Cardiac Manifestations of Acute Neurologic Lesions

Medullary Control of Cardiovascular Function

The interplay between the heart and brain is best exemplified through the medullary control of the autonomic nervous system. Disruptions to this pathway can lead to arrhythmias and other autonomic disturbances as occur in epilepsy, traumatic brain injury, and genetic cardiac conditions. In general, the rostral ventral lateral medulla is a principal site of sympathetic activation, sending presympathetic neurons to the intermediolateral cell column of the spinal cord, which projects onto the stellate ganglion. The stellate ganglion then sends postganglionic sympathetic fibers directly to cardiac myocytes, activating beta-1 adrenergic receptors. Through a G-protein coupling process, intracellular cyclic adenosine monophosphate levels and protein kinase A activity are elevated, triggering a phosphorylation cascade on multiple downstream targets including L-type calcium channel receptors, the sarcoplasmic reticulum, and slow-delayed potassium channels. The outcome is an influx of calcium causing increased myocardial contractility, as well as a shortening of the myocardial action potential that promotes chronotropy.

When the blood pressure is low, baroreceptor activity from the aortic arch and carotid sinuses is diminished. This signal is relayed to the solitary nucleus of the medulla, which decreases activation of the caudal ventrolateral medulla and increases activity of the rostral ventral lateral medulla. A heightened sympathetic cardiovascular response ensues. Conversely, when blood pressure is elevated, increased baroreceptor activity inhibits the rostral ventral lateral medulla, resulting in an attenuated sympathetic response. Direct parasympathetic influences on cardiac function can also occur through excitatory neurons in the nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which synapse with postganglionic neurons in the intrinsic cardiac ganglia. Acetylcholine activation of the cardiac muscarinic receptors reduces myocyte contractility and decreases the heart rate.

Genetic imbalances in the autonomic control of cardiac function can lead to life-threatening conditions. In catecholamine polymorphic ventricular tachycardia (CPVT), mutations in the cardiac RYR-2 ryanodine receptor result in abnormal levels of intracellular calcium, causing arrhythmias during sympathetic stimulation from stress and exercise. Surgeons have therefore attempted sympathetic denervation of the heart by resecting the left lower stellate ganglion and parts of the thoracic ganglia. Among a cohort of 63 patients with CPVT who underwent cardiac sympathetic denervation between 1988 and 2014, the incidence of major cardiac events was reduced from 100 to 32 percent ( P <0.001) over a 43-month period, and the rate of associated shocks from an implanted cardioverter defibrillator declined from 3.6 to 0.6 shocks per person per year ( P <0.001).

Paraventricular Nucleus of the Hypothalamus

In addition to the medulla, the paraventricular nucleus of the hypothalamus plays an important role in both autonomic and neurohumoral regulation of the heart. On a neural level, the paraventricular nucleus receives afferent information from the solitary nucleus, and transmits efferent signals to the rostral ventral lateral medulla to regulate sympathetic activity. Overactivation of this sympathetic outflow has been implicated in the pathology of ischemic heart failure, particularly in chronic settings. By inhibiting activity of the paraventricular nucleus in mice, researchers have demonstrated reduced peri-infarct apoptosis and improved cardiac recovery after myocardial infarction, highlighting the link between the hypothalamus and cardiovascular function. Electrical stimulation of the hypothalamus has also been associated with cardiac arrhythmias, with sympathetic regions located posteriorly, and parasympathetic areas anteriorly.

On an endocrine level, the paraventricular nucleus is involved in the stress response of the hypothalamic–pituitary–adrenal axis by secreting corticotropin-releasing factor into the portal system. This stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary lobe. Elevations in ACTH increase serum cortisol levels, which can contribute to a multitude of long-term cardiovascular complications, including hypertension, obesity, and insulin resistance.

The Limbic System and Amygdala

Emotional stimuli such as fear and anxiety can trigger autonomic responses related to the central nucleus of the amygdala. Sitting deep within the medial temporal lobes, the amygdala receives information from the prefrontal and orbitofrontal regions and sends projections to brainstem areas involved in autonomic control, thereby mediating the cardiac response to emotion. Chronic stress has been associated with cardiovascular disease, but the mechanism by which the brain is involved is poorly understood. In 2017, Tawakol and co-workers studied 293 patients with imaging techniques and found that higher levels of resting amygdalar activity predicted the risk of developing future cardiovascular events, including myocardial infarctions and unstable angina, independent of baseline cardiovascular risk. The higher levels of amygdalar activity were also associated with increased bone-marrow activity and arterial inflammation. One hypothesis is that amygdala-mediated stress increases the production of inflammatory cytokines from the bone marrow, triggering a cascade of downstream arterial inflammation leading to cardiovascular disease.

Functional magnetic resonance imaging (fMRI) has now elucidated a complex network of regions involved in cardiac control. By having subjects complete tasks to elicit autonomic responses, and observing heart rate variability together with fMRI data, researchers have identified both cortical (prefrontal area, insula, anterior cingulate) and subcortical (amygdala, hypothalamus, hippocampus formation) structures involved in autonomic regulation. Moreover, sympathetic activity has been shown to localize to the prefrontal region, anterior cingulate, right anterior insula, and the left posterior insula, whereas parasympathetic activity is derived from the posterior cingulate and lateral temporal cortices, hippocampal formation, and bilateral dorsal insula. The left amygdala also contains features of both sympathetic and parasympathetic activity. This topography in function may help explain the variety of cardiac manifestations seen after ischemic injury to the brain, ranging from alterations in blood pressure to heart rate variability and arrhythmias.

Insular Cortex

The insular cortex has widespread connectivity with areas of the brain that are known to be involved in autonomic control. Injury to this region has been associated with increased renal sympathetic nerve activity, elevated norepinephrine levels, and adverse cardiac events including QT prolongation, abnormal repolarization, tachycardia/bradycardia, and new-onset atrial fibrillation. Historically, it was believed that greater sympathetic representation occurred in the right insula and more parasympathetic representation featured on the left. This led to speculation that left-sided insular strokes manifested with increased and often unchecked cardiac sympathetic tone, resulting in worse cardiac outcomes, arrhythmias, and even sudden death. By contrast, however, it has also been argued that the morbidity and mortality of patients is higher among those with right-sided insular strokes, especially in the context of ECG abnormalities. The clinical significance of laterality in insular involvement remains controversial.

Using voxel-based lesion mapping on MRIs, a study in 2017 revealed that injury to the dorsal-anterior aspect of the insula was associated with elevations in cardiac troponin and myocardial damage. This suggests that in addition to the classic right-to-left grouping of insular injury, there also exists a ventral-to-dorsal subdivision that plays an equally important role in autonomic function. Ischemic injury to the dorsal anterior insula impairs parasympathetic tone, despite being on the sympathetically associated right side. Indeed, conflicting observational outcomes in patients with insular strokes may well be attributed to the heterogeneity of autonomic mapping on the insular structure itself.

Catecholamine Surge on Cardiomyocytes

It has been speculated that during neurologic injury, increased sympathetic activity triggers a massive release of catecholamines directly at the myocardial nerve endings. Myocardial tissue adjacent to these nerve endings is thereby vulnerable to excitatory damage. Excessive binding of catecholamines to the beta-receptors on cardiomyocytes leads to an abnormal influx of intracellular calcium, resulting in electrical instability, abnormal myocyte contraction, and oxidative stress. These processes then converge into cardiac injury in the form of arrhythmogenesis, coagulative myocytolysis, and microvascular dysfunction.

Histologically, catecholamine-induced subendocardial lesions include scattered foci of swollen myocytes surrounded by infiltrating monocytes, interstitial hemorrhages, and myofibrillar degeneration. Collectively, these pathologic changes have been called contraction band necrosis or coagulative myocytolysis ( Fig. 10-1 ). The pattern of myofibrillar necrosis localizing near cardiac nerves is identical to other lesions thought to be of sympathetic origin such as catecholamine infusion, “voodoo death,” hypothalamic stimulation, or reperfusion of transiently ischemic cardiac muscle. In patients with CAD, myocardial necrosis typically follows a vascular distribution where timing of injury occurs in a delayed fashion after progressive ischemia and muscle cell death. In neurogenic myocytolysis, however, myocardial damage can be visible within minutes of onset, with appreciable differences observed on a cellular level that include mononuclear infiltration, early calcification, and a hypercontracted state of myocardial cells.

Experimental and clinical studies have addressed the neurogenic catecholamine-mediated mechanism of cardiac dysfunction. In a cohort of patients with SAH who had echocardiograms and nuclear scans of cardiac innervation and perfusion, regions of contractile dysfunction were associated with abnormalities in myocardial sympathetic innervation while cardiac perfusion was normal. The degree of cardiac innervation was measured with a scintigraphic evaluation using [ ¹²³ I]metaiodobenzylguanidine (MIBG), cardiac perfusion was measured using [ ^99m Tc]sesta-methoxyisobutylisonitrile ( MIBI), and regions of myocardial dysfunction were determined by echocardiography simultaneously in the patients. Patients with functional cardiac denervation had worse regional wall motion scores and more troponin release than patients without evidence of cardiac denervation. Fig. 10-2 illustrates normal perfusion and global denervation in a patient with SAH whose echocardiogram showed global left ventricular systolic dysfunction. All study subjects had normal perfusion imaging, which excluded significant CAD and supported a neurogenic mechanism of cardiac injury.

Catecholamine Surge on Coronary Microvasculature

Despite the evidence for a neurologically mediated mechanism of cardiac impairment independent of CAD, there is also evidence to support a centrally mediated source of injury to the coronary microvasculature. During SAH, the body’s stress response leads to elevated levels of cortisol (via the hypothalamic–pituitary–adrenal axis), endothelin/angiotensin II (via neurohumoral responses), and circulating catecholamines (via the adrenal medulla). Together, these factors incite peripheral vascular constriction and induce coronary microvascular spasm, contributing to demand ischemia of the heart. Catecholamines and endothelin bind directly to α ₁ -receptors and endothelin A receptors on the coronary microvasculature, respectively, which leads to vasoconstriction and a reduction in coronary blood flow. In Takotsubo cardiomyopathy, which can be seen after SAH, studies have shown increased plasma levels of the vasoconstricting peptide, endothelin-1, as well as decreased expression of the endothelin-1 regulating miRNA 125a-5p, when compared to healthy controls. Delivery of intravenous adenosine, a potent vasodilator, has also been shown transiently to improve left ventricular function and myocardial perfusion in patients with Takotsubo cardiomyopathy, as compared to patients with ST-elevation myocardial infarctions. As a result, these studies support the hypothesis that microcirculatory vasospasm may be a cause of transient cardiac injury and is potentially driven by the neurohumoral and catecholaminergic responses to neurologic injury.