The Overlooked Organ

Corresponding Author

Cardiovascular disease (CVD) is the leading cause of death and long-term disability in the United States. CVD includes coronary artery disease, heart failure, arrhythmia, stroke, and cardiopulmonary arrest. Cardiopulmonary arrest, in particular, is a medical emergency that requires immediate intervention; without it, there is a sudden failure of the heart to deliver adequate blood flow to support vital organs, including the brain, which is especially vulnerable, because it depends on continuous delivery of oxygen and glucose to sustain ion gradients essential for neuronal function. The complexity of ischemic brain injury following cardiopulmonary arrest presents significant therapeutic challenges, because it involves multiple pathological processes including impaired cerebral blood flow, neuroinflammation, and mitochondrial dysfunction, ultimately leading to irreversible neuronal death and cognitive decline.^1,2

To date, all preclinical interventions aimed at rescuing the brain following CVD-related insults have failed to translate successfully into clinical therapies, with the exception of therapeutic hypothermia.^3,4 Therapeutic hypothermia involves temporarily lowering core body and brain temperatures (typically to ∼92 °F) using cooling blankets, ice packs, or specialized temperature-control systems. The primary goals are to reduce cerebral metabolic demand, limit oxidative stress and free radical damage, attenuate excitotoxicity, and decrease intracranial pressure, thereby preserving vulnerable neuronal tissue in the aftermath of ischemic injury. Despite its promise, therapeutic hypothermia has significant limitations, most notably a narrow therapeutic window of 6 to 12 hours postinjury. Consequently, fewer than 10% of patients qualify for this intervention. These limitations highlight the urgent need for novel therapeutic strategies with broader treatment windows and improved efficacy for mitigating ischemic brain injury.

Most survivors of CVD, particularly those who experience cardiopulmonary arrest or stroke, do not die from myocardial dysfunction but rather from severe brain injury and long-term neurocognitive deficits. Given this clinical reality, it is unsurprising that research has historically focused on mitigating brain damage following CVD by targeting processes such as neuroinflammation, mitochondrial dysfunction, and neuronal death. However, despite decades of effort, none of the preclinical drug development efforts focused exclusively on the brain have achieved translational success in human trials. Why have these brain-centric approaches failed? The paper by Li et al⁵ in this issue of the JACC: Basic to Translational Science offers a compelling and novel perspective on this topic and raises the question that perhaps we have been targeting the wrong organ all along by overlooking the potential contribution of the injured heart itself to driving secondary brain injury.

The concept of the heart-brain axis, describing the bidirectional communication between the cardiovascular and central nervous systems, is a growing field that integrates cardiology, neurology, and immunology. Heart-brain axis has roots dating back to the 19th and 20th centuries. The term "neurocardiology" gained prominence in the 1990s and early 2000s, emphasizing the role of the autonomic nervous system in regulating cardiac function.^6,7 It has long been recognized that emotional and psychological stress can adversely affect heart health, and conversely, that cardiovascular diseases elevate the risk and worsen the prognosis of a wide range of neurological disorders. These interconnections have shaped our modern understanding of the heart-brain axis, which is now viewed as a promising and underexplored therapeutic target for neurological diseases, including cardiopulmonary arrest–induced ischemic brain injury.

The present study by Li et al⁵ builds upon the authors' earlier work, particularly their 2022 publication in Circulation Research,⁸ which utilized a rodent model to demonstrate that cardiac-derived extracellular vesicles (EVs) can modulate sympathetic outflow in the setting of heart failure. EVs are nanosized, membrane-bound particles released by nearly all cell types. EVs carry diverse biological molecules, including proteins, lipids, and RNAs (including microRNAs), and act as key mediators of intercellular communication both locally and systemically.^9,10 In their current study, the authors extend their prior findings by elucidating a novel mechanism of heart-brain communication and its impact on neuroinflammation and neuronal viability. They demonstrate that cardiac stress leads to the release of EVs enriched in miRNA-21-5p, which can cross the blood-brain barrier. Once in the brain, these EVs are preferentially taken up by microglia, leading to their activation and promoting neuroinflammatory and neurotoxic responses. This paper is significant in that it introduces a novel and compelling concept: myocardial injury can precipitate secondary brain injury via EV-mediated signaling. This emerging paradigm has broad implications for our understanding of the heart-brain axis and may open new therapeutic avenues for addressing neurocognitive deficits in patients with CVD.

From a diagnostic perspective, routine blood sampling and analysis of cardiac-derived EVs could serve as promising biomarkers for predicting brain health and long-term neurocognitive outcomes in CVD patients. From a therapeutic standpoint, given the ability of EVs to cross the blood-brain barrier, intravenous administration of microglia-targeting EVs engineered to carry antisense oligonucleotides against miRNA-21 could potentially suppress CVD-induced microglial activation and neuroinflammation. Furthermore, brain-targeted EVs could be loaded with neurotrophic factors (eg, brain-derived neurotrophic factor, nerve growth factor, or neurotrophins) to promote neuronal repair and resilience following CVDs.

In summary, these findings underscore the urgent need for a more integrated approach to patient care, especially for clinicians managing ischemic brain injury or neurodegenerative diseases. It is no longer sufficient to treat the brain in isolation. Given the emerging evidence of bidirectional communication along the heart-brain axis, careful monitoring and proactive support of heart function should be incorporated into neurological care protocols, as the brain and heart operate in concert.

Funding Support and Author Disclosures

This work was supported by the following grants and awards: American Heart Association 24SCEFIA1255866 and 24TPA1300751 to Dr Wu; Saunders Endowment and Corridor Undergraduate Research Funding to Dr Tipparaju; and NIH/NINDS 5R01NS126273-03 and American Heart Association 23TPA1069224 to Dr Lee. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.