Commentary: Brain–Heart Crosstalk

Paul et al. describe a patient who presented with a large right supraclavicular mass encasing the brachial plexus, the jugular, subclavian, and vertebral vessels and extending into the superior mediastinum. Mediastinal masses, especially in the superior and the anterior mediastinum, concern the anesthesiologist because of the proximity to major vascular structures and the risk of dynamic or fixed obstruction of the airways. Twenty percent of the mediastinal tumors are neurogenic in origin.[1] Some of these tumors release catecholamines, thus presenting as tachycardia, hypertension, new-onset myocardial infarctions, sweating, pallor, or diarrhea.[2] The reference article does not describe the tumor’s histology or hemodynamic manifestations. Cardiovascular manifestation of neurogenic diseases has attracted much attention and has developed a new branch of medicine—neuro-cardiology. Heart–brain cross-talk is a growing field for research, and much of this intertwined networking needs to be better understood. Many case reports have described cardiovascular manifestations in the context of neurological insults since the 1900s. It was Sir Walter Cannon who compiled these early reports to attempt a physiological explanation for this heart–brain crosstalk in the year 1942. The heart can be a culprit and a victim in many neurological conditions. It is well-established that cardiovascular risk factors like hypertension and chronic heart failure predispose to stroke. Cardiac diseases result in about 22-39% of strokes.[3] Compared to the general population, acute ischemic stroke (AIS) is twice as common in coronary artery disease patients, six times in nonvalvular atrial fibrillation (AF), and 17 times in those with valvular AF.[4] On the contrary in some, AIS can induce cardiovascular dysfunction. In 60-90%, stroke manifests as early ECG abnormalities, arrhythmias, autonomic dysfunction, stress cardiomyopathy, systolic, diastolic heart failure, and pulmonary edema.[5,6] Common ECG abnormalities described are T wave inversion, ST depression, and QTc interval prolongation. Arrhythmias range from atrial fibrillation to supraventricular tachycardias, ventricular ectopic, and ventricular tachycardia. Myocardial dysfunction in AIS starts within the first 24 hours. The primary pathophysiologic explanations for heart–brain cross-talk have been postulated to be the activation of the hypothalamic–pituitary–adrenal (HPA) axis producing catecholamine surge, immune and inflammatory responses, and gut dysbiosis. The HPA axis releases catecholamines by activating the sympathetic chain of ganglia at the spinal cord level, increasing cellular oxidative stress and cellular calcium, thus triggering apoptosis. Sympathetic neurons from the spinal cord descend via the cervical and upper thoracic ganglia to form the post-ganglionic neurons that terminate on the sinoatrial and the atrioventricular nodes. The increased sympathetic activity also induces the expression of the forkhead box O gene (FOXO) that contributes to myocardial ischemia. The resultant activation of the cardiac sympathetic fibers stimulates the baroreceptors, sending activating signals back to the medulla, thus forming a self-propagating cycle. These signals are re-transmitted to the heart via the autonomic nerves, bringing about the catecholamine storm. The hyperinflammatory response induced by AIS also disrupts the gut–blood barrier, thus producing the translocation of gut pathogens into the bloodstream. These pathogens trigger further inflammatory cascades and decrease nitric oxide levels via the production of trimethylamine N oxide (TMAO) molecules, thus increasing the risk of thrombosis and platelet activation. This cascade worsens heart failure and predisposes to coronary thrombosis and myocardial ischemia, thus culminating in cardiac remodeling. The neurological events that initiate cardiac dysfunction can range from AIS and traumatic brain injury (TBI) to intracranial space-occupying lesions. Lacunar infarcts can also produce regional wall motion abnormalities (RWMA), myocardial dysfunction, or elevation of cardiac enzymes in approximately 70% of those affected. However, the cardiac presentations are variable depending on the site and type of neurological injury. Based on functional MRI studies, heart–brain cross-talk occurs mainly through a neuro-cardiac axis and neuro-cardiac reflexes. The neuro-cardiac axis is formed by all the major areas of the brain, including the pre-frontal cortex, amygdala, insular cortex, anterior cingulate cortex, and the brainstem that controls the autonomic nervous system.[7] Although ischemia of the posterior hypothalamus, caudal ventrolateral medulla, nucleus tractus solitarius, and the dorsal motor vagal nucleus are major areas implicated in the centrally mediated catecholamine storm, specific areas of the brain are commonly linked to certain cardiovascular manifestations [Table 1]. To state a few, the right frontal lobe infarcts are commonly associated with stress cardiomyopathies. The left insular cortex is implicated in arrhythmias, QTc interval prolongation, left bundle branch blocks, and sudden cardiac deaths.[7] Bilateral temporal lobe lesions commonly present with arrhythmias. Myocardial infarctions are the main manifestations of left parietal infarcts.[7] AIS on the right side is more associated with systolic myocardial dysfunction.[7]Table 1: Areas of Brain Commonly Linked to Cardiovascular ManifestationsThe presentations include neurogenic pulmonary edema, stress cardiomyopathies with demonstrable RWMA, and systolic or diastolic heart failures. Patients with a previously normal heart may present with pulmonary edema following an acute neurological insult, which is termed neurogenic pulmonary edema (NPE). The NPE correlates to the acuity and severity of the neurological insult. There are many clinicopathological explanations for NPE, most of which hover around autonomic imbalance. Davison compiled four theories of NPE.[8] First is the neuro-cardiac theory, where a high catecholamine surge induces direct myocardial injury with evidence of myocytolysis and contraction band necrosis that distribute along the sympathetic innervation of the heart. Second is the neuro-hemodynamic theory, where the diminution of ventricular compliance following a catecholamine-induced high systemic vascular resistance and not the catecholamines per se causes a rise in left atrial pressures inducing pulmonary edema. The above two theories need to explain some reports of exudative alveolar fluid in NPE and its occurrence much after the resolution of the hyper-catecholamine state leading to the coining of the third theory. The blast theory points to alveolar endothelial injury following the catecholamine surge. The 4th theory is of pulmonary venule adrenergic hypersensitivity, where it was hypothesized that neurological injury directly destroyed the pulmonary venules regardless of systemic, pulmonary, or left atrial hypertension. Myocardial dysfunction in the setting of stroke can present as cardiomyopathy. In the background of normal coronaries, these are termed stress cardiomyopathies: the two variants are the neurogenic stunned-myocardium (NSM) and the Takotsubo cardiomyopathy (TCM). Although the etiopathogenesis in both is a centrally mediated catecholamine storm, the two have minor differences. NSM always has a demonstrable neurological insult as the trigger. In contrast, any stressful event can bring about TCM. Physical, emotional, peri-operative stress, blood product-related, or drug-induced histamine release are all potential triggers for TCM. However, there is some evidence of activity in certain areas, namely, the posterior insular cortex, peri-insular regions, the frontal cortex, the subcortex, and the caudate in TCM.[9] TCM presents as an acute coronary syndrome with demonstrable RWMA. However, the RWMA classically does not correspond to any epicardial coronary arterial territory.[10] It is postulated that catecholamine surge induces the transformation of the Gs protein in the ventricular myocardium to Gi proteins, signaling the beta 2 adrenergic receptors to produce the negative inotropic effect. Beta 2 receptor concentration is highest in the ventricular apex instead of the base. Hence, the characteristic wall motion defect seen is apical ballooning or apical and mid-cavitary hypokinesis with basal hyperkinesia. This hypothesis also explains the reversal of the cardiomyopathy with the normalization of epinephrine levels, which converts the Gi proteins back to Gs proteins. Worsening of the ischemic neurological insult, apical thrombus formation, arrhythmias, cardiogenic shock, and dynamic left ventricular outflow tract obstruction are some complications that can occur in stress cardiomyopathy. Neurogenic cardiomyopathy or NSM also presents as myocardial dysfunction. However, contrary to TCM initiated by physical or emotional stress, NSM is always triggered by a neurological insult like AIS, TBI, or subarachnoid hemorrhage (SAH). The caudal ventrolateral medulla, tractus solitarius, dorsal motor vagal nucleus, and posterior hypothalamus are the critical structures involved in ischemic or traumatic injury-initiated neurogenic cardiomyopathy. This culminates in a centrally mediated surge in catecholamine levels resulting in systemic and pulmonary vasoconstriction, tachycardia, and increased inotropy. It also triggers inflammatory mediator release causing increased vascular permeability. The presentation is pulmonary edema, arrhythmia, cardiogenic shock, apical thrombus, or dynamic outflow tract obstruction. The myocardial dysfunction in NCM is postulated to be due to transient coronary vasospasm, microvascular dysfunction, and aborted myocardial infarction (MI) by resolution of a coronary thrombus and catecholamine-induced myocardial contraction band necrosis. Common ECG manifestations of NCM are QT prolongation, ST segment abnormalities, T wave inversions, torsades de pointes, and ventricular and supraventricular arrhythmias. Associated elevation of troponins and RWMA on echo makes it difficult to distinguish from acute MI. Cell death in NSM occurs in a hypercontractile state and around the nerves supplying the heart, contrary to vascular territories as in acute MI. Although apical ballooning is the classically described RWMA in TCM, apical sparing occurs in more than half of NSM patients. NSM is usually reversible if managed conservatively, although missed recognition of this entity may cause cardiac death. An alternate pathway of cardiac involvement in neurological injury is through the neuro-cardiac reflexes. The trigeminal-cardiac reflex (TCR), Cushing’s, vagal, and diving reflexes are critical. TCR is initiated by stimulating the sensory branches of the trigeminal nerve and presents as bradyarrhythmia, persistent premature atrial contractions, hypotension, apnea, or gastric hypermobility.[11,12] The impulse runs through afferent fibers through the gasserian ganglion to the trigeminal nucleus in the 4th ventricle, where it communicates with the efferent neurons of the vagus nucleus and nucleus ambiguus via internuncial nerve fibers of the reticular formation formation [Figure 1].[12] The stimulation of the cardiac vagal motor neurons from these nuclei produces the vagal response.[13] Oculocardiac reflex during squint surgeries and mandibular–maxillary reflex during craniomaxillofacial surgeries are examples of peripheral TCR. Cushing’s reflex occurs when increased intracranial pressure compromises cerebral blood perfusion. The hypothalamus activates the sympathetic nervous system to increase mean arterial pressure to re-establish cerebral blood flow. Vagal reflex is characterized by bradycardia, arterial vasodilatation, and myocardial depression. An acute emotional stress or painful stimulus activates the hypothalamus, consequently stimulating the medullary cardiovascular center that, in turn, activates the vagal motor neurons.Figure 1: Trigemino-cardiac reflex arcSimilarly, an acute increase in inotropy or a reduction in blood volume can trigger the mechanoreceptors of the heart and cause bradycardia and hypotension. The vagal reflex can also be activated during head and neck surgeries, especially at the cerebellopontine angle. The diving response characterized by bradycardia, expiratory apnea, vasoconstriction of blood vessels to limbs and skin, and increased blood pressure is also activated through the TCR. The diving response is also known to provide neuroprotection by improving cerebral blood flow and reducing the brain’s oxygen demand.