Search Results (59)

Background: Long-term cognitive impairment is common among ICU patients who required invasive mechanical ventilation (IMV). Its etiology is likely multifactorial. This preregistered study examined the association between the duration of IMV and cognitive function post-ICU, as well as the moderating effects of age and cognitive reserve. Methods: A secondary analysis was conducted using data from a published study of COVID-19 ICU survivors. One year after discharge, participants underwent a neuropsychological assessment. Linear regression models were used to evaluate associations between the variables. Results: Among patients who received IMV via endotracheal intubation, ventilation duration was not significantly associated with cognitive performance. In contrast, among tracheostomized patients, longer IMV duration was associated with better cognitive outcomes (Cohen’s f² = 0.21). Age had a small negative main effect; in combination with IMV duration, f² increased to 0.31. Cognitive reserve showed a strong positive association with cognitive outcome; in combination with IMV duration, f² increased to 0.67. The interaction terms were negligible in both cases. Conclusions: We hypothesize that, compared to endotracheal intubation, IMV via tracheostoma may not only reduce the need for sedation, but also provide a more efficient respiratory support, therefore contributing to positive cognitive outcomes. However, IMV via tracheostomy still represents a form of positive pressure ventilation (PPV), which carries risks, such as ventilator-induced lung injury and reduced cardiac output and brain perfusion. These concerns about PPV, combined with our findings, indicate that alternative, non-invasive modes, such as negative pressure ventilation (NPV), warrant evaluation in future trials. Full article

Myocardial infarction (MI) triggers complex heart–brain interactions that increase the risk of stroke, cognitive decline, and mortality. Neuroinflammation and oxidative stress serve as critical mediators of these complications. We evaluated the neuroprotective effects of nebivolol, a β-blocker with nitric oxide-releasing properties, during acute MI. Male Sprague-Dawley rats were divided into sham-operated controls, MI-induced controls, and MI groups treated with oral nebivolol or intravenous loading followed by oral nebivolol. MI was induced by left anterior descending coronary artery ligation. Cardiac function was assessed by echocardiography and hemodynamic measurements. Brain tissues were analyzed for proinflammatory cytokines, oxidative stress markers, and histopathological changes. Nitric oxide synthase (NOS) isoform expression was evaluated by immunohistochemistry. MI induced significant neuroinflammation in the cerebral cortex and hippocampus, characterized by elevated cytokines, increased oxidative stress, upregulated iNOS expression, and altered histological patterns (necrosis, astrocytosis, gliosis, demyelination). Intravenous nebivolol significantly reduced these neuroinflammatory markers, normalized cytokine levels, prevented structural brain changes, and attenuated iNOS expression, while oral administration showed minimal effects. Both routes preserved cardiac function without affecting infarct size. These findings demonstrate that nebivolol, particularly via intravenous administration, provides significant NO-dependent neuroprotection during acute MI, supporting its potential as a dual-action therapeutic strategy targeting both cardiac and neurological complications. Full article

Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to its role in neuroprotection and neuroinflammation. Building upon our previously identified S1R ligand (compound 1), we designed and synthesized six novel benzamide derivatives through pharmacomodulation to optimize affinity, selectivity, and safety profiles. Among these, compound 2 demonstrated superior S1R affinity, improved selectivity over the sigma-2 receptor (S2R), and favorable ADME properties, including enhanced permeability and markedly reduced in vitro cardiac toxicity compared to the lead compound. Functional assays confirmed the agonist activity of key derivatives, while safety evaluations revealed low cytotoxicity and minimal off-target receptor interactions. Collectively, these findings support compound 2 as a promising candidate for further preclinical development in S1R-related CNS disorders. Full article

Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Utilizing a rat CPB model and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we demonstrated that IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis revealed the enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-Neutralizing monoclonal antibody (mAb) and the ERS inhibitor 4-phenylbutyric acid (4-PBA) significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, wherein heat shock protein 90 (Hsp90) competitively regulated Act1-IRE1 interactions. Co-immunoprecipitation confirmed the enhanced Hsp90-Act1 binding post-CPB, promoting IRE1 phosphorylation and downstream caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via IRE1-JNK1 signaling, reversible by IRE1 inhibition. These findings identify the hippocampus as a key vulnerable region and delineate a novel IL-17A/Act1-IRE1-JNK1 pathway driving ERS-dependent apoptosis. Targeting IL-17A or Hsp90-mediated chaperone switching represents a promising therapeutic strategy for CPB-associated neuroprotection. This study provides critical insights into the molecular crosstalk between systemic inflammation and neuronal stress responses during cardiac surgery. Full article

Various cardiac pathologies such as ischemic/non-ischemic heart disease, valvular heart disease and genetic heart disease may impair cardiac function and lead to heart failure (HF). Each individual condition but also the common endpoint of HF may involve the brain and the immune system next to the heart. The interaction of these systems plays an important role, particularly in the pathogenesis and prognosis of HF, and stress plays a pivotal role in this interaction. The stress system (SS) of the body can be activated by any stress factor exceeding a predefined threshold and all body structures including brain, heart and immune system can be affected. The SS is also responsible for body homeostasis. Both acute and chronic stress may lead to the development of acute and chronic heart disease. Magnetic Resonance Imaging (MRI) is the ideal noninvasive tool without radiation that can provide valuable information about the effect of the SS in various systems/organs using targeted protocols. A holistic approach provided by MRI has the potential to improve our knowledge regarding stress mechanisms on the axis of heart–brain–immune system in HF that may impact effective, individualized treatment. In this review paper, we describe how MRI can be used as a noninvasive tool to assess the effect of stress on the brain–immune system-heart-axis, discussing current possibilities, limitations and future directions. Full article

The intricate brain–heart interaction, essential for physiological balance, is largely governed by the autonomic nervous system (ANS). This bidirectional communication, involving both the sympathetic and parasympathetic branches of the ANS, is critical for maintaining cardiac homeostasis. Dysregulation of the ANS is a significant factor in cardiovascular diseases. Beyond the ANS, higher brain functions, particularly through interoceptive prediction, contribute to this dynamic interplay. The Cav1.3 L-type calcium channel, expressed in both the central nervous system (CNS) and the heart, is crucial for this interaction. Cav1.3, a key regulator of cellular excitability, exhibits genetic variations that are linked to both neurological and cardiac disorders, highlighting its pivotal role in the brain–heart axis. This review aims to delve into the under-explored role of Cav1.3 in brain–heart interaction, specifically examining how it modulates ANS activity and, consequently, the cardiac function. This will illuminate its significant role in the broader context of brain–heart interactions. Full article

Evaluating brain oxygen metabolism during cardiac arrest and cardiopulmonary resuscitation (CPR) is essential for improving neurological outcomes and guiding clinical interventions in high-stress medical emergencies. This study focused on two key indicators of brain oxygen metabolism: the cerebral metabolic rate of oxygen (CMRO₂) and the oxidation state of redox cytochrome c oxidase (rCCO). Using advanced techniques such as hyperspectral near-infrared spectroscopy (hNIRS) and laser Doppler flowmetry (LDF), we conducted a comprehensive analysis of their relationship in pigs during and after cardiac arrest and CPR. Both the entire duration of these experiments and specific time intervals were investigated, providing a detailed view of how these metrics interact. The data reveal a non-linear relationship between rCCO and CMRO₂. Our findings contribute to a deeper understanding of how the brain manages oxygen during critical episodes, potentially guiding future interventions in neurological care and improving outcomes in emergency medical settings. Full article

Fentanyl is a synthetic opioid widely used for its potent analgesic effects in chronic pain management and intraoperative anesthesia. However, its high potency, low cost, and accessibility have also made it a significant drug of abuse, contributing to the global opioid epidemic. This review aims to provide an in-depth analysis of fentanyl’s medical applications, pharmacokinetics, metabolism, and pharmacogenetics while examining its adverse effects and forensic implications. Special attention is given to its misuse, polydrug interactions, and the challenges in determining the cause of death in fentanyl-related fatalities. Fentanyl misuse has escalated dramatically, driven by its substitution for heroin and its availability through online platforms, including the dark web. Polydrug use, where fentanyl is combined with substances like xylazine, alcohol, benzodiazepines, or cocaine, exacerbates its toxicity and increases the risk of fatal outcomes. Fentanyl undergoes rapid distribution, metabolism by CYP3A4 into inactive metabolites, and renal excretion. Genetic polymorphisms in CYP3A4, OPRM1, and ABCB1 significantly influence individual responses to fentanyl, affecting its efficacy and potential for toxicity. Fentanyl’s side effects include respiratory depression, cardiac arrhythmias, gastrointestinal dysfunction, and neurocognitive impairments. Chronic misuse disrupts brain function, contributes to mental health disorders, and poses risks for younger and older populations alike. Fentanyl-related deaths require comprehensive forensic investigations, including judicial inspections, autopsies, and toxicological analyses. Additionally, the co-administration of xylazine presents distinct challenges for the scientific community. Histological and immunohistochemical studies are essential for understanding organ-specific damage, while pharmacogenetic testing can identify individual susceptibilities. The growing prevalence of fentanyl abuse highlights the need for robust forensic protocols, advanced research into its pharmacogenetic variability, and strategies to mitigate its misuse. International collaboration, public education, and harm reduction measures are critical for addressing the fentanyl crisis effectively. Full article

Background: Myocardial infarction (MI) can range from mild to severe cardiovascular events and typically develops through complex interactions between genetic and lifestyle factors. Objectives: We aimed to understand the genetic predisposition associated with MI through genetic correlation, colocalization analysis, and cells’ gene expression values to develop more effective prevention and treatment strategies to reduce its burden. Methods: A polygenic risk score (PRS) was employed to estimate the genetic risk for MI and to analyze the dietary interactions with PRS that affect MI risk in adults over 45 years (n = 58,701). Genetic correlation (rg) between MI and metabolic syndrome-related traits was estimated with linkage disequilibrium score regression. Single-cell RNA sequencing (scRNA-seq) analysis was performed to investigate cellular heterogeneity in MI-associated genes. Results: Ten significant genetic variants associated with MI risk were related to cardiac, immune, and brain functions. A high PRS was associated with a threefold increase in MI risk (OR: 3.074, 95% CI: 2.354–4.014, p < 0.001). This increased the risk of MI plus obesity, hyperglycemia, dyslipidemia, and hypertension by about twofold after adjusting for MI-related covariates (p < 0.001). The PRS interacted with moderate fat intake (>15 energy percent), alcohol consumption (<30 g/day), and non-smoking, reducing MI risk in participants with a high PRS. MI was negatively correlated with the consumption of olive oil, sesame oil, and perilla oil used for cooking (rg = −0.364). MI risk was associated with storkhead box 1 (STOX1) and vacuolar protein sorting-associated protein 26A (VPS26A) in atrial and ventricular cardiomyocytes and fibroblasts. Conclusions: This study identified novel genetic variants and gene expression patterns associated with MI risk, influenced by their interaction with fat and alcohol intake, and smoking status. Our findings provide insights for developing personalized prevention and treatment strategies targeting this complex clinical presentation of MI. Full article

Multi-organ chips are effective at emulating human tissue and organ functions and at replicating the interactions among tissues and organs. An arrayed brain–heart chip was introduced whose configuration comprises open culture chambers and closed biomimetic vascular channels distributed in a horizontal pattern, separated from each other by an endothelial barrier based on fibrin matrix. A 300 μm-high and 13.2 mm-long endothelial barrier surrounded each organoid culture chamber, thereby satisfying the material transport requirements. Numerical simulations were used to analyze the construction process of fibrin barriers in order to optimize the structural design and experimental manipulation, which exhibited a high degree of correlation with experiment results. In each interconnective unit, a cerebral organoid, a cardiac organoid, and endothelial cells were co-cultured stably for a minimum of one week. The permeability of the endothelial barrier and recirculating perfusion enabled cross talk between cerebral organoids and cardiac organoids, as well as between organoids and endothelial cells. This was corroborated by the presence of cardiac troponin I (cTnI) in the cerebral organoid culture chamber and the observation of cerebral organoid and endothelial cells invading the fibrin matrix after one week of co-culture. The arrayed chip was simple to manipulate, clearly visible under a microscope, and compatible with automated pipetting devices, and therefore had significant potential for application. Full article

Individuals diagnosed with Parkinson’s disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches. Full article

Background: Degenerative aortic valve stenosis (AS) is the most common valvular heart disease among the elderly. Once cardiac symptoms occur, current guidelines recommend aortic valve replacement. Progressive degeneration/calcification reduces leaflet mobility with gradual cardiac output (CO) impairment. Low CO might induce abnormal brain-aging with cognitive impairment and increased risk of dementia, such as Alzheimer’s disease or vascular dementia. On the contrary, cognitive improvement has been reported in patients in whom CO was restored. Transcatheter aortic valve implantation (TAVI) has proven to be a safe alternative to conventional surgery, with a similar mid-term survival and stroke risk even in low-risk patients. TAVI is associated with an immediate CO improvement, also effecting the cerebrovascular system, leading to an increased cerebral blood flow. The correlation between TAVI and cognitive improvement is still debated. The present study aims at evaluating this relationship in a cohort of AS patients where cognitive assessment before and after TAVI was available. Methods: a total of 47 patients were retrospectively selected. A transcranial Doppler ultrasound (TCD) before and after TAVI, a quality of life (QoL) score, as well as a mini-mental state examination (MMSE) at baseline and up to 36 months, were available. Results: TAVI was associated with immediate increase in mean cerebral flow at TCD. MMSE slowly increase at 36-months follow-up with improved QoL mainly for symptoms, emotions and social interactions. Conclusions: this proof-of-concept study indicates that TAVI might induce cognitive improvement in the long-term as a result of multiple factors, such as cerebral flow restoration and a better QoL. Full article

Arrhythmias and depression are recognized as diseases of the heart and brain, respectively, and both are major health threats that often co-occur with a bidirectional causal relationship. The autonomic nervous system (ANS) serves as a crucial component of the heart–brain axis (HBA) and the pathway of interoception. Cardiac activity can influence emotional states through ascending interoceptive pathways, while psychological stress can precipitate arrhythmias via the ANS. However, the HBA and interoception frameworks are often considered overly broad, and the precise mechanisms underlying the bidirectional relationship between depression and arrhythmias remain unclear. This narrative review aims to synthesize the existing literature, focusing on the pathological mechanisms of the ANS in depression and arrhythmia while integrating other potential mechanisms to detail heart–brain interactions. In the bidirectional communication between the heart and brain, we emphasize considering various internal factors such as genes, personality traits, stress, the endocrine system, inflammation, 5-hydroxytryptamine, and behavioral factors. Current research employs multidisciplinary knowledge to elucidate heart–brain relationships, and a deeper understanding of these interactions can help optimize clinical treatment strategies. From a broader perspective, this study emphasizes the importance of considering the body as a complex, interconnected system rather than treating organs in isolation. Investigating heart–brain interactions enhance our understanding of disease pathogenesis and advances medical science, ultimately improving human quality of life. Full article

The close interaction between neurons and astrocytes has been extensively studied. However, the specific behavior of these cells after ischemia-reperfusion injury and hypothermia remains poorly characterized. A growing body of evidence suggests that mitochondria function and putative transference between neurons and astrocytes may play a fundamental role in adaptive and homeostatic responses after systemic insults such as cardiac arrest, which highlights the importance of a better understanding of how neurons and astrocytes behave individually in these settings. Brain injury is one of the most important challenges in post-cardiac arrest syndrome, and therapeutic hypothermia remains the single, gold standard treatment for neuroprotection after cardiac arrest. In our study, we modeled ischemia-reperfusion injury by using in vitro enhanced oxygen-glucose deprivation and reperfusion (eOGD-R) and subsequent hypothermia (HPT) (31.5 °C) to cell lines of neurons (HT-22) and astrocytes (C8-D1A) with/without hypothermia. Using cell lysis (LDH; lactate dehydrogenase) as a measure of membrane integrity and cell viability, we found that neurons were more susceptible to eOGD-R when compared with astrocytes. However, they benefited significantly from HPT, while the HPT effect after eOGD-R on astrocytes was negligible. Similarly, eOGD-R caused a more significant reduction in adenosine triphosphate (ATP) in neurons than astrocytes, and the ATP-enhancing effects from HPT were more prominent in neurons than astrocytes. In both neurons and astrocytes, measurement of reactive oxygen species (ROS) revealed higher ROS output following eOGD-R, with a non-significant trend of differential reduction observed in neurons. HPT after eOGD-R effectively downregulated ROS in both cells; however, the effect was significantly more effective in neurons. Lipid peroxidation was higher after eOGD-R in neurons, while in astrocytes, the increase was not statistically significant. Interestingly, HPT had similar effects on the reduction in lipoperoxidation after eOGD-R with both types of cells. While glutathione (GSH) levels were downregulated after eOGD-R in both cells, HPT enhanced GSH in astrocytes, but worsened GSH in neurons. In conclusion, neuron and astrocyte cultures respond differently to eOGD-R and eOGD-R + HTP treatments. Neurons showed higher sensitivity to ischemia-reperfusion insults than astrocytes; however, they benefited more from HPT therapy. These data suggest that given the differential effects from HPT in neurons and astrocytes, future therapeutic developments could potentially enhance HPT outcomes by means of neuronal and astrocytic targeted therapies. Full article

The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin in the regulation of the coronary blood flow and cardiac contractions. The interactions of angiotensin peptides, AVP, and insulin in the heart and in the brain are also discussed. The intracardiac production and the supply of angiotensin peptides and AVP from the systemic circulation enable their easy access to the coronary vessels and the cardiomyocytes. Coronary vessels and cardiomyocytes are furnished with AT1 receptors, AT2 receptors, Ang (1-7) receptors, vasopressin V1 receptors, and insulin receptor substrates. The presence of some of these molecules in the same cells creates good conditions for their interaction at the signaling level. The broad spectrum of actions allows for the engagement of angiotensin peptides, AVP, and insulin in the regulation of the most vital cardiac processes, including (1) cardiac tissue oxygenation, energy production, and metabolism; (2) the generation of the other cardiovascular compounds, such as nitric oxide, bradykinin (Bk), and endothelin; and (3) the regulation of cardiac work by the autonomic nervous system and the cardiovascular neurons of the brain. Multiple experimental studies and clinical observations show that the interactions of Ang II, Ang(1-7), AVP, and insulin in the heart and in the brain are markedly altered during heart failure, hypertension, obesity, and diabetes mellitus, especially when these diseases coexist. A survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be applied in patients suffering from both the cardiovascular and metabolic diseases. Full article