The Brain-Heart Axis: Neuroinflammatory Interactions in Cardiovascular Disease.

PURPOSE OF REVIEW: The role of neuroimmune modulation and inflammation in cardiovascular disease has been historically underappreciated. Physiological connections between the heart and brain, termed the heart-brain axis (HBA), are bidirectional, occur through a complex network of autonomic nerves/hormones and cytokines, and play important roles in common disorders. RECENT FINDINGS: At the molecular level, advances in the past two decades reveal complex crosstalk mediated by the sympathetic and parasympathetic nervous systems, the renin-angiotensin aldosterone and hypothalamus-pituitary axes, microRNA, and cytokines. Afferent pathways amplify proinflammatory signals via the hypothalamus and brainstem to the periphery, promoting neurogenic inflammation. At the organ level, while stress-mediated cardiomyopathy is the prototypical disorder of the HBA, cardiac dysfunction can result from a myriad of neurologic insults including stroke and spinal injury. Atrial fibrillation is not necessarily a causative factor for cardioembolic stroke, but a manifestation of an abnormal atrial substrate, which can lead to the development of stroke independent of AF. Central and peripheral neurogenic proinflammatory factors have major roles in the HBA, manifesting as complex bi-directional relationships in common conditions such as stroke, arrhythmia, and cardiomyopathy.

Delirium in older adults after percutaneous coronary intervention: Prevalence, risks, and clinical phenotypes.

INTRODUCTION: In-hospital delirium is more common among older adults and is associated with increased mortality and adverse health-related outcomes. We aim to establish the contemporary prevalence of delirium among older adults undergoing percutaneous coronary intervention (PCI) and the impact of delirium on in-hospital complications. METHODS: We identified older adults aged ≥75 years in the National Inpatient Sample who underwent inpatient PCI for any reason from 2016 to 2020 and stratified them into those with and without delirium. The primary outcome was in-hospital mortality, and secondary outcomes encompassed post-procedural complications. RESULTS: Delirium occurred in 14,130 (2.6 %) hospitalizations in which PCI was performed. Patients who developed delirium were older and had more comorbidities. Patients with in-hospital delirium had higher odds of in-hospital mortality (adjusted odds ratio [aOR] 1.27, p = 0.002) and non-home discharge (aOR 3.17, p < 0.001). Delirium was also associated with higher odds of intracranial hemorrhage (aOR 2.49, p < 0.001), gastrointestinal hemorrhage (aOR 1.25, p = 0.030), need for blood transfusion (aOR 1.52, p < 0.001), acute kidney injury (aOR 1.62, p < 0.001), and fall in hospital (aOR 1.97, p < 0.001). CONCLUSION: Delirium among older adults undergoing PCI is relatively common and associated with higher odds of in-hospital mortality and adverse events. This highlights the importance of vigilant delirium prevention and early recognition in the peri-procedural setting, especially for older adults.

Effects of Psychological Stress on Vascular Physiology: Beyond the Current Imaging Signal.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

The Foundational Role of Cardiovascular Imaging in the Characterization of Mental Stress-Induced Myocardial Ischemia in Patients with Coronary Artery Disease.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Cardiovascular Imaging of Biology and Emotion: Considerations Toward a New Paradigm.

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.

Relationship Between Depressive Symptoms and Health Status in Peripheral Artery Disease: Role of Sex Differences.

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<0.001) presented with severe depressive symptoms. In the adjusted model, patients with depressive symptoms had worse health status at each time point (all P<0.0001). Results were similar for EQ-5D Visual Analogue Scale scores. The magnitude in 1-year change in health status scores did not differ by sex. Depressive symptoms explained 19% of the association between sex differences in 1-year Peripheral Artery Questionnaire summary scores. 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.

Effect of ß-blockers on triggering of symptomatic atrial fibrillation by anger or stress.

BACKGROUND: Anger and stress can trigger episodes of atrial fibrillation (AF) in patients with a history of AF. OBJECTIVE: The purpose of this study was to determine whether ß-blockers can protect against emotionally triggered AF. METHODS: 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 ß-blocker use and emotion tested. RESULTS: Sixty percent were prescribed ß-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 ß-blockers (odds ratio 22.5; 95% confidence interval 6.7-75.4, P < .0001 for patients not prescribed ß-blockers vs odds ratio 4.0, 95% confidence interval 1.7-9.5, P = .002 for those prescribed ß-blockers; P = .02 for the interaction). Exclusion of patients on sotalol did not affect findings. CONCLUSION: Anger or stress can trigger AF, but use of ß-blockers greatly attenuates this deleterious physiological response.

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1ß Production.

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-1ß (IL-1ß) 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-1ß expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1ß levels. Moreover, we found that elevated IL-1ß 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-1ß expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

Post-traumatic Stress Disorder and Cardiovascular Disease.

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.

Body Mass Index and Risk for Mental Stress Induced Ischemia in Coronary Artery Disease.

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.

Confluence of depression and acute psychological stress among patients with stable coronary heart disease: effects on myocardial perfusion.

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 Beck Depression Inventory-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.

Cardiac repolarization instability during psychological stress in patients with ventricular arrhythmias.

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] µV, 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.

Autonomic contribution to endothelin-1 increase during laboratory anger-recall stress in patients with coronary artery disease.

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 ß-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.

Depression predicts elevated endothelin-1 in patients with coronary artery disease.

OBJECTIVE: To examine the relationship of depression severity to circulating endothelin-1 (ET-1), which has previously been linked to plaque rupture and postacute coronary syndrome (ACS) survival. Depression carries an independent two- to four-fold increased risk of early morbidity and mortality after ACS. The pathway(s) linking depression to event-free survival remains to be determined. METHODS: Patients with documented history of coronary artery disease (n = 101) provided a resting morning blood sample that was assayed for ET-1, and they 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 >3.5-fold likelihood of being at or above this risk threshold in association with a BDI score of ≥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 patients 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.

Tendency to angry rumination predicts stress-provoked endothelin-1 increase in patients with coronary artery disease.

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 beta 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.