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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

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.

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.

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.

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.

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.