Pathophysiological Interactions Research Articles

Modulating Sympathetic Nervous System with the use of SGLT2 Inhibitors: Where There is Smoke, There is Fire?

Heart failure (HF) has become even more prevalent in recent years, as a result of improved diagnostics and an increase in the risk factors predisposing to its pathology. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) emerged as one of the key pharmacotherapy options for both reduced and preserved ejection fraction, providing cardio- and renoprotection and improving mortality and cardiovascular (CV) outcomes. The pleiotropism of SGLT2i has led to multiple efforts to understand their distinct pathophysiological interactions with various pathways, including microcirculation, endothelial dysfunction, and inflammation. More recently, the role of SGLT2i on the sympathetic nervous system (SNS) is starting to be recognized, especially as observations of retained or reduced heart rate (HR) despite volume contraction have been noted by investigators in the large clinical trials testing the safety and efficacy of these agents. Both preclinical and clinical studies have been performed, with conflicting results. Interestingly, in both settings, whilst there are indications of SNS modulation by SGLT2i, other studies contradict such findings, without showing, however, worsening of the autonomic homeostasis. Given the importance of neuromodulation in HF, in both pharmacological and interventional therapies, in this review, we aim to describe the role of SNS in CV disease, focusing on HF, analyse preclinical and clinical data regarding the efficacy of SGLT2i in modulating autonomic dysfunction by examining various markers of SNS activation, as well as provide the most plausible theoretical backgrounds on the mechanism of benefit of SNS from the inhibition of SGLT2 receptors.

Hypertension in cardiovascular and kidney disease, recent trends: treating two diseases as one.

Hypertension and chronic kidney disease (CKD) are closely interlinked pathophysiologic states, such that high blood pressure is an independent risk factor for disease progression in both adult and paediatric patients with kidney disorders and progressive decline in kidney function can conversely lead to worsening blood pressure (BP) control. Hypertension in CKD is not only associated with GFR loss, but increases cardiovascular risk, which is the leading source of mortality and morbidity in this population. Given this complex relationship between hypertension, CKD and CVD, beside an optimal management of BP in CKD is mandatory to break an established vicious pathophysiological cycle that leads to adverse outcomes. New promising molecules for the treatment of chronic kidney disease, with interesting mechanisms, particularly regarding their pathophysiological interactions with arterial hypertension, are available or under development and in the very next future they may change the way we treat high blood pressure in CKD patients.

Impact of diabetes mellitus on endodontic treatment outcomes

Diabetes mellitus (DM) is a chronic metabolic disorder that affects various systemic functions, including oral health. Its impact on endodontic treatment outcomes has become a significant concern for dental practitioners. The relationship between DM and endodontic outcomes is complex, involving several pathophysiological mechanisms. Hyperglycemia leads to the formation of advanced glycation end-products, causing vascular dysfunction and impaired blood supply to the pulp, which exacerbates pulpal inflammation and increases the risk of necrosis. Additionally, chronic low-grade inflammation and an impaired immune response in diabetic patients contribute to a higher susceptibility to infections, delayed healing, and compromised tissue repair after endodontic procedures. Diabetic patients often experience lower success rates and prolonged recovery following endodontic treatment due to these systemic challenges. Reduced bone healing, persistent periapical lesions, and altered microbial flora are common complications that can hinder treatment success. Effective management of endodontic treatment in diabetic patients requires a multifaceted approach that includes strict glycemic control, the use of enhanced antimicrobial strategies, and the adoption of minimally invasive techniques to reduce tissue trauma. Additionally, patient education and close monitoring of the healing process are essential for minimizing complications. Understanding the pathophysiological interactions between diabetes and pulpal inflammation, as well as the factors that influence healing and success rates, is crucial for optimizing endodontic care in diabetic patients. By addressing both systemic and local factors, dental practitioners can improve the prognosis of endodontic treatment and ensure better outcomes for patients with diabetes. Ongoing research into the mechanisms underlying these complications will further enhance the ability of clinicians to manage endodontic cases effectively in this growing patient population.

Cardiovascular Risk in Patients with Coexisting Diabetes and Hypertension: A Comprehensive Review

Cardiovascular diseases (CVDs) remained the leading cause of morbidity and mortality globally, with diabetes and hypertension serving as significant contributors to this burden. The coexistence of these two chronic conditions (diabetes and hypertension) exacerbated cardiovascular risk through complex pathophysiological interactions, including insulin resistance, endothelial dysfunction, chronic inflammation, and vascular remodeling. This review provided an in-depth analysis of the cardiovascular risks associated with the coexistence of diabetes and hypertension, emphasizing the multifaceted interplay between these conditions. Utilizing a comprehensive literature review and analysis of current clinical practices, the article explored key pathophysiological mechanisms, assessed cardiovascular risk assessment strategies, and evaluated management approaches. Effective management necessitated a combined approach of pharmacological treatment, lifestyle modifications, and integrated care strategies. Future research should focus on novel therapeutic agents and integrated management strategies to enhance our understanding and treatment of these interrelated conditions, aiming to reduce cardiovascular risk and improve patient outcomes. Keywords: Cardiovascular Risk, Diabetes and Hypertension, Pathophysiological Mechanisms, Risk Assessment, Management Strategies.

Renin-angiotensin system-mediated nitric oxide signaling in podocytes.

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1-7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes.NEW & NOTEWORTHY The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function.

Osteoarthritis in People with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Background: Arthritis, particularly osteoarthritis (OA), is a common synovial condition observed in individuals with multiple sclerosis (MS). Despite its high prevalence and significant impact on the quality of life of MS individuals, there is a gap in the current literature regarding the prevalence of OA in this population and its relation to MS pathology. This systematic review and meta-analysis aimed to estimate the prevalence of OA in the MS population and explore potential associations with demographic and MS-specific characteristics. Methods: Adhering to PRISMA guidelines, a systematic search of the MEDLINE PubMed, Scopus and Google Scholar databases was conducted. Results: Fifteen studies were included in the systematic review and meta-analysis. The aggregated prevalence of OA in the MS population was 27% (95% CI: 15-40%), with substantial heterogeneity (I2 = 99.9%). Sensitivity analysis, excluding one study, showed a prevalence of 21% (95% CI: 16-28%). The risk ratio of OA in MS versus controls was 1.07 (95% CI: 0.84-1.37), indicating no significant difference. Meta-regression revealed no associations between OA prevalence and age or disease duration in MS patients. Conclusions: This study reports a 21-27% prevalence of OA in people with MS. Understanding the implications of OA in pain and mobility domains, as well as the challenges in distinguishing OA symptoms from MS manifestations, underscores the need for further research to elucidate the pathophysiological mechanisms and interactions between these conditions. Additional studies are warranted to enhance clinical management and improve outcomes for individuals with MS and co-existing OA.

Prevalence and risk factors of self-reported hearing loss, tinnitus, and dizziness in a population-based sample from rural northeastern Germany

A close anatomical and physiological relationship is known between the senses of hearing and balance, while an additional pathophysiological interaction is supposed. The mechanisms underlying this association are not yet fully understood, especially in individuals without a known specific otologic disorder. In particular, only scarce information on the combined occurrence of audiovestibular sensory impairment is available so far. Therefore, this study aims to provide further insight into the prevalence and co-prevalence of the audiovestibular symptoms hearing loss, tinnitus and dizziness. Additionally, the influence of potential risk factors from lifestyle habits as well as cardiovascular and metabolic conditions on the development of those symptoms is studied. Data was analyzed from 8134 individuals from the population-based Study of Health in Pomerania (SHIP). SHIP pursues a broad and comprehensive examination program in chronologically separated cohorts with longitudinal follow-up. Cohorts are sampled from Western Pomerania, a rural region of north-eastern Germany. The study population represents a cross-sectional analysis from the cohorts SHIP-START (recruited 1997–2001) and SHIP-TREND (recruited 2008–2012), sampled for baseline investigations (SHIP-START-0 and SHIP-TREND-0) at the age of 20–79 years. Audiovestibular symptoms as outcome variables were assessed by structured questionnaires. Additionally, individuals were comprehensively characterized regarding modifiable lifestyle factors as well as cardiovascular and metabolic disorders, allowing the assessment of their role as exposure variables. We calculated a weighted prevalence of 14.2% for hearing loss, 9.7% for tinnitus, and 13.5% for dizziness in the population. Prevalence increased with age and differed among the sexes. A considerable share of 28.0% of the investigated individuals reported more than one symptom at once. The prevalence of hearing loss as well as tinnitus increased between the two cohorts. A moderate positive correlation was found between the occurrence of hearing loss and tinnitus (phi-coefficient 0.318). In multivariable regression analyses, education was identified as a significant protective factor while only smoking was significantly associated with all three symptoms. Furthermore, several cardiovascular risk factors contributed to both hearing loss and dizziness. In conclusion, audiovestibular symptoms are highly prevalent in the investigated population. A considerable but complex influence of risk factors points towards a relation with neuronal as well as cardiovascular disease processes. To clarify the underlying mechanisms, the interaction between the senses of hearing and balance as well as the mode of action of the risk factors should be evaluated in more detail in the future.

The Role and Implications of COVID-19 in Incident and Prevalent Heart Failure.

This review examines the pathophysiological interactions between COVID-19 and heart failure, highlighting the exacerbation of heart failure in COVID-19 patients. It focuses on the complex mechanisms driving worse outcomes in these patients. Patients with pre-existing heart failure experience more severe symptoms and higher mortality rates due to mechanisms such as cytokine storms, myocardial infarction, myocarditis, microvascular dysfunction, thrombosis, and stress cardiomyopathy. Elevated biomarkers like troponin and natriuretic peptides correlate with severe disease. Long-term cardiovascular risks for COVID-19 survivors include increased incidence of heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock. COVID-19 significantly impacts patients with pre-existing heart failure, leading to severe symptoms and higher mortality. Elevated cardiac biomarkers are indicators of severe disease. Acute and long-term cardiovascular complications are common, calling for ongoing research into targeted therapies and improved management strategies to better prevent, diagnose, and treat heart failure in the context of COVID-19.

Navigating Lipodystrophy: Insights from Laminopathies and Beyond.

Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.

Forms of Non-Apoptotic Cell Death and Their Role in Gliomas-Presentation of the Current State of Knowledge.

In addition to necrosis and apoptosis, the two forms of cell death that have been known for many decades, other non-apoptotic forms of cell death have been discovered, many of which also play a role in tumors. Starting with the description of autophagy more than 60 years ago, newer forms of cell death have become important for the biology of tumors, such as ferroptosis, pyroptosis, necroptosis, and paraptosis. In this review, all non-apoptotic and oncologically relevant forms of programmed cell death are presented, starting with their first descriptions, their molecular characteristics, and their role and their interactions in cell physiology and pathophysiology. Based on these descriptions, the current state of knowledge about their alterations and their role in gliomas will be presented. In addition, current efforts to therapeutically influence the molecular components of these forms of cell death will be discussed. Although research into their exact role in gliomas is still at a rather early stage, our review clarifies that all these non-apoptotic forms of cell death show significant alterations in gliomas and that important insight into understanding them has already been gained.

Sindrom Kardiovaskular-Ginjal-Metabolik: Konsep Terkini untuk Klinisi

Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic abnormality resulting from complex pathophysiological interactions among cardiovascular disease, chronic kidney disease, and metabolic risk factors, particularly diabetes mellitus and obesity. In clinical practice, the management of CKM syndrome encounters some significant challenges, including the lack of clinicians’ knowledge regarding the most up-to-date therapy, limited drug availability, and restrictions on health insurance. Those issues potentially lead to a rise in morbidity and mortality rates of patients with CKM syndrome. This article elucidates the most updated concept of CKM syndrome regarding its pathophysiology, diagnostic approach, and treatment based on clinical stages ranging from stage 0 to stage 4. Some emerging medications have proven to improve the prognosis of patients with CKM syndrome by targeting any of the pathophysiological interactions, namely sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, angiotensin-enzyme converting inhibitors, and angiotensin receptor blockers. Recent studies have proven their efficacy in reducing hospitalisation rates and cardiovascular-related mortality. Not only by applying current clinical guidelines in practice, CKM syndrome should also be managed holistically in a multidiscipline manner starting from health promotion to curative treatment. Hence, the current concept of CKM syndrome pointing to holistic and multidiscipline management hopefully could prevent the progressivity of the disease and reduce the morbidity and mortality rates.

State of the art: Alternative overlap syndrome-asthma and obstructive sleep apnea.

In the general population, Bronchial Asthma (BA) and Obstructive Sleep Apnea (OSA) are among the most prevalent chronic respiratory disorders. Significant epidemiologic connections and complex pathogenetic pathways link these disorders via complex interactions at genetic, epigenetic, and environmental levels. The coexistence of BA and OSA in an individual likely represents a distinct syndrome, that is, a collection of clinical manifestations attributable to several mechanisms and pathobiological signatures. To avoid terminological confusion, this association has been named alternative overlap syndrome (vs overlap syndrome represented by the chronic obstructive pulmonary disease-OSA association). This comprehensive review summarizes the complex, often bidirectional links between the constituents of the alternative overlap syndrome. Cross-sectional, population, or clinic-based studies are unlikely to elucidate causality or directionality in these relationships. Even longitudinal epidemiological evaluations in BA cohorts developing over time OSA, or OSA cohorts developing BA during follow-up cannot exclude time factors or causal influence of other known or unknown mediators. As such, a lot of pathophysiological interactions described here have suggestive evidence, biological plausibility, potential or actual directionality. By showcasing existing evidence and current knowledge gaps, the hope is that deliberate, focused, and collaborative efforts in the near-future will be geared toward opportunities to shine light on the unknowns and accelerate discovery in this field of health, clinical care, education, research, and scholarly endeavors.

Патофізіологічні особливості портопульмональної гіпертензії: огляд англомовної літератури

Portopulmonary hypertension (PPH) is the coexistence of pulmonary arterial hypertension (PAH) and portal hypertension in patients with or without cirrhosis. PAH may develop in 2-6% of patients with portal hypertension and is the result of complex pathophysiological interactions between the portal and pulmonary circulations. The pathogenic mechanisms are unknown and depend both on the underlying severity of the liver disease and on the adaptation of the heart to the disease of the pulmonary vessels. Various pathophysiological aspects appear to be involved in the development of PPH, including angiogenesis, genetics, humoral changes, and inflammation with increased pulmonary phagocytosis. Female gender and estrogen metabolism with elevated estrogen levels are associated with the development of PPH. Of particular interest is the activation of powerful local vasoconstrictor systems, the imbalance between vasoconstrictors and vasodilators, which contributes to the narrowing of pulmonary vessels. Increased pulmonary blood flow causing shear stress can lead to endothelial damage and dysfunction with vasoconstriction and progressive vascular remodeling. However, only a small number of patients develop PPH, which indicates the involvement of other factors. Therefore, other numerous theories have been proposed that require further study.

The involvement of neuroinflammation in an animal model of dementia and depression

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Causal effects and metabolites mediators between immune cell and risk of colorectal cancer: a Mendelian randomization study.

The involvement of immune cells in colorectal cancer (CRC) and their interplay with metabolic disorders are yet to be fully elucidated. This study examines how peripheral immune cells, inferred genetically, affect CRC and investigates the intermediary roles of metabolites. We employed a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal influence of immune cells on CRC. Additionally, a two-step MR strategy was utilized to pinpoint potential metabolites that mediate this effect. Our analysis incorporated data from genome-wide association studies (GWAS), involving 731 immune cell types, 1,400 metabolites, and CRC outcomes. The primary method of analysis was randomized inverse variance weighting (IVW), supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks were conducted using Cochran's Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis. The study identified 23 immune cell types and 17 metabolites that are causally linked to CRC. Our mediation analysis highlighted that nine metabolites act as intermediaries in the relationship between nine specific immune cells and CRC risk. Notably, The ratios of Adenosine 5'-monophosphate (AMP) to aspartate and Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) were found to concurrently mediate the promoting effects of Myeloid DC %DC and BAFF-R on B cells in colorectal cancer (CRC). Moreover, iminodiacetate (IDA) was found to mediate the protective effect of CD14+ CD16- monocytes on CRC, contributing 11.8% to this mediation. In contrast, IDA was also seen to decrease the protective effect of IgD+ CD38br %B cells on CRC risk, with a mediation effect proportion of -10.4%. This study delineates a complex network involving immune cells, metabolites, and CRC, suggesting a multifaceted pathophysiological interaction. The identified causal links and mediation pathways underscore potential therapeutic targets, providing a foundation for interventions aimed at modulating immune responses to manage CRC.

The key role of vitamin C in the treatment of pulmonary hypertension of meat-type chickens: role of caspase-3

Ascites is a prominent example of the pathophysiological interaction between the heart and lungs in broilers. Previous experiments have shown that the amount of apoptosis increases in heart failure and pulmonary hypertension. In the current study, the effect of vitamin C on apoptosis was investigated by measuring the expression of the CASP3 gene in the heart and lungs of chickens with ascites. For this purpose, 90 one-day-old meat-type chickens were divided into three groups (sham (basal diet), control (basal diet +1.5 mg/kg of triiodothyronine (T3)), and treatment group (basal diet + 1.5 mg/kg of T3 + 1200 ppm of vitamin C)) and bred for 49 days. On the 21st and 49th days after rearing, 15 chickens from each group were selected randomly, and the right ventricle/ total ventricle weight ratio (RV/TV), as well as the expression level of CASP3 genes in the lung and right ventricle of all groups were measured and compared. The amount of mRNA related to CASP3 gene at the age of 21 and 49 days demonstrated a meaningful decrease in the treatment group compared to the control group (P<0.05). This significant difference indicates the reduction of apoptosis in the group treated with vitamin C. Also, RV/TV as an index of the induction of this syndrome improved in the treatment group at the age of 21 and 49 days (P<0.05). Finally, according to the current study's findings, vitamin C has ameliorating effects in treating ascites in meat-type chickens.

Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models.

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1-CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.

Interaction of heart failure and stroke: A clinical consensus statement of the ESC Council on Stroke, the Heart Failure Association (HFA) and the ESC Working Group on Thrombosis.

Heart failure (HF) is a major disease in our society that often presents with multiple comorbidities with mutual interaction and aggravation. The comorbidity of HF and stroke is a high risk condition that requires particular attention to ensure early detection of complications, efficient diagnostic workup, close monitoring, and consequent treatment of the patient. The bi-directional interaction between the heart and the brain is inherent in the pathophysiology of HF where HF may be causal for acute cerebral injury, and-in turn-acute cerebral injury may induce or aggravate HF via imbalanced neural and neurovegetative control of cardiovascular regulation. The present document represents the consensus view of the ESC Council on Stroke, the Heart Failure Association and the ESC Working Group on Thrombosis to summarize current insights on pathophysiological interactions of the heart and the brain in the comorbidity of HF and stroke. Principal aspects of diagnostic workup, pathophysiological mechanisms, complications, clinical management in acute conditions and in long-term care of patients with the comorbidity are presented and state-of-the-art clinical management and current evidence from clinical trials is discussed. Beside the physicians perspective, also the patients values and preferences are taken into account. Interdisciplinary cooperation of cardiologists, stroke specialists, other specialists and primary care physicians is pivotal to ensure optimal treatment in acute events and in continued long-term treatment of these patients. Key consensus statements are presented in a concise overview on mechanistic insights, diagnostic workup, prevention and treatment to inform clinical acute and continued care of patients with the comorbidity of HF and stroke.

Engineering Mesoscopic 3D Tumor Models with a Self-Organizing Vascularized Matrix.

Advanced in vitro systems such as multicellular spheroids and lab-on-a-chip devices have been developed, but often fall short in reproducing the tissue scale and self-organization of human diseases. A bioprinted artificial tumor model is introduced with endothelial and stromal cells self-organizing into perfusable and functional vascular structures. This model uses 3D hydrogel matrices to embed multicellular tumor spheroids, allowing them to grow to mesoscopic scales and to interact with endothelial cells. It is shown that angiogenic multicellular tumor spheroids promote the growth of a vascular network, which in turn further enhances the growth of cocultivated tumor spheroids. The self-developed vascular structure infiltrates the tumor spheroids, forms functional connections with the bioprinted endothelium, and can be perfused by erythrocytes and polystyrene microspheres. Moreover, cancer cells migrate spontaneously from the tumor spheroid through the self-assembled vascular network into the fluid flow. Additionally, tumor type specific characteristics of desmoplasia, angiogenesis, and metastatic propensity are preserved between patient-derived samples and tumors derived from this same material growing in the bioreactors. Overall, this modular approach opens up new avenues for studying tumor pathophysiology and cellular interactions in vitro, providing a platform for advanced drug testing while reducing the need for in vivo experimentation.

Glycemic and lipid profile of patients with COVID-19: Impact on morbidity and mortality

IntroductionRecent studies have shown that patients with COVID-19, who have underlying diabetes mellitus, develop a severe clinical course and have increased mortality. Similarly, dyslipidemia is a common complication in patients with COVID-19, indicating that there may be a pathophysiological interaction between lipid metabolism and SARS-CoV-2. The main manifestation is hypocholesterolemia, which is associated with severe illness and unfavorable outcome. AimThe aim of the present study was to assess the impact of glucose and lipid levels on the progression and outcome of patients with COVID-19 infection. Material and MethodsThe study sample consisted of 301 patients who became ill with SARS-CoV-2 and hospitalized during the calendar year 2021. Data were collected from the patients themselves and from their clinical and laboratory follow-up. ResultsA total of 301 patients were included in the study, 56.8% were male and 82.4% of patients were not vaccinated for SARS-CoV-2 at baseline. The mean age was 66.7 years and the body mass index was 28.8. More specifically 27.6% had diabetes mellitus and 34.2% reported known dyslipidemia. The comparison of the course of the disease with the laboratory data of patients, on the day of admission, found that death was more frequently observed in the elderly [83.0±11.0 (p<0.001)], in patients with abnormal glucose values [159.8±51.4 (p=0.039)], abnormal creatinine values (p<0.001), low glomerular filtration rate (p<0.001), lower total cholesterol values (p=0.044), higher triglycerides values [124±64,8 (p=0,003)], abnormal CRP values (p<0.001), cTnT (p=0.001), D-dimers (p<0.001), and SatO2 (p<0.001). ConclusionThe present study showed that death was more frequently observed in subjects with hyperglycemia and hypocholesterolemia, and other pathological findings. It is therefore evident that these patients should be a priority in the development of studies and guidelines.