Brain–Heart Interaction: Cardiac Complications After Stroke

Experimental animal studies and clinical data indicate a gradient of NSC, where electrocardiographic abnormalities are found in 40% to 100% of SAH patients and 5% SAH patients have serious cardiac arrhythmias.¹⁸ Cardiac arrhythmias are associated with an increased risk of cardiovascular comorbidity, prolonged hospital stay, and poor outcome or death after SAH.¹⁸ The life-threatening ventricular arrhythmia is also associated with elevated creatine phosphokinase myocardial fraction mass and increased troponin T level in left side of intracerebral hemorrhagic stroke patients.¹⁹ Eighty percent of patients exhibit ischemic-like electrocardiographic changes within 1 year after intracerebral hemorrhage or SAH.²⁰ In SAH patients, the Hunt–Hess grading score of severity shows that electrocardiographic changes are observed consistently at the lower grades, but echocardiography changes are found predominately in patients with higher grades.²¹ It is likely that less severe electrocardiographic changes precede structural alterations, as QTc (the interval between peak contraction and repolarization) prolongation does not predict ventricular wall motion abnormalities, but more severe electrocardiographic changes like inverted T waves and elevated Troponin levels, secreted by damaged sarcomeres, can predict ventricular wall motion abnormalities.¹⁶ Lee et al²² found that in spontaneous and traumatic brain hemorrhage patients, 7.2% (no history of cardiac disease patients) show acute cardiac dysfunction and 43% have LV hypertrophy.²² Acute cardiac dysfunction is independently associated with in-hospital death^22,23 and associated with a diminished 1-year functional outcome.²⁰ LV diastolic dysfunction reflects abnormalities in atrial filling by venous return, atrial contraction, and ventricular relaxation capabilities. Although LV diastolic dysfunction is a cause of cardioembolic stroke (present in 15%–25% of the population, increasing with age and hypertension²⁴), more than half of SAH patients develop LV diastolic dysfunction, despite experiencing a stroke of noncardioembolic origin.

The risk of cardiac complications increases proportionally to the severity of ischemic stroke and neurological deficits.¹⁵ Likewise, impaired cardiac function as a consequence of severe acute ischemic stroke is a predictor of worse functional outcome and secondary complications.²⁵ Clinically relevant secondary complications such as vasospasm, delayed cerebral ischemia, and pulmonary edema require active management. Recent evidence suggests that ischemic stroke can cause cardiac dysfunction even in the absence of risk factors and pre-existing heart disease.²⁶ During the first 3 months after acute ischemic stroke, 19.0% of patients experience at least 1 serious cardiac adverse event; 28.5% have LV ejection fraction <50%; and 13% to 29% have systolic dysfunction.^27,28 Approximately 67% of acute ischemic stroke patients have electrocardiographic abnormalities of ischemic and arrhythmic in the first 24 hours after stroke.²⁹ Cardiac arrhythmias are common reasons for death after acute ischemic stroke.²⁶ About 88% of stroke patients who sustain damage to the insular cortex in the right cerebral hemisphere develop myocardial injury in the weeks after ischemic stroke.¹

Stroke (lacunar subtype) also induces heart problems in ≤70% of patients, with clinical manifestations such as electrocardiographic changes, reduced LV ejection fraction, ventricular wall motion abnormalities, and increases in serum cardiac enzymes.^28,30 However, there is a paucity of studies investigating the mechanisms of small or lacunar stroke-induced cardiac dysfunction in both clinical and experimental research.

cTnI (cardiac troponin I) is considered a more specific and sensitive biomarker for the detection of cardiac damage and LV dysfunction than CK-MB.³¹ CK-MB is not completely cardiac specific and may increase in skeletal muscle injury, kidney failure, intramuscular injection, strenuous exercise, and after exposure to several toxins and drugs.³¹ CK-MB elevations are most likely of noncardiac origin in patients with large hemispheric stroke.³¹ Increased circulating cTnI is associated with poor clinical outcome and cardiac function, such as ST-segment elevation in myocardial infarction patients,³² as well as in patients with advanced myocardial hypertrophy, fibrosis, and cardiovascular death.^33,34

Serum cTnI or cTnT (cardiac troponin T) levels are indicators of cardiac damage after ischemic stroke, intracerebral hemorrhage stroke, and SAH. Elevation of serum myocardial enzymes is reported in 11% to 21% of SAH patients and in 1% to 17% of ischemic stroke patients.³⁵ SAH patients have higher levels of circulating hsTnT (high-sensitivity troponin T) and NT-proBNP (N-terminal fragment of B-type natriuretic peptide).^36,37 Twenty-two percent of brain hemorrhage patients have TnI elevation and 59% have NT-proBNP elevation.³⁸ In acute ischemic stroke patients, 5% to 8% patients have high level of circulating cTnI and cTnT,^39,40 and 65% patients have increased levels of circulating NT-proBNP.⁴⁰ A recent study reported that patients who had acute ischemic stroke in the dorsal anterior insular cortical region of the right hemisphere had elevated relative changes of high-sensitivity cTnT levels, which can induce autonomic dysbalance, sympathetic activation, and myocardial injury.⁴¹

The level of hsTnT and NT-proBNP are strongly related with poor long-term outcome in SAH patients and are associated with increased stroke severity, mortality, and worse neurological functional outcome after ischemic stroke.^36,42,43 However, using multivariate regression analysis, Etgen et al⁴⁴ reported that neither cardiac troponins nor NT-proBNP influence morbidity and mortality if other risk factors are considered. Nigro et al⁴² found that BNP, but not hsTnT level, predicts short- and long-term prognosis after cerebrovascular events. Among the reported independent predictors of elevated cTnI are female sex, larger body surface area, and higher heart rate.⁴⁵ The American Stroke Association recommends a baseline electrocardiographic and baseline troponin assessment in patients with acute stroke to identify concurrent myocardial ischemia or cardiac arrhythmias.⁴⁶ Myocardial enzymes and biomarkers of cardiac dysfunction after brain hemorrhage and ischemic stroke are summarized in Table 2.

Heart rate variability (HRV) serves as an assessment tool for autonomic cardiac control and is a measurement of the variation in the heart beat interval (interval between successive R peaks in the QRS complex of ECG) reflecting the instantaneous fluctuation in heart rate. Heart rate fluctuation may result from the neurohumoral regulation of the body to adapt to different physiological conditions, or in response to certain pathological conditions. Heart rhythm oscillations may be categorized into 4 primary frequency bands: high-frequency (HF), low-frequency (LF), very-low-frequency, and ultralow-frequency. Respiration modulates vagal (parasympathetic) activity that contributes to the HF component of heart rate variability.⁴⁷ LF is thought to be the combined sympathetic and vagal response to arterial baroreceptors.⁴⁸ Although not an accurate measure, it is commonly interpreted that a low LF to HF ratio reflects greater parasympathetic activity relative to sympathetic activity, whereas a high LF to HF ratio indicates higher sympathetic activity relative to parasympathetic activity.⁴⁷ Dysfunction in the CNS can have downstream effects on spinal cord preganglionic autonomic nerves and result in HRV changes. Changes in HRV may represent an inadequate response of the autonomic nervous system to the stress associated with a more severe condition.⁴⁹ Studies have indicated a neural source of HRV changes in ischemic stroke patients.⁵⁰ In SAH patients, lowered LF/HF ratio is decreased in patients with pulmonary edema and indicates poor quality recovery and high mortality.⁵¹ Left hemisphere lesions in ischemic stroke patients induce increased HF (parasympathetic) rhythms, whereas right hemisphere lesions increase the LF/HF ratio.⁵² HRV decrease is associated with acute stroke severity, post-stroke depression, poor-quality recovery, and mortality.^49,53

Many patients develop early-onset depression related to the degree of their functional deficits or late-onset depression.^54,55 Post-stroke depression including anxiety, fear, and stress is psychological and biochemical in nature and is largely dependent on the extent of neurological functional deficits.^54,55 Ischemic stress can cause Takotsubo cardiomyopathy.¹⁵ The HPA axis is a master regulator of body hormones that integrates emotion, stress, physical activity state, and metabolism.⁵⁶ The HPA axis consisting of the complex interactions between the 3 endocrine glands—hypothalamus, pituitary, and adrenal glands—is an important part of the neuroendocrine system. The hypothalamic paraventricular nucleus is the main control center of the HPA and secretes corticotropin-releasing factor such as corticotrophin-releasing hormone and vasopressin that stimulate the pituitary gland to release adrenocorticotropic hormone, especially under stressful conditions.⁵⁷ Adrenocorticotropic hormone stimulates the adrenal gland to release the steroid hormone cortisol. Serum cortisol levels have been correlated with stroke severity and extent of insular damage.⁵⁸ Prolonged elevation of cortisol may be neurotoxic and has been associated with increased post-stroke mortality.⁵⁹ The paraventricular nucleus also projects directly to the rostral ventrolateral medulla, which integrates cardiac afferents, baroreceptor activity, and inputs from higher brain regions into sympathetic outflow to the heart. Stimulation of the hypothalamus activates sympathetic output and induces electrocardiographic abnormalities, arrhythmias, and myocardial necrosis.⁶⁰ Activation of the paraventricular nucleus of the hypothalamus in rats subjected to ischemic stroke causes arrhythmias mediated by glutamate via activation of N-methyl-d-aspartic acid receptors.⁶¹ Reduction of paraventricular nucleus activity promotes improved recovery of cardiac function after myocardial infarction.⁶² Activation of the HPA axis after ischemic stroke causes a significant increase in catecholamines.⁶³ The catecholamine surge hypothesis is the most widely accepted mechanism of brain–heart interaction.

The catecholamine surge theory has been closely linked to heart damage after physical and emotional stressors. Catecholamine surge can cause cardiac hypertrophy or myocardial ischemia.^64,65 The autonomic nervous system regulates the release of catecholamines from the adrenal glands. Brain injury can cause elevated sympathetic tone with an additional increase in catecholamine secretion.⁶⁶ Neurological injury causes excessive circulating catecholamines and massive catecholamine release from myocardial nerve endings.⁶⁶ The myocardium adjacent to the nerve is damaged.⁶⁷ The sympathetic nerve can directly release catecholamines and thereby induce cardiomyocyte toxicity. Long-term elevation of serum catecholamine produces cardiotoxicity⁶⁸ and may trigger edema in regions of hypokinesia, transient fibrosis, inflammation, and contraction band necrosis.^69,70 Experimental animal studies have demonstrated an increase in plasma catecholamine levels after ischemic stroke that was directly proportional to the incidence of myocardial lesions and cardiac damage.⁷¹ The increased catecholamine levels is correlated with QT-interval prolongation and myocardial damage after SAH, whereas hypothalamic stimulation induces electrocardiographic changes without associated myocardial damage.^72,73

Catecholamines act on the heart via β receptors to increase the strength and rate of contraction.⁷⁴ The β receptors couple to the stimulatory G protein and activate adenylyl cyclase and increase cytosolic cAMP. cAMP binds to the regulatory subunits of protein kinase A, which phosphorylates sarcolemmal L-type Ca²⁺ channels and sarcoplasmic phospholamban, which overloads mitochondria.⁷⁵ Mitochondrial Ca²⁺ overload triggers oxidative stress, and the subsequent opening of their inner membrane permeability transition pore along with osmotic swelling and loss of ATP synthesis leads to myocardial cell death.⁷⁵ Although pretreatment with β-blockers has been reported to decrease the incidence of myocardial lesion⁷⁶ and β blockers are commonly prescribed after Takotsubo cardiomyopathy, some studies have reported a lack of significant effect of β blockers on recurrence of Takotsubo syndrome rate.⁷⁷

Sympathetic and parasympathetic physiology and regulation of brain–heart interaction has been described in detail elsewhere.⁷⁸ The forebrain plays an important role in the regulation of the autonomic nervous system in patients with hemorrhagic and ischemic stroke. Stimulating the orbital surface of the frontal lobe and the anterior cingulate gyrus affects blood pressure and heart rate.⁷⁹ The insular cortex is regarded as a vital part of the central autonomic network.⁸⁰ Ischemic lesions in the insular cortex increase the risk of cardiac complication and can cause blood pressure variations, cardiac arrhythmias, and myocytolysis.^81,82 The location of an ischemic lesion also affects cardiac function after stroke, and studies have reported cardiac dysfunction after ischemic damage to both left and right insular cortex.^52,80,83 It seems that the right hemisphere primarily controls sympathetic activity, whereas parasympathetic activity is mainly controlled by the left hemisphere.^71,72 Therefore, a right insular lesion decreases sympathetic tone and results in parasympathetic overactivity.⁸⁰ Right insular lesions are associated with higher mortality at an early stage compared with other sites.⁸⁴ Brain infarctions in the left hemisphere are associated with fewer incidences of arrhythmias, an increased risk of adverse cardiac outcome, increased long-term mortality, and decreased cardiac wall motion compared with stroke in other locations.^85,86 Elevated activity of the sympathetic nervous system observed in the acute phase of SAH induces myocardial damage and contributes to the development of cardiac dysfunction.⁸⁷ Therefore, intensive heart monitoring will be particularly essential for patients with insular cortical damage. Figure 2 summarizes the role of the HPA axis, catecholamine surge, and sympathetic regulation in mediating cardiac dysfunction after stroke.

The neurovascular unit is a functional unit encompassing the anatomic and metabolic interactions between the neuronal, glial, and vascular components of the brain. The blood–brain barrier (BBB) composed of endothelial cells, astrocytic end feet, pericytes, and a thick basement membrane is at the core of the neurovascular unit.^88,89 The BBB serves as a dynamic interface between the brain and the circulatory system, limiting the entry of potential neurotoxins and microscopic and hydrophilic molecules.^88,89 The BBB also protects the brain from variations in blood composition and helps maintain constant and optimal cerebral metabolism and neuronal activity. Disruption of the neurovascular unit and BBB is a major step in the pathophysiological cascade after stroke and contributes to secondary tissue damage. Increased BBB permeability disturbs cerebral autoregulation, leads to neuronal damage, and facilitates the invasion of inflammatory factors into the injured brain.⁹⁰ In a vicious cycle, BBB disruption promotes entry of inflammatory factors into the ischemic brain, and inflammation increases BBB permeability. Increased BBB permeability is found in almost half the patients at 24 hours post-cardiac surgery even in the absence of stroke.⁹¹ Additionally, cardiac dysfunction and cardiac surgery can lead to cerebral ischemia and stroke via hypoperfusion and cardiac embolization, respectively, and trigger systemic inflammatory responses that may either induce or aggravate BBB disruption.⁹¹ BBB disruption facilitates the entry of brain-derived antigens and extracellular vesicles derived from injured brain cells to enter the blood stream and encounter peripheral immune cells, as described in detail in the following section. Therefore, there exists a close relationship between cardiac function and BBB integrity, but the effects are most likely indirect.

Immune system activation leading to inflammation after stroke is an important factor in stroke progression. The complex interplay of the local and systemic inflammatory responses after stroke involves many immune cell types and circulating signals and is important in understanding both infection and other secondary complications. The complex role of inflammation in stroke pathogenesis has been reviewed elsewhere.^92,93 In the following section, we discuss inflammatory and immune responses that may mediate brain–heart interaction after stroke, which is summarized in Figure 3.

In the acute phase of brain injury, local inflammatory responses in the brain parenchyma include microgliosis, astrogliosis, and cytokine/chemokine secretion, which occur concomitantly with endothelial cell activation.⁹⁴ Ischemia can lead to endothelial cell damage directly or indirectly via the release of reactive oxygen species.⁹⁵ Damaged endothelial cells can increase oxidative stress and rupture the BBB.⁹⁵ In addition, damaged endothelial cells and astrocytes at the site of inflammation can shed extracellular vesicles that rapidly cross the BBB and enter the bloodstream.⁹⁶ On reaching peripheral organs such as the liver, the protein and microRNA (miR) cargo of these endothelial cell and astrocyte-derived extracellular vesicles regulate acute cytokine response and mediate trafficking of peripheral immune cells to injured brain tissue.⁹⁶ Extracellular vesicles are emerging as intrinsic communication mediators between the brain and immune system.⁹⁶ The role of microvesicles and miR as mediators of brain damage induced heart dysfunction is discussed in detail later in this review.

BBB disruption facilitates the infiltration of peripheral macrophages and neutrophils into brain after stroke onset.^97,98 Subsequent to ischemia onset, there is an increase in extracellular ATP as a result of neuronal and glial depolarization and damaged plasma membrane of injured brain cells.⁹³ High extracellular ATP levels can activate resident microglia and stimulate inflammatory cytokine production.⁹³ Microglia and macrophages can assume a neurodegenerative M1 phenotype and increase inflammation by releasing proinflammatory cytokines. In the initial few minutes to hours after stroke onset, there is an increased production of proinflammatory cytokines (interleukins [eg, IL-6 and IL-1β), tumor necrosis factor-α, etc), integrins, adhesion molecules (VCAM-1 [vascular cell adhesion protein], ICAM-1 [intercellular adhesion molecule], P-selectin, etc), chemokines, and their receptor molecules.^93,99,100 These proinflammatory molecules can further damage the BBB, initiate the recruitment of peripheral immune cells into the cerebral microcirculation and ischemic brain, and pass through the BBB into the circulation, inducing systemic inflammation.¹⁰⁰ On the contrary, the microglia and macrophages can also assume an anti-inflammatory M2 phenotype and clear cellular debris from the injured brain.⁹³

Systemic inflammatory responses are mainly driven by many cytokines, chemokines, stress hormones, and parasympathetic and sympathetic regulation.¹⁰¹ In acute ischemic stroke, lymphocyte influx begins ≈48 hours after stroke, and the invading T lymphocytes promote detrimental inflammatory cascades and induce delayed brain damage.^97,99 Although an optimal-level leukocyte infiltration is beneficial to the ischemic brain, in excess, it leads to increased intracranial pressure resulting in poor outcome or mortality.^93,99,100 The spleen plays a central role in mediating the peripheral immune response to ischemic stroke by increasing circulating lymphocytes and proinflammatory cytokines and chemokines such as tumor necrosis factor-α, MCP-1 (monocyte chemoattractant protein-1), interferon-γ, IL-6, and IL-2, exacerbating inflammation in the acute phase after stroke.¹⁰² Increased tumor necrosis factor-α level induces degradation of TnI, which has been associated with impaired cardiac contractility.¹⁰³ Splenectomy 8 weeks after chronic heart failure has been reported to significantly improve LV systolic function and reduce cardiomyocyte hypertrophy, suggesting a role of spleen in mediating cardiac function.¹⁰⁴ At a later time point, splenic atrophy and decrease in T-cell proliferation and inflammatory cytokines secretion lead to a state of immunosuppression.¹⁰⁵

Damage-associated molecular patterns including various heat-shock proteins are released by dying brain cells after ischemic stroke.¹⁰⁶ Injured astrocytes, neurons, and oligodendrocytes release brain-derived antigens such as glial fibrillary acidic protein, S100, and MBP (myelin basic protein).¹⁰⁷ Damage-associated molecular patterns and brain-derived antigens can also pass the ruptured BBB and enter the systemic circulation. Damage-associated molecular patterns can activate TLRs (Toll-like receptors) and lead to cytokine and chemokine production.¹⁰⁸ In experimental stroke, lymphocyte response to the brain-derived antigens, such as MBP, leads to antigen-specific secretion of transforming growth factor-β, consistent with a regulatory T cells’ response.¹⁰⁹ However, in the presence of systemic inflammation, the antigen-specific autoimmune response is characterized by T-helper cells 1 and TLR activation and secretion of proinflammatory interferon-γ), IL-2, etc.^110,111 TLR-4 is expressed on the cell surface of cardiomyocytes. TLR-4 activation and chronic inflammation with increased release of proinflammatory cytokines such as tumor necrosis factor-α IL-6, IL-1β have been implicated in developing heart failure and poor prognosis of heart disease.¹¹² Transforming growth factor-β induces IL-6 increase while decreasing MCP-1 and VCAM-1 in vascular pericytes and is also instrumental in the transition from fibroblasts to myofibroblasts that may play a role in cardiac fibrosis observed in NSC.^113,114

Systemic inflammatory responses are activated after spontaneous intracerebral hemorrhage, ischemic stroke, and SAH.¹¹⁵ Systemic inflammatory responses carry an increased risk of subsequent intracranial complications such as vasospasm and normal pressure hydrocephalus, as well as systemic secondary complications.¹¹⁶ The immune system is involved in this process in the early phases after stroke and correlates with ischemic stroke and SAH progression.¹¹⁶ Systemic inflammatory response syndrome was found in ≈50% of SAH patients on admission, and 85% of patients developed systemic inflammatory response syndrome within the first 4 days after admission.¹¹⁷ Systemic inflammatory response syndrome is indicated by abnormal leukocyte counts, high respiratory and heart rate (>90 bpm), and abnormal body temp and can increase the risk of developing vasospasm and secondary complications.¹¹⁷ In ischemic stroke patients, the number of CD74⁺ cells (the MHC [major histocompatibility complex] class II invariant chain present on all class II expressing cells, including monocytes, macrophages, and dendritic cells) were significantly increased in peripheral blood mononuclear cells compared with healthy controls.¹¹⁸ The increased CD74-positive cells were mainly on CD4⁺ T cells, monocytes, and dendritic cells.¹¹⁸ In heart diseases such as myocardial infarction, elevation of circulating blood monocytes is associated with poor cardiac function and predicts poor recovery of LV systolic function at 3 months post-injury.¹¹⁹

There is also some evidence of cross-talk between inflammatory responses and sympathetic activation in ischemic and hemorrhagic stroke.^120,121 The proinflammatory cytokines released by damaged neuronal and glial cells stimulate the posterior hypothalamus to increase sympathetic output and circulating catecholamine level.^122–124 van der Bilt et al¹²¹ found that catecholaminergic stress after brain hemorrhage coincided with influx of inflammatory cells into the heart and induced cardiac damage after SAH. Neutrophils were found embedded in the inflamed myocardium along with thrombi.¹²¹ The coupling of catecholamine release with parasympathetic dysfunction regulates inflammation that induces myocardial dysfunction, thrombi formation, and cardiomyocyte cell death.¹²¹ Therefore, inflammation may play an important role and as a link between brain injury and cardiac damage after ischemic stroke and SAH. The role of immune response and inflammation after stroke in mediating cardiac dysfunction is summarized in Figure 3.

Gut microbiome dysbiosis after stroke can lead to intestinal paralysis and bacterial and endotoxin translocation to blood leading to systemic inflammation,^125–127 as discussed in detail in the following section.

Our knowledge and understanding of the human microbiome and its involvement in various diseases are increasing. In particular, there is an emerging body of evidence based from experimental studies that suggests an interaction between the gut microbiome and heart as well as the gut microbiota and the CNS, referred to as gut–heart axis and brain–gut axis, respectively. The gut–blood barrier mainly regulates the absorption of nutrients and water while preventing toxins and pathogenic microorganisms from entering the blood stream. In gastrointestinal, metabolic, cardiovascular, and cerebrovascular diseases, disruption of the gut–blood barrier integrity resulting in increased intestinal permeability enables microbiota-derived molecules to enter the blood stream.¹²⁵

The brain–gut axis can affect normal brain functioning and influence the pathological cascade of events in neurological diseases including stroke and TBI.^128,129 The brain–gut axis comprising neural and humoral pathways with signaling molecules such as cytokines, hormones, and neuropeptides can regulate immune response and lymphocyte population.^129,130 Alterations to the normal gut microbiota or gut dysbiosis caused by acute brain lesions can affect neuroinflammatory and immune responses in the brain and worsen neurological function.¹³¹ In patients with large-artery atherosclerotic ischemic stroke or transient ischemic attack, significant gut dysbiosis is indicated by increased opportunistic bacteria and decreased beneficial bacteria.¹³² It has also been suggested that commensal gut microbiota exert protection against ischemic damage, and their depletion or dysbiosis increases post-stroke mortality in mice and influences stroke outcome.¹³³ In addition, the extent of increase of proteobacteria in the gut of stroke patients is proportional to stroke severity.¹³² Dietary choline and l-carnitine are transformed by gut microbiota to trimethylamine, and its oxidation yields the proatherogenic metabolite that is largely considered a disease marker.¹³⁴

In ischemic stroke, gut dysbiosis via stress-mediated intestinal paralysis can alter T-cell homeostasis, promote migration of T cells from the intestine to the ischemic brain, and increase proinflammatory responses resulting in poor stroke outcome.¹³⁰ In mice subjected to transient focal cerebral ischemia, trafficking of intestinal T cells from the gut to the meninges of the brain increases neuroinflammation and the secretion of proinflammatory cytokine IL-17, which can stimulate the production of several other cytokines and chemokines and facilitate the infiltration of cytotoxic immune cells and neutrophils into the injured brain.¹³⁰ In mice subjected to transient focal cerebral ischemia, stroke increased gut permeability proportional to stroke severity; promoted bacterial translocation from the gut to mesenteric lymph nodes and peripheral organs such as spleen, liver, and lungs; and triggered adaptive and innate immune responses.¹³⁵ In ischemic stroke patients, gut dysbiosis and increased bacterial counts of Lactobacillus ruminis subgroup in the fecal gut microbiota was associated with elevated systemic inflammation and altered metabolism.¹³⁶ Bacterial metabolites have also been implicated to mediate communication between the commensal gut microbiota and the immune system, tipping the balance in favor of proinflammatory mechanism.¹³⁷

Increased gut permeability can promote inflammatory responses, whereas systemic inflammation can increase gut permeability.¹²⁵ Bacterial and endotoxin translocation to the blood stream, increased proinflammatory cytokines, and systemic inflammation can induce or exacerbate cardiac dysfunction.^126,127 In an independent large clinical cohort, 3 gut microbiota–dependent metabolites including choline, trimethylamine-N-oxide, and betaine were found to be predictors of cardiovascular disease.¹³⁴ Gut microbes can directly contribute to platelet hyper-reactivity and increase the risk of thrombosis via trimethylamine-N-oxide generation.¹³⁸ Altered trimethylamine-N-oxide levels has been associated with impaired cardiac function, heart attack, and heart failure.^126,138 Elevated trimethylamine-N-oxide levels in the plasma of patients presenting with chest pain was found to be a predictor of short-term and long-term risk of myocardial infarction, stroke, need for revascularization, or even death.¹³⁹ Figure 4 summarizes the role of gut dysbiosis in mediating cardiac damage after stroke. Future studies are warranted to investigate the role of the gut microbiome in cardiac damage after stroke and investigate whether stroke-induced gut dysbiosis promotes a proinflammatory cascade, which then leads to dysfunction of other organs including the heart.

Microvesicles are lipid bilayer-covered cell fragments that range in diameter from 100 nm to 1 µm and are released into the extracellular environment by several cell types typically during cell activation or cell death via necrosis or apoptosis. Microvesicles are produced by the outward budding and fission of plasma membrane. In addition to intercellular communication via cell contact, microvesicles constitute an important mode of communication by serving as vehicles for intercellular transfer of membrane and cytosolic proteins, lipids, and RNA either locally or over long distances.¹⁴⁰ Because microvesicles retain the signature membrane protein composition of the parent cell, they can be classified by flow cytometry into different cellular microvesicles, such as endothelial microvesicles, leukocyte microvesicles, and platelet microvesicles or brain-derived microvesicles. Microvesicle shedding can also be triggered by pathological activation of inflammatory processes and activation of coagulation or complement systems or even by shear stress in the circulation. Microvesicles have a bilayered phospholipid structure exposing coagulant-active phosphatidylserine and expressing various membrane receptors, and they serve as cell-to-cell shuttles for bioactive molecules such as lipids, growth factors, miR, and mitochondria.¹⁴⁰ Microvesicles have been implicated in endothelial dysfunction, inflammation, and thrombosis.¹⁴¹ In addition, microvesicles may also be targeted as a therapeutic delivery tool by either inhibiting their release from diseased cells or manipulating their cargo to enable shuttling of secretory molecules such as cytokines, chemokines, and growth factors.¹⁴²

MiRs are short sequences of noncoding RNA (ca. 22 nucleotides), which regulate gene expression both transcriptionally and post-transcriptionally.¹⁶⁰ MiRs can regulate several genes, pathways, and biological networks, either acting alone or in concert with other miRs. MiRs regulate many biological processes regulating tissue repair, including angiogenesis, inflammation, and hypoxia–response.¹⁶⁰ About 50 circulating miRs are believed to be associated with cardiovascular diseases including miR-1, miR-16, miR-27b, miR-30d, miR-126, miR-133, miR-143, miR-145, miR-208, and the let-7 family.¹⁶¹ Several miRs with key cardiac and vascular function have been reported to be affected after stroke including the following: miR-23, miR-24, miR-29, miR-30, miR-103, and miR-222 were upregulated, whereas miR-126 was downregulated.¹⁶² Microvesicles also contain abundant miRs.

Endothelial cell–specific miR-126 has a key role in maintaining vascular integrity and regulating angiogenesis.¹⁶³ Circulating miR-126 level is significantly decreased in patients with ischemic stroke until at least 24 weeks.¹⁶⁴ Endothelial cell dysfunction is a principal step in atherosclerosis. MiR-126 deficiency has been highly associated with heart failure, atrial fibrillation, and coronary artery disease and may be associated with stroke-induced severe cardiac complications.^163,165 Coronary artery disease or ischemic heart disease includes stable and unstable angina, myocardial infarction, and sudden cardiac death. In myocardial infarction, circulating miR-1 increases and miR-126 decreases in proportion with cTnI plasma concentration levels.¹⁶⁶ Vascular miR-126 has been demonstrated to be consumed or taken up by the heart from the bloodstream according to a transcoronary gradient.¹⁶⁷ It has been demonstrated that ischemic stroke decreases serum and heart miR-126 expression, as well as induces post-stroke cardiac dysfunction.¹⁶⁸ Conditional specific endothelial cell miR-126 knockout mice exhibited enhanced cardiac dysfunction and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after ischemic stroke compared with miR-126 knockout control stroke mice.¹⁶⁸ The study demonstrated that decreased miR-126 may play a role in brain–heart interaction after ischemic stroke.¹⁶⁸

In addition, circulating miR-145 also significantly increases within 24 hours of cerebral ischemia, and circulating miR-145 level is positively correlated with elevated serum inflammatory factor IL-6.¹⁶⁹ MiR-145 modulates endothelial cell function in angiogenesis and vessel stabilization.¹⁷⁰ Circulating miR-145 changes has also been reported in patients with coronary artery disease and acute myocardial infarction.¹⁷¹ Therefore, other miRs may also regulate brain–heart interaction.