously in multivariate logistic regression models, including DAB-VR score and potential confounders, to evaluate the contribution of DAB-VR to the prediction of change in ET-1. Results: In the multivariate model, DAB-VR score significantly predicted ET-1 increase (odds ratio, 1.34; 95% confidence interval, 1.10–1.1.63; p = .004), controlling for age, history of diabetes, hypercholesterolemia, rate pressure product, use of β blockers, and statins. Conclusions: A tendency to angry rumination independently predicted AR stress-provoked ET-1 increase among patients with CHD. Given the involvement of ET-1 in plaque rupture, anger rumination tendency may identify vulnerability to anger-triggered acute coronary syndrome through prolongation of initial anger mobilization. The contribution of ruminative thinking to sustained poststress ET-1 elevation and the synergistic relationship of ET-1 during emotional stress with norepinephrine and nitric oxide remain to be explored.

ICD Shocks Increase TWA. Introduction: While implantable defibrillator shocks save lives, shock can lead to ventricular arrhythmias. However, the mechanism of shock-related proarrhythmia remains unclear. We evaluated the impact of ICD shock on repolarization instability, a factor associated with ventricular arrhythmogenesis. Methods and Results: Sixty-five patients with ICDs underwent ambulatory ECG monitoring during defibrillation testing 3 months postimplant. TWA was analyzed continuously in the time domain during baseline, sedated, and post-shock states. RR, QRS, and QT intervals and catecholamines were also measured continuously. Adequate pre- and post-shock Holter data were recorded in 55 patients, 48 male, mean 64 ± 12 years, 50 with coronary disease, 48 with prior spontaneous or induced arrhythmia. TWA significantly increased after shock, from 9.6 ± 0.5 to 11.9 ± 0.6 µV, as did QRS duration, epinephrine, and norepinephrine levels, compared with sedated and baseline states. RR intervals decreased minimally. TWA changes with shock were not associated with RR or QRS duration changes, but were associated with changes in epinephrine. Conclusions: ICD shock, even in the sedated state, increases repolarization instability as measured by TWA, an effect mediated in part by sympathetic stimulation. This association between shock and TWA may have important mechanistic and clinical implications for optimization of defibrillation therapy. (J

Psychological Stress and Repolarization. Introduction: Psychological stress can precipitate ventricular arrhythmias in patients with ICDs, as well as sudden death. However, the physiologic pathways remain unknown. We sought to determine whether psychological stress induced in the laboratory setting alters indices of repolarization associated with arrhythmogenesis. Methods and Results: Patients with ICDs and a history of ventricular arrhythmia underwent ambulatory ECG monitoring during a laboratory mental stress protocol (anger recall and mental arithmetic). Continuous changes in repolarization indices which have correlated with temporal and spatial myocardial heterogeneity of repolarization, including T-wave alternans (TWA), T-wave amplitude (Tamp), and T-wave area (Tarea) were analyzed in the time domain. In the 33 patients (85% male, 88% with coronary artery disease, mean ejection fraction 30%), norepinephrine, epinephrine, BP, and HR increased during mental stress. TWA increased from 22 (interquartile range 16-27) at baseline to 29 (21-38) uV during mental stress (P < 0.001). Changes in TWA correlated with changes in HR, systolic BP, and catecholamines. Tamp and Tarea also increased with mental stress (P < 0.01) but did not correlate with changes in other variables. Conclusion: Psychological stress increased TWA, Tamp, and Tarea. Autonomically mediated repolarization changes may be a pathophysiologic link between emotion and arrhythmia in susceptible patients.

“My life is in the hands of any rascal who chooses to put me in a passion.” — —Sir John Hunter This quote from one of the major medical figures of the 18th century describes the association of his expression of anger to his experience of angina.1 In 1793, Dr Hunter was engaged in rancorous argument during the course of a faculty meeting and died suddenly. Narrative reports of angina pectoris in association with an individual’s experience of provocative, stressful circumstances, although not as dramatic as that made by Hunter, date from the time of Celsus to the dawn of modern medicine. These observations gave rise to the pioneering work of Rosenman et al2 on what they came to call “behavior pattern A.” Their work in turn encouraged others to pursue constitutional factors—the personality—that might give rise to risk for stress-related effects on the heart. The resulting literature on emotion, personality, and coronary artery disease (CAD) has, however, very often dealt with narrow concerns, without sufficient integration of biological and social variables that reflect the contextual nature of psychosocial stress. In addition, methodological drift in the conduct of studies on Type A and associated personality factors, combined with the failure in studies to account for concurrent progress in the care of the cardiac patient, produced results that conflicted with the earlier, promising findings.2 These issues have been discussed elsewhere.3 Hence, although we intuitively continue to link emotional factors and coronary syndromes, the nature of the link remains unclear. One consequence of the conflicting research findings on stress, emotion, and coronary syndromes is the absence of a conceptual framework, which is necessary if an effect on clinical awareness and practice is to be realized. In our pursuit of this framework, few discriminators are available to guide our …

Background Depression is prevalent in coronary heart disease ( CHD ) patients and increases risk for acute coronary syndrome ( ACS ) recurrence and mortality despite optimal medical care. The pathways underlying this risk remain elusive. Psychological stress (PS) can provoke impairment in myocardial perfusion and trigger ACS . A confluence of acute PS with depression might reveal coronary vascular mechanisms of risk. We tested whether depression increased risk for impaired myocardial perfusion during acute PS among patients with stable CHD . Methods and Results Patients (N=146) completed the B eck D epression I nventory‐I ( BDI ‐I), a measure of depression linked to recurrent ACS and post‐ ACS mortality, and underwent single‐photon emission computed tomography myocardial perfusion imaging at rest and during acute PS . The likelihood of new/worsening impairment in myocardial perfusion from baseline to PS as a function of depression severity was tested. On the BDI ‐I, 41 patients scored in the normal range, 48 in the high normal range, and 57 in the depressed range previously linked to CHD prognosis. A BDI ‐I score in the depressed range was associated with a significantly greater likelihood of new/worsening impairment in myocardial perfusion from baseline to PS (odds ratio =2.89, 95% CI : 1.26 to 6.63, P =0.012). This remained significant in models controlling ACS recurrence/mortality risk factors and medications. There was no effect for selective serotonin reuptake inhibitor medications. Conclusions Depressed patients with CHD are particularly susceptible to impairment in myocardial perfusion during PS. The confluence of PS with depression may contribute to a better understanding of the depression‐associated risk for ACS recurrence and mortality.

Myocardial ischemia provoked by mental and emotional stress has been the focus of research for almost 40 years. In this paper, we briefly review the literature on this ischemic phenomenon, followed by a more focused review of research findings that have been disseminated over the past year. We use these reviews to highlight important issues concerning research methods, particularly the methods used to myocardial ischemia provoked by mental and emotional stress, along with outstanding questions that bear on clinical utility and integration.

The test/retest reproducibility of brain measures of 5-HT2A receptors with positron emission tomography (PET) and [ 18 F]deuteroaltanserin was examined in a group of eight healthy human subjects. PET measures of 5-HT2A receptors were obtained under an equilibrium paradigm, with a 40-min PET acquisition starting approximately at 300 min (308±11 min) after bolus plus constant infusion of the radiotracer. Three brain outcome measures were obtained at equilibrium, V 3 (ratio of specific brain uptake to free parent plasma concentration of radiotracer), V 3 ′ (ratio of specific brain uptake to total parent plasma concentration) and RT (ratio of specific to non-displaceable brain uptakes). V 3 ′ and RT had high test/retest reproducibility, as measured by mean intra-subject% change for cortical brain areas of 14.1 and 11.0%, respectively. They also had high reliability, as measured by mean intra-class correlation coefficients (ICC) for cortical brain areas of 0.86 and 0.88, respectively. V 3 had low test/retest reproducibility, due to high variability in the measures of free parent tracer in plasma. This study supports the feasibility of equilibrium imaging of 5-HT2A receptors with PET and [ 18 F]deuteroaltanserin. The equilibrium imaging method with [ 18 F]deuteroaltanserin allows a single acquisition and blood measurement to provide an image whose pixel values equal a receptor volume of distribution. Since the single image pixel values are proportional to receptor densities, the images can be used in pixel-by-pixel statistical methods, such as SPM, to assess the distribution and density of 5-HT2A receptors in neuropsychiatric disorders.

Objectives. We sought to investigate the mechanism of a mental stress–induced fall in left ventricular ejection fraction (LVEF) in patients with coronary artery disease. Background. Mental stress induces a fall in LVEF in a significant proportion of patients with coronary artery disease. This is accompanied by an increase in heart rate, blood pressure and rate–pressure product. Whether the mental stress–induced fall in LVEF is due to myocardial ischemia, altered loading conditions or a combination of both is not clear. Methods. Left ventricular (LV) function was studied noninvasively by serial equilibrium radionuclide angiocardiography and simultaneous measurement of peak power, a relatively afterload-independent index of LV contractility, in 21 patients with coronary artery disease (17 men, 4 women) and 9 normal subjects (6 men, 3 women) at baseline, during mental stress and during exercise. Peripheral vascular resistance (PVR), cardiac output (CO), arterial and end-systolic ventricular elastance (Ea, Ees) and ventriculoarterial coupling (V/AC) were also calculated. Patients underwent two types of mental stress—mental arithmetic and anger recall—as well as symptom-limited semisupine bicycle exercise. Results. Nine patients (43%) had an absolute fall in LVEF of ≥5% (Group I) in response to at least one of the mental stressors, whereas the remaining patients did not (Group II). Group I and Group II patients were similar in terms of baseline characteristics. Both groups showed a significant but comparable increase in systolic blood pressure (15 ± 7 vs. 9 ± 10 mm Hg, p = 0.12) and a slight increase in heart rate (7 ± 4 vs. 8 ± 7 beats/min, p = 0.6) and a comparable increase in rate–presure product (2.2 ± 0.9 vs. 1.9 ± 1.2 beats/min × mm Hg, p = 0.6) with mental stress. However, PVR increased in Group I and decreased in Group II (252 ± 205 vs. −42 ± 230 dynes·s·cm−5, p = 0.006), and CO decreased in Group I and increased in Group II (−0.2 ± 0.4 vs. 0.6 ± 0.7 liters/min, p = 0.02) with mental stress. There was no difference in the change in peak power (p = 0.4) with mental stress. With exercise, an increase in systolic blood pressure, heart rate, rate–pressure product and CO and a fall in PVR were similar in both groups. Of the two mental stressors, anger recall resulted in a greater fall in LVEF and a greater increase in diastolic blood pressure. Exercise resulted in a fall in LVEF in 7 patients (33%). However, exercise-induced changes in LVEF and hemodynamic variables were not predictive of mental stress–induced changes in LVEF and hemodynamic variables. Conclusions. Abnormal PVR and Earesponses to mental stress and exercise are observed in patients with a mental stress–induced fall in LVEF. Peripheral vasoconstrictive responses to mental stress contribute significantly toward a mental stress–induced fall in LVEF.

Although positron emission tomography (PET) provides important physiological information, a major limitation of this technique is poor anatomical resolution. Combining the superior anatomical resolution of magnetic resonance imaging (MRI) with the physiologic information of PET could be an important advance for clinical and research applications of PET. The purpose of this study was to develop reliable methods for using MRI in the definition of brain regions of interest (ROIs) for application to coregistered PET brain images. First, specific criteria were developed for definition of ROIs on coregistered MRI using anatomical landmarks from a standard anatomical atlas. ROIs were then drawn by three independent raters using the criteria on 11 MRI scans, which had been coregistered to PET [18F]2-fluoro-2-deoxyglucose (FDG) brain scans. These MRI-based templates were used to determine activity in various brain regions on the PET scans, which were used in the determination of regional brain metabolic rates. There was a high level of agreement between raters for the measurement of regional metabolic rates, with intra-class correlation coefficients ranging from 0.63–0.98. These findings suggest that specific ROI criteria based on coregistered MRI are a reliable method of measuring activity from PET images. The use of a standard and widely available atlas and readily applicable criteria for ROIs should facilitate a standard method of measurement which can be applied in a similar manner at different PET sites.

The accuracy of technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) for the assessment of myocardial viability in patients with coronary artery disease and left ventricular (LV) dysfunction is not defined completely. This study determines whether the performance of Tc-99m sestamibi SPECT for viability detection differs between patients with mild-tomoderate coronary artery disease. Patients with regional and/or global LV dysfunction were separated into 2 groups on the basis of LV ejection fraction (EF) at rest: group 1 (LVEF >25%, mean 36 ± 6%, n = 9), and group 2 (LVEF ≤25%, mean 17 ± 5%, n = 11). All patients underwent semiquantitative Tc-99m sestamibi SPECT and positron emission tomography (PET) at rest with N-13 ammonia and F-18 fluorodeoxyglucose. The overall regional concordance of SPECT and PET for viability detection was 89% in group 1 and 78% in group 2 (p = 0.002). Discordance in group 2 was almost exclusively due to PET viable and/or SPECT nonviable regions. In regions with hypoperfusion at rest by PET, concordance was 78% in group 1 and only 64% in group 2 (p = 0.0015). In regions with reduced perfusion and relatively increased metabolic activity (“flow: metabolism mismatch”), Tc-99m sestamibi SPECT identified 88% of regions in group 1 as viable, but only 42% of regions in group 2 (p = 0.002). Thus, while Tc-99m sestamibi semiquantitative SPECT at rest shows a good concordance with PET for the detection of myocardial viability in patients with coronary artery disease with mild-to-moderate LV dysfunction, it may underestimate myocardial viability in patients with severe LV dysfunction, particularly in those patients with hypoperfusion at rest as assessed by PET.

No-carrier-added [ N-methyl - 11 C]LY257327 was synthesized by methylation of the free base of the desmethyl precursor LY214281 with [ 11 C]methyl iodide in anhydrous acetonitrile. Synthesis time was 52 ± 3 min, radiochemical yield (based on [ 11 C]methyl iodide) was 35 ± 8%, radiochemical purity was 99 ±1%, and specific activity at EOB was 3900 ± 1300 mCi/μmol. Two in vivo studies in baboon were carried out before and after pretreatment with the selective serotonin reuptake inhibitor citalopram. The first experiment showed high accumulation of radioactivity in midbrain, striatum, and thalamus, with slightly lower accumulation in the occipital and cerebellum regions. The radioactivity concentration peaked 5 min postinjection, decreasing steadily for the rest of the scanning time. The second experiment (blocked with citalopram) showed only partial inhibition of incorporation in all of the same brain regions. Although [ N-methyl - 11 C]LY257327 displayed high brain uptake (5% of injected dose at 5 min postinjection) and localized in serotonergic areas of the brain, its target-to-nontarget ratio and its insensitivity to citalopram blocking suggest that its accumulation is dominated by nonspecific uptake. Therefore, [ N-methyl - 11 C]LY257327 is not a useful agent for measuring serotonin reuptake sites in vivo by positron emission tomography.

The ability of nuclear cardiology techniques to assess myocardial perfusion is vital in the cardiology consultants’ evaluation of patients with suspected or known coronary artery disease. This chapter will begin with a description of the physiologic principles underlying perfusion imaging. With this intellectual framework, the consultant can employ nuclear cardiology techniques to assist in the diagnosis of coronary artery disease, to assess cardiovascular prognosis and risk stratification, and to guide medical and revascularization strategies in the management of coronary artery disease. This chapter concludes with an overview of the performance of nuclear cardiology tests.

A randomized, double blind, parallel study was performed to compare the effects of nifedipine gastrointestinal therapeutic system (GITS) to hydrochlorothiazide (HCTZ) in the management of the elderly hypertensive. Eighteen patients, mean age 65 +/- 5 years, with Stage I-III diastolic hypertension (sitting diastolic BP between 90 and 115 mm HG) were included in each treatment group. Following a 2 to 8 week placebo washout phase, patients received either nifedipine GITS or HCTZ and were titrated over 5 weeks to achieve a goal diastolic blood pressure less than 90 mm Hg. Patients were then continued on medication during an 8 week maintenance phase. Treatment effect on systolic and diastolic blood pressure was assessed. Serum electrolytes, lipids, blood urea nitrogen, and creatinine were measured before and after treatment. Posttreatment changes in renal and cardiovascular function, as well as left ventricular mass were evaluated. The results showed significant reductions in systolic and diastolic blood pressure with both drugs; no treatment difference was found, although goal blood pressure was achieved more rapidly with nifedipine GITS (28 v 34 days, P < .05). BUN was significantly increased only after diuretic therapy (P < .01) and serum potassium fell to a greater degree with HCTZ (0.3 mEq/L v 0.1 mEq/L) than with nifedipine GITS. No statistically significant changes in left ventricular mass, ejection fraction, glomerular filtration rate, or renal blood flow were seen after therapy with either drug. However, the time peak LV diastolic filling rate decreased with nifedipine GITS (197 to 164 msec) and increased with HCTZ (172 to 198 msec). This treatment difference approached statistical significance (P = .07). Adverse side effects of treatment were reported by 50% of nifedipine GITS patients and 28% of patients treated with HCTZ. This treatment difference was not statistically significant. We conclude that both nifedipine GITS and HCTZ monotherapy provide significant blood pressure reduction in older hypertensives with Stage I-III diastolic hypertension. Both drugs are well tolerated with no significant adverse effect on renal or cardiovascular function after short term therapy.

Diastole, that portion of the cardiac cycle that begins with isovolumic relaxation and ends with mitral valve closure, results in ventricular filling and involves both active (energy-dependent) and passive processes. The interactions between active processes (myocardial relaxation) that primarily influence early ventricular filling and passive processes, such as loading conditions, myocardial compliance, and valvular disease, are complex. Clinical methods to assess ventricular filling include cardiac catheterization, radionuclide angiography, and echocardiography. Any measurements of diastolic function must be made with an understanding of the determinants of ventricular filling and the limitations of the diagnostic test. Many cardiac disorders are characterized by elevated pulmonary venous pressures in the face of normal systolic ventricular function, which suggests a primary abnormality of diastolic function. Abnormalities in diastolic function have been observed in coronary artery disease, congestive heart failure (with and without systolic dysfunction), hypertrophic cardiomyopathy, hypertension, and in healthy elderly subjects. Identification of these abnormalities may be useful clinically, particularly in patients with symptoms of heart failure and normal systolic function. Data are not available to determine the optimal therapy for such patients, although evidence suggests that calcium channel blockers, beta blockers, and agents that reverse myocardial hypertrophy may be useful. This review briefly summarizes the physiology of diastole, the methods of clinical assessment of diastolic function, and the role of diastolic function in cardiovascular disease.

Thirty patients with stable angina pectoris and ischemia on stress perfusion imaging underwent continuous ambulatory left ventricular (LV) function monitoring. Mental stress was induced by mental arithmetic. Fifteen patients developed transient LV dysfunction during mental arithmetic. Patients were followed for 2 years for adverse cardiac events. Twelve patients had cardiac events over 1 year (myocardial infarction in 4, and unstable angina in 8). Nine of 15 patients (60%) with and only 3 of 15 (20%) without mental stress-induced LV dysfunction developed cardiac events (p = 0.025). A higher proportion of patients with cardiac events were taking beta blockers (p = 0.01) and had lower resting heart rates (p = 0.002) than those without cardiac events. There was no difference in the baseline characteristics between the groups of patients with and without cardiac events. At 2-year follow-up, 10 of 15 patients (67%) with mental stress-induced LV dysfunction had adverse events compared with only 4 of 15 (27%) with no mental stress-induced LV dysfunction (p = 0.025). Thus, in this cohort of patients with stable angina pectoris, mental stress-induced LV dysfunction was associated with higher cardiac events on follow-up. The exact mechanism of this association is not clear. Mental stress may be a trigger for adverse cardiac events in these patients. Transient LV dysfunction in response to mental stress may be a marker of abnormal cardiovascular reactivity to emotional and psychological stimuli in patients with coronary artery disease and may be useful for risk stratification.

The central benzodiazepine receptor tracer [ N -methyl- 11 C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [ 11 C]methyl iodide. The [ 11 C]CH 3 I (prepared by reduction of [ 11 C]CO 2 with LiAlH 4 followed by reaction with HI) was reacted with noriomazenil in N,N -dimethylformamide and Bu 4 N + OH − for 1 min at 80 °C and purified by HPLC (C 18 , 34% CH 3 CN/H 2 O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [ 11 C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [ 11 C]flumazenil PET and [ 123 I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [ 11 C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

3,5,6,7,8,8a-Hexahydro-7,7,8a-trimethyl-[6S-(6α,8α,8αβ)]-6,8-methano-2H-1,4-benzoxazino-2-one (2) was investigated as chiral auxiliary for asymmetric NCA nucleophilic synthesis of 6-[ 18 F]Fluoro-L-DOPA. Direct condensation of 3,4-dimethoxy-2-[ 18 F]fluorobenzaldehyde (1a) or 6-[ 18 F]fluoropiperonal (1b) in the presence of NaH with 2 gave the corresponding [ 18 F]-3-[(2-fluorophenyl)methylene]-3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[6S-(3Z,3α,6α,8α,8αβ)]-6,8-methano-2H-1,4-benzoxazin-2-one derivative 3a or 3b as a single stereoisomer. L-Selectride® promoted hydrogenation of the olefinic double bond of these derivatives, in presence of tertbutyl alcohol, afforded the corresponding [ 18 F]-3-[(2-fluorophenyl)methyl]-3,5,6,7,8,8a-hexahydro-7,7,8a-trimethyl-[3S-(3α,6α,8α,8αβ)]-6,8-methano-2H-1,4-benzoxazin-2-one derivatives (4a,b) without affecting the orientation of diastereofacial discrimination. Deprotection of the derivatives 4a,b yielded 6-[ 18 F]fluoro-L-DOPA (e.e. >90%, 3% radiochemical yield (EOB), total synthesis time 125 min, specific activity >2000 mCi/μ mol). Direct deprotection/reduction of the compounds 3a,b provides the enantiomeric mixture of 6-[ 18 F]fluoro-D,L-DOPA (10-12% radiochemical yield) and, after chiral separation, 6-[ 18 ]fluoro-L-DOPA (e.e. 98%, 4-5% radiochemical yield). A cold enantioselective synthesis of 6-fluoro-L-DOPA has been effected with total chemical yield 15% (e.e. 93.4%)

OBJECTIVES Depression has been related to mortality in patients with CAD and to medical morbidity after CABG; however, prior studies have not examined the contribution of presurgical depressive symptoms to mortality after CABG. The purpose of this study was to determine the independent contribution of presurgical symptoms of depression to 2-year cardiac mortality after CABG. METHODS Eighty-nine consecutive veteran nonemergent CABG patients recruited between December 1996 and June 1998 completed the BDI 1 to 7 days before surgery. Mortality risk was assessed by medical co-morbidity and RIS. RESULTS Significant univariate contributions to two-year cardiovascular mortality were found for RIS (chi2 = 6.57, p

Introduction Changes in the autonomic nervous system activity are a major trigger of life-threatening ventricular tachyarrhythmias (VTAs). Mental arithmetic, a condition administered in a laboratory setting, can provide insight into the autonomic nervous system activity effects on cardiac physiology. We examined the responses of cardiac repolarization to laboratory-induced psychological stressors in patients with implantable cardioverter-defibrillators (ICDs) with the objective of identifying the indices that differentiate patients with and without subsequent VTA in follow-up. Methods Continuous electrocardiographic signals were recorded using 3 standard bipolar (Holter) leads in 56 patients (age, 63.6 ± 11.9; female, 12%; left ventricular ejection fraction, 32.3 ± 11) with ICDs during mental arithmetic. The patients were separated into those with subsequent VTA during 3 to 4 years of follow-up (group 1: n = 9) and those without VTA (group 2: n = 47). Changes in repolarization (QT interval, mean T wave amplitude [Tamp], and T wave area) were analyzed during 5 minutes at baseline, stress, and recovery. The temporal instability of Tamp and T wave area was examined using the range (Δ) and variance ( σ 2 ) of beat-to-beat variations of the corresponding parameters. Results There were no significant differences in heart rate between the 2 groups at baseline (61 vs 63 beats per minute, P = .97), stress (64 vs 65 beats per minute, P = .40), and recovery (62 vs 61 beats per minute, P = .88). However, during mental stress and poststress recovery, ΔTamp was almost 2-fold greater in group 1 compared with group 2 (111 [57-203] vs 68 [44-94] μ V, P = .04, respectively). Changes in QT intervals were also greater in group 1 compared with group 2 ( P = .02). Conclusion Among patients with ICDs, changes of Tamp after psychological stress were greater in those with subsequent arrhythmic events. This might signal proarrhythmic repolarization response and help identify patients who would benefit the most from ICD implantation and proactive management.

Objectives. We examined the relationship of the psychological profile to left ventricular dysfunction induced during mental stress.Background. The contribution of psychological factors to mental stress-provoked silent myocardial ischemia has not been explored.Methods. Thirty patients with chronic stable coronary artery disease and a reversible defect on stress thallium-201 imaging completed a psychological assessment by questionnaire and Structured Interview, serially administered mental stress and brief walking exercise. Blood pressure, electrocardiogram (ECG) and left ventricular indexes were obtained by ambulatory serial radionuclide ventriculography. Silent ventricular dysfunction was defined by a decrease ≥0.05 in ejection fraction or ≥1 mm in ST segment on the ECG in the absence of symptoms.Results. Of the 30 patients, 15 (Group I) had evidence of silent left ventricular dysfunction during mental arithmetic. The other 15 (Group II) showed no change. In addition, 18 of 30 patients had this dysfunction during the Structured Interview. Both ischemic and nonischemic groups developed comparable and significant increases in heart rate and blood pressure. Group I patients were distinguished by higher scores on measures of aggressive responding (p < 0.001), trait anger (p < 0.0001), hostile affect (p < 0.003) and an index of behavioral reactivity (p < 0.003) and a lower score on anger control (p < 0.001). No other variables, including historical and clinical indexes, discriminated between the two groups.Conclusions. Patients with coronary artery disease and mental stress-provoked silent ventricular dysfunction were distinguished by a psychological profile consistent with emotional reactivity to social interaction and mental provocation, with anger as the predominant affective state. Patients with such a profile may be at risk of frequent silent left ventricular dysfunction.

Negative emotions such as anger, anxiety, and sadness can precipitate ventricular arrhythmias [(1)][1] and myocardial infarction [(2)][2], but whether emotion may similarly trigger atrial fibrillation (AF) has not been systematically evaluated. Pharmacological autonomic manipulations alter atrial

Congestive heart failure (CHF) is typically associated with impaired left ventricular (LV) systolic performance. Few reports exist describing the long-term outcome in patients with CHF and normal LV systolic function. Fifty-two patients initially hospitalized with CHF and intact LV function (ejection fraction greater than or equal to 45%) were followed for 7 years. Mean age when initially identified was 71 +/- 11 years (range 36 to 96), and average LV ejection fraction was 61 +/- 11%. CHF was graded by a clinicoradiographic index, with a mean of 7.0 +/- 2.3 (range 3 to 12, 13 indicates worst CHF). A third heart sound was present in 19 patients (37%), and 17 (33%) had presented with acute pulmonary edema. Principal cardiovascular diagnoses were coronary artery disease in 27 (52%), hypertensive heart disease in 16 (31%) and restrictive cardiomyopathy in 7 (13%). At 7 years, cardiovascular mortality was 46% (24 of 52), and noncardiovascular mortality was 10% (5 of 52). Survival was not correlated with age, principal diagnosis, third heart sound, pulmonary edema at presentation, LV ejection fraction, or presence or degree of LV diastolic dysfunction. Cardiovascular morbidity, consisting of nonfatal recurrent CHF, myocardial infarction, unstable angina or other cardiovascular events occurred in 29% (15 of 52). Combined cardiovascular mortality and morbidity was 75% (39 of 52). In patients with CHF, intact LV systolic function does not confer the same favorable prognosis it defines in other clinical situations. For such patients, the risk of future cardiovascular events is high, a finding that should be considered when designing therapeutic strategies in this group.

The individual and additive effects of positive end-expiratory pressure (PEEP) and right coronary artery (RCA) occlusion on left ventricular end-diastolic pressure-volume relations (LVEDPVR) were examined in six anesthetized dogs. Right ventricular (RV) and left ventricular (LV) ejection fractions (EF), end-diastolic volume (EDV) and end-systolic volumes (ESV) were measured by thermodilution as PEEP was added before and after RCA occlusion. PEEP alone caused a decline in cardiac output, transmural left atrial pressure (LAP) (6.0 +/- 0.6 to 3.2 +/- 1.4 mm Hg, p less than 0.05), and LVEDV (49 +/- 3 to 36 +/- 4 ml, p less than 0.05). RVEDV, the mean slope (+/- SD) of the LVEDPVR (0.37 +/- 0.16 to 0.30 +/- 0.19) and LAP at a common LV volume (35 ml, V35) did not change with PEEP. RCA occlusion caused cardiac output and RVEF (38 +/- 5 to 27 +/- 5%, p less than 0.05) to decline and RVESV (25 +/- 4 to 33 +/- 6 ml, p less than 0.05) to increase. RVEDV, the slope of the LVEDPVR, and LAP at V35 were unchanged from baseline. The addition of PEEP after RCA occlusion caused cardiac output to decline further. However, unlike before occlusion, there was no change in LAP (6.5 +/- 1.3 to 5.0 +/- 1.4 mm Hg) despite a decline in LVEDV (47 +/- 3 to 29 +/- 6 ml, p less than 0.05). RVESV and RVEDV increased with PEEP after RCA occlusion as did LAP at V35. The slope of the mean LVEDPVR tended to increase (0.98 +/- 1.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial ischemia that results from emotional provocation occurs in as many as 30% to 50% of patients with coronary artery disease during the discourse of their lives. This emotionally provoked or mental stress ischemia is associated with poor prognosis, with emerging treatment strategies. This article outlines the conceptual constructs that support the pathophysiologic underpinnings, and biobehavioral aspects associated with this mental stress ischemia. We review a biobehavioral model in which cognitive stress is transduced in the brain. The response of the brain to psychosocial stress is a highly sophisticated and integrated process by which sensory inputs are evaluated and appraised for their importance in relation to previous experience and current goals. The biologic consequences of such stress transduced in the central nervous system has its effect on cardiovascular flow and function through changes in autonomic balance, which result in various biologic processes that culminate in the perturbation of flow and function of the heart.

Redistribution thallium-201 imaging 2 to 4 h after exercise may be incomplete and therefore may be inadequate to fully assess myocardial variability. Late redistribution imaging 24 h after exercise has been proposed to overcome this limitation of thallium stress imaging. However, because of poor count density the image quality on these studies is often suboptimal. In the present study the diagnostic information on 24-h planar thallium redistribution images was compared with that on images obtained after a reinjection of thallium at rest.Eighty-four patients with a stress thallium-201 defect had delayed redistribution imaging after 2 to 4 h and 24 h later, and again after an injection of thallium at rest. Defect reversibility on 24-h redistribution images was compared quantitatively with that on images after injection of thallium at rest. The quality of thallium images at rest was consistently better than that of 24-h redistribution images. Poor quality studies occurred in 13% of 24-h redistribution images compared with 0.4% of the studies at rest. Significantly more defect reversibility was detected on images after the reinjection at rest.Of 41 patients who appeared to have a fixed defect at 2- to 4-h redistribution imaging, 11 (27%) had a reversible defect by 24-h redistribution imaging compared with 29 (71%) after thallium-201 reinjection. No clinical variables at the time of stress testing were predictive of late defect reversibility. It is concluded that in patients with fixed a thallium defect at 2 to 4 h after exercise, reimaging after a reinjection at rest provides better diagnostic information than does 24-h late redistribution imaging.

Small case-series suggest the possibility of “adrenergically-mediated” atrial fibrillation (AF) in humans, and pharmacological autonomic manipulations can alter atrial electrophysiology. Whether AF can be triggered by emotional arousal is unknown. In this prospective, controlled, electronic-diary-based study of emotions preceding AF, patients with a history of paroxysmal or persistent AF, (N=75, mean age 58 years, 60% male, 60% taking beta-blocking medications) recorded their rhythm on event-monitor at the time of AF symptoms, and completed a diary entry querying mood states for the preceding 30 minutes (pre-AF “case period”) over a one-year follow-up. Also, patients underwent monthly 24-hour holter-monitoring, and were prompted by the diary to complete an entry twice per hour. Diaries recorded during sinus comprise the controls. Further, patients completed a diary each night. Patients’ exposure to each emotion was compared between the pre-AF case period and control periods using GEE modeling. Similarly, emotion on a nightly diary preceding AF on the following day was compared to that emotion on other nightly diaries. 119 AF episodes, (in 23 subjects), and 5796 holter-confirmed sinus rhythm control-periods had associated diary data. 95 pre-AF nightly diaries and 9306 control nightly diaries were completed. The likelihood of an AF episode was increased by negative emotions and decreased by happiness whether reported immediately preceding an AF episode, or the night before (table ). Impact of emotion was gender-specific: anger increased the odds of subsequent AF for men, worry for women. In stratified analysis, emotion triggered AF only in those not taking beta-blockers (data not shown). Negative emotions can trigger AF, while happiness is protective. Whether interventions aimed at reducing the physiological effects of emotional stress may lessen AF burden requires further study.

ObjectivesThis study sought to determine whether T-wave alternans (TWA) induced by anger in a laboratory setting predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICDs).BackgroundAnger can precipitate spontaneous ventricular tachycardia/ventricular fibrillation and induce TWA. Whether anger-induced TWA predicts future arrhythmias is unknown.MethodsSixty-two patients with ICDs underwent ambulatory electrocardiography during a mental stress protocol, 3 months after the ICD was implanted. T-wave alternans was analyzed using time-domain methods. After a ≥1 year follow-up, ICD stored data was reviewed to determine incidence of ICD-terminated ventricular tachycardia/ventricular fibrillation.ResultsPatients with ICD-terminated arrhythmias during follow-up (n = 10) had higher TWA induced by anger, 13.2 μV (interquartile range [IQR] 9.3 to 16 μV), compared with those patients without future ventricular arrhythmias, 9.3 μV (IQR 7.5 to 11.5 μV, p < 0.01). Patients in the highest quartile of anger-induced TWA (>11.9 μV, n = 15) were more likely to experience arrhythmias by 1 year than those in the lower quartiles (33% vs. 4%) and during extended follow-up (40% vs. 9%, p < 0.01 for both). In multivariable regression controlling for ejection fraction, prior clinical arrhythmia, and wide QRS, anger-induced TWA remained a significant predictor of arrhythmia, with likelihood in the top quartile 10.8 times that of other patients (95% confidence interval: 1.6 to 113, p < 0.05).ConclusionsAnger-induced TWA predicts future ventricular arrhythmias in patients with ICDs, suggesting that emotion-induced repolarization instability may be 1 mechanism linking stress and sudden death. Whether there is a clinical role for anger-induced TWA testing requires further study.

Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.

Evidence points to a significant role for psychological factors in the pathogenesis of cardiovascular disease (CVD). Mental stress, including psychological, psychosocial, or emotional stress, is recognized as a risk factor for the development of CVD. It also seems to contribute to the onset of—and can directly precipitate acute—coronary syndromes (ACS), fatal arrhythmias, and acute heart failure.

Myocardial ischemia provoked in the laboratory during mental stress (MSI) in patients with stable coronary artery disease (CAD) predicts subsequent clinical events. The pathophysiology of MSI differs from that of exercise ischemia, and the mechanisms tying MSI to poor prognosis are not known. C-reactive protein (CRP) is a risk marker for cardiovascular events in patients with CAD, but little is known regarding the relationship of CRP to MSI. The purpose of this study was to examine the association of CRP to risk of MSI in CAD patients. Eighty-three patients with stable CAD underwent simultaneous single-photon emission computed tomography (SPECT) imaging with technetium-99m tetrofosmin myocardial perfusion imaging (MPI) and transthoracic echocardiography (TTE), at rest and during MS induced by laboratory mental stress. Serum CRP levels were measured 24 h after MS. MSI was defined by the presence of a new perfusion defect on SPECT and/or new regional wall motion abnormality on TTE during MS. Of the 83 patients, 30 (36%) developed MSI. There was no difference in gender, sex, BMI, histories of diabetes, hypertension, smoking, lipid profile, medications used (including statins, beta-blockers, ACE inhibitors, and aspirin), or hemodynamic response during MS between those with and without MSI. In univariate logistic regression analysis, each unit (1 mg/L) increase in CRP level was associated with 20% higher risk of MSI (OR 1.2, 95% CI 1.01-1.39, P=.04). This relationship remained in multivariate models. These data suggest that levels of CRP may be a risk marker for MSI in patients with CAD.