Global trends and emerging themes in youth physical literacy research: a bibliometric analysis (2000-2025).

The human heart, long perceived as a mere mechanical pump, can be profoundly and acutely broken by the mind. This is vividly exemplified by Takotsubo syndrome (TTS), often termed “broken heart syndrome,” a transient form of acute heart failure typically triggered by severe emotional or psychological stress, such as the grief of loss, intense fear, or overwhelming anxiety (). The condition predominantly affects postmenopausal women and presents with symptoms mimicking an acute coronary syndrome, including chest pain and electrocardiographic changes, but in the absence of obstructive coronary artery disease (). The COVID-19 pandemic provided a stark, real-world illustration of this mind-heart connection, where the profound psychological stressors of social isolation, fear of infection, and societal upheaval led to a documented surge in TTS cases, even among individuals without evidence of SARS-CoV-2 infection itself (). This phenomenon underscores that emotional distress can be directly transduced into myocardial injury, challenging the traditional cardiocentric view of heart disease. The pathophysiology of TTS is thought to involve a catecholamine storm, where a massive sympathetic nervous system (SNS) outflow in response to stress leads to excessive epinephrine and norepinephrine release, causing direct myocardial stunning and microvascular dysfunction (). This clinical narrative serves as a compelling entry point into a far more extensive and intricate biological dialogue, revealing that the heart does not operate in isolation but is a central participant in a continuous, multidirectional conversation orchestrated by the brain and mediated by the immune system. This narrative challenges the conventional paradigm of cardiovascular disease (CVD) research, which has historically focused on local vascular pathology, lipid metabolism, and hemodynamic forces, often overlooking the brain as the central controller and the immune system as a critical effector. CVD remains the leading cause of global mortality, and while traditional risk factors like hypertension and dyslipidemia are well-established, they do not fully account for disease susceptibility or progression. Accumulating evidence now compellingly demonstrates that the nervous and immune systems are indispensable actors in the initiation, progression, and complications of CVD (). This recognition has given rise to the integrative concept of the “neuroimmune cardiovascular axis” (or neuroimmune-cardiovascular axis) (). This axis represents a dynamic, bidirectional communication network where the central nervous system (CNS), through the autonomic nervous system (ANS) and neuroendocrine pathways, engages in real-time dialogue with the peripheral immune system and the cardiovascular system itself (). It is not a simple linear pathway but a complex circuit involving afferent sensory nerves that relay signals from the heart and vessels to the brain, and efferent sympathetic and parasympathetic nerves that convey commands back to cardiovascular and immune tissues (). This communication is facilitated by a rich language of mediators, including neurotransmitters (e.g., norepinephrine, acetylcholine), neuropeptides (e.g., neuropeptide Y, substance P), cytokines, chemokines, and hormones, which collectively fine-tune vascular tone, immune surveillance, and tissue repair under physiological conditions (). In pathological states, however, this finely tuned axis becomes dysregulated, driving cardiovascular pathogenesis. Chronic psychosocial stressors, such as social isolation or loneliness, can lead to sustained activation of the SNS and the hypothalamic-pituitary-adrenal (HPA) axis, creating a state of chronic low-grade inflammation and oxidative stress that accelerates atherosclerosis (). This neuroimmune dysregulation is a central mechanism in hypertension, where immune cell infiltration into the vessel wall, kidney, and key cardiovascular regulatory centers in the brain contributes to increased vascular resistance and sympathetic tone (). For instance, activated T cells and macrophages release pro-inflammatory cytokines like interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α), which promote endothelial dysfunction, oxidative stress, and vascular remodeling (). Conversely, signals from diseased cardiovascular tissues feed back to the CNS. In atherosclerosis, specialized “neuroimmune cardiovascular interfaces” (NICIs) form in the adventitia of diseased arteries, where expanded axon networks interact closely with immune cells (). These NICIs are part of a structural “artery-brain circuit” (ABC), where nociceptive afferents from the arterial adventitia project to the spinal cord and higher brain regions like the amygdala, while sympathetic efferents from the brainstem and hypothalamus project back to the adventitia via ganglia (). Activation of this circuit, including increased splenic sympathetic nerve activity, can exacerbate disease