Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function.

Effects of Exercise Training on Behavior and Brain Function after High Dose Isoproterenol-Induced Cardiac Damage

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After four weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function.

Cardiac-generated sympathetic stress alters heart-brain communication, reduces EEG-theta activity, and increases locomotor behavior

Brain modulation of myocardial activity via the autonomic nervous system is increasingly well characterized. Conversely, how primary alterations in cardiac function, such as an intrinsic increase in heart rate or contractility, reverberate on brain signaling/adaptive behaviors - in a bottom-up modality - remains largely unclear. Mice with cardiac-selective overexpression of adenylyl cyclase type 8 (TGAC8) display increased heart rate and reduced heart rhythm complexity associated with a nearly abolished response to external sympathetic inputs. Here, we tested whether chronically elevated intrinsic cardiac performance alters the heart-brain informational flow, affecting brain signaling and, thus, behavior. To this end, we employed dual lead telemetry for simultaneous recording of EEG and EKG time series in awake, freely behaving TGAC8 mice and wild-type (WT) littermates. We recorded EEG and EKG signals, while monitoring mouse behavior with established tests. Using heart rate variability (HRV) in vivo and isolated atria response to sympathomimetic agents, we first confirmed that the TGAC8 murine heart evades autonomic control. The EEG analysis revealed a substantial drop in theta-2 (4-7 Hz) activity in these transgenic mice. Next, we traced the informational flow between EKG and EEG in the theta-2 frequency band via the Granger causality statistical approach and we found a substantial decrement in the extent of heart/brain bidirectional communication. Finally, TGAC8 mice displayed heightened locomotor activity in terms of behavior, with higher total time mobile, distance traveled, and movement speed while freezing behavior was reduced. Increased locomotion correlated negatively with theta-2 waves count and amplitude. Our study shows that cardiac-born persistent sympathetic stress disrupts the information flow between the heart and brain while influencing central physiological patterns, such as theta activity that controls locomotion. Thus, cardiac-initiated disorders, such as persistently elevated cardiac performance that escapes autonomic control, are penetrant enough to alter brain functions and, thus, primary adaptive behavioral responses.

Abstract 16855: NOX4 NADPH Oxidase Mediates Diastolic Dysfunction in Stress Cardiomyopathy via Regulation of Inflammation and Fibrosis

Acute sympathetic stress in adults results in catecholamine overload and often leads to development of stress cardiomyopathy complicated by long-lasting diastolic dysfunction. We previously reported that activation of β-adrenergic signaling in the heart increases reactive oxygen species-mediated inflammasome activation and IL-18 release, inducing myocardial inflammation, fibrosis, and dysfunction. Here we tested the hypothesis that NOX4 NADPH oxidase is a primary mediator of myocardial inflammation and diastolic dysfunction in the setting of acute stress. Acute stress in wild-type and mice with cardiomyocyte (CM)-specific Nox4 deletion ( Nox4 CM-/- ) was induced with a single dose of β-adrenergic receptor agonist isoproterenol (ISO; 5 mg/kg) injection. After 3 days, ISO-treated wild-type mice had higher myocardial H 2 O 2 , inflammasome activation and IL-1β, IL-18, IL-6, CCL2, and TNF-α levels and enhanced myocardial interstitial macrophage infiltration compared with vehicle-treated or Nox4 CM-/- mice (p<0.001). Wild-type mice left ventricles had increased presence of activated fibroblasts (periostin + ) and myofibroblasts (α-actin-2 + ) and significantly higher interstitial collagen deposition compared with Nox4 CM-/- mice 7 days post-ISO. Assessment of left ventricular function showed significantly increased mitral valve E, decreased deceleration time, decreased tissue Doppler E’ and increased E/E’ without changes in ejection fraction and end systolic or diastolic volumes, suggesting restrictive pattern of diastolic dysfunction with increased filling pressure in wild-type compared with control or Nox4 CM-/- mice. ISO treatment of ventricular CMs isolated from wild-type mice significantly increased levels of H 2 O 2 and expression of NLRP3 and cleaved caspase-1 and IL-18 as compared with Nox4 -deficient or wild-type CMs pretreated with NOX4/NOX1 inhibitor GKT137831. These data suggest that NOX4 NADPH oxidase is a critical mediator of CM sympathetic overstimulation inducing inflammasome activation and cytokine release, myocardial inflammation, and fibrosis, resulting in impaired diastolic function. Inhibiting myocardial NOX4 during acute sympathetic stress may be beneficial to preserve cardiac function.