Neurobehavioral

Research has shown that the expression of negative emotions in response to a real or perceived provocation seems to consistently correlate with acute cardiac events. A biomedical model incorporating simultaneous Heart-Brain endpoints with behavior which is manifested and shaped by latent cultural and social determinants is our challenge.

The published work of our group has shown that there are pathophysiologic distinctions in cerebral and cardiovascular determinants of Mental Stress Ischemia compared to ischemia which results from exercise and that these patients have a poor prognosis. Work of others have confirmed our initial reports regarding prognosis and independent reports that there is a survival advantage when rehabilitation strategies are tailored accordingly. Given that it has been shown that up to 75% of CAD subjects are vulnerable to myocardial ischemia in response to mental stressors this is a leading public health issue and merits the attention of serious scientific inquiry. I have been privileged to mentor and organize colleagues into this endeavor. Given the novelty and difficulty of these experimental designs which employs simultaneous biomedical measurements of heart and brain performance or electrophysiologic instability while inducing ischemia-- the risks for failure were high. However with each success we found that very few could replicate the comprehensive approach to this difficult problem. Thus, our institution has led the way in reporting fundamental observations related to the pathophysiologic antecedents and consequences of this clinical presentation.  Accordingly Dr. Burg was the first to define the personality profile of subjects in the laboratory setting who became ischemic to mental stress (JACC). Rachel Lampert was the first to report the association of anger and ventricular tachycardia in daily life, and defined the incessant nature of Ventricular Tachycardia, which required shock in the lab for those undergoing an Anger Recall, using the patients as their own control (both in Circulation). I was fortunate to have the first report of the distinct Brain activation patterns of those who became ischemia to mental stress, (PNAS), and the first report that epicardial stenosis is more independent of eventual mental stress ischemia compared to ischemia provoked by adenosine in the same subject (Lancet, first author, J. Arrighi). Below is an update on these findings. The combined support for the faculty that comprise this research program includes currently: 4 RO-1’s and a Merit Review in addition to several other foundation grants, which position our efforts towards a program project grant in the next several years.

Robert Soufer, M.D.

The overarching research theme of our research is the elucidation of those mechanisms, which transduce cognitive stress as a provocation of myocardial ischemia. Specifically, we are interested in the neurobiology and coronary flow dynamics that results from mentally stressful tasks. Our work utilizes simultaneous measurements of brain activation and myocardial function/coronary flow with PET imaging, echocardiography and pulse arterial tonometry during laboratory mental stress. We are developing conceptual constructs based upon our previous work, which support a model that suggests certain regional and global brain activation maps are associated with coronary flow responses specific to psychosocial stress.

Our goal for the next academic year is to describe the pathophysiologic mechanisms of mental stress induced myocardial ischemia, which differs from those that are a result of exercise. We have the largest series of subjects to date (n=160) undergoing simultaneous imaging with PET during Mental Stress and then again with dobutamine as a surrogate for exercise in a population of CAD subjects. Our results thus far support our hypothesis of  regional activation in the brain that promote parasympathetic withdrawal, increase in sympathetic tone and decrease LV flow/ function that  is not observed in the dobutamine group (exercise surrogate) is thus far confirmed.  A manuscript based on these results is in preparation. We have studies that show a gender interaction that has just been analyzed and these data will be prepared and submitted afterwards.

An individual’s biological substrate interacts within this neurobehavioral context thru genetic, endocrine, immune and neural processes. Many of these processes are shape by inflammatory responses. Accordingly we have a published a study where we found that CRP levels are significantly correlated with a subject’s vulnerability to Mental Stress after controlling for degree of CAD, risk factors and medications. This establishes proof of principle that inflammatory processes may also be associated with other dimensions of CAD expression. In the upcoming year we will work collaboratively with our Vascular Biology colleagues to develop other constructs which may contribute to Mental Stress Ischemia, such as our recent data suggesting an up regulation of ET-1. We have observed an inverse relationship of TNF-alpha and parasympathetic withdrawal in subjects who become ischemic and have specific regional brain activation. Finally, we have developed a noninvasive stress test, peripheral arterial tonometry (PAT), to index those most vulnerable to Mental Stress Ischemia.

Rachel Lampert, M.D.

Psychological stress and sudden cardiac death have been strongly correlated in epidemiological studies, yet the underlying physiologic link remains poorly understood. The ICD population allows evaluation of effects of mental stress on arrhythmia.
Dr. Lampert’s landmark study in this population was published in Circulation. This report described the effects of emotional stress with a standardized anger protocol upon ventricular tachycardia. This past year these observations were extended with publications concerning several clinical electrophysiologic correlates which may explain the increased risk in these patients. A recent report in JACC described an increase in T wave heterogeneity in those who are vulnerable to ventricular tachycardia as a result of psychological stress.

Future directions include the mechanisms and prognostic implications of this effect, as well as effects of gender and psychological profile. Ongoing studies include emotional triggering of atrial fibrillation and the role of stress reactivity, as well as the impact of anger on T-wave heterogeneity in daily life, that is the theme of her current RO-1.

A second, related area of interest involves heart rate variability, a measurement of autonomic balance derived from ambulatory ECG monitoring. Heart rate variability can provide a measure of effects of acute or chronic stress. Completed investigations include a study of correlations of socioeconomic status and life stress with heart rate variability, as well as the impact of depression on HRV, and ongoing studies, done in collaboration with a large NIH-funded consortium in Psychiatry, are examining the effects of cumulative adverse life experience on autonomic function as measured by HRV.

Matthew M. Burg, Ph. D.

Dr. Burg holds appointments as Associate Clinical Professor in the Department of Medicine at both Yale and Columbia University Schools of Medicine.  His research focus is broadly on the role of stress and emotional factors in the development, progression and expression of CHD.  His collaborations with Drs. Soufer and Lampert on laboratory-based studies have served to identify the importance of anger and associated emotions for the provocation of myocardial ischemia in patients with CAD, and both atrial and potentially fatal ventricular arrhythmias in clinical populations.  Ongoing studies focus on the pathophysiology of stress and emotion provoked cardiovascular phenomena that are prognostically relevant, and the underlying pathophysiology.  This work has elaborated in particular, how the propensity to re-experience anger regarding past incidents is associated with a cascade that includes release of vasoactive proteins and alteration in autonomic tone consistent with dysregulation of inflammatory processes.  This work has also shown that these processes are evident in patients with elevated symptoms of depression, which is a clinical presentation that increases recurrent ACS and mortality risk over 2-fold. 

Dr. Burg also conducts clinical trials research.  He has been site-PI for the NHLBI funded ENRICHD randomized clinical trial, which sought to determine the effect on medical prognosis of treating depression and low social support in immediate post-MI patients, and for the two NHLBI funded Projects (COPES and CODIACS) that successfully tested a patient preference, stepped-care approach to depression treatment for persistently depressed post-ACS patients. He is PI for an ongoing randomized clinical trial of stress management treatment for new recipients of ICD and for ICD patients who have recently experienced a shock terminated ventricular arrhythmia that has, along with laboratory based indices, incidence of shock treated ventricular arrhythmias as its endpoint.  In collaboration with Dr. Lampert, this RCT is also the basis for her investigation of ambulatory T-wave alternans in relation to daytime episodes of moderate emotional arousal, with a particular focus on anger.