Neurohumoral Pathways Research Articles

Gut-Brain Axis Modulation of Metabolic Disorders: Exploring the Intertwined Neurohumoral Pathways and Therapeutic Prospects.

A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary studies indicates the significance of thegut-brain axis, which regulates bidirectional signaling between the gastrointestinal tractand the cognitive system, and is crucial for regulating hostmetabolism and cognition. Intimate connections between the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit inboth directions. The gut-brain axissuccessfully establishesthat the wellness of the brain is always correlated with the extent to which the gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the gastrointestinal system works. The lateststudies, however, revealed that the gut microbiota interacts with the brain via the gut-brain axisto control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signaling pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be incorporated in the future.

The prognostic role of clinical features and biomarkers in patients hospitalized with cardiorenal syndromes

Abstract Background Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, is an entity characterized by high morbidity and mortality. Objective To evaluate the prognostic role of risk factors and biomarkers in patients hospitalized for CRS. Methods In this prospective, observational cohort study, 113 consecutive patients hospitalized for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers were measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. Results Patients were classified into two groups; Group 1 (N = 59): discharged being dialysis-independent, Group 2 (N = 54): death/dialysis dependence at discharge. No major differences were detected in baseline characteristics between the two groups. Group 2 patients used renin-angiotensin-aldosterone system blockers (RAASb) less often (Group 1: 69.5% vs. Group 2: 46.3%, p = 0.01) and more frequently presented with oliguria/anuria (Group 1: 28.8% vs. Group 2: 70.4%, p<0.001) and any infection (Group 1: 33.9% vs. Group 2: 55.6%, p = 0.02). No dissimilarities were noted in echocardiographic markers. Group 2 patients had significantly lower hemoglobin, serum albumin, bicarbonate, and 25-hydroxy-vitamin D (25OHD) (Figure 1). At the same time, N-terminal prohormone brain natriuretic peptide, serum potassium, and parathyroid hormone (PTH) were significantly higher in Group 2 patients (Figure 1). In a multivariate regression analysis, lack of RAASb was independently associated with a 17.7-fold increased risk of death or dialysis dependence at discharge, while the decreasing 25OHD/PTH ratio (β coefficient -0.01, p = 0.007) and increasing admission serum potassium levels (β coefficient 0.82, p = 0.03) increased the possibility of facing the composite endpoint. Following a receiver operating characteristic curve analysis, 25OHD/PTH ratio emerge as the most accurate predictor of facing the composite endpoint, with an ideal cutoff of 103.7 (sensitivity 81%, specificity 74%) (Figure 2). Conclusion Lack of prior RAASb use, high admission serum potassium, and a low 25OHD/PTH ratio are associated with poor prognosis in patients hospitalized for CRS.Figure 1Figure 2

THE PROGNOSTIC ROLE OF CLINICAL FEATURES AND BIOMARKERS IN PATIENTS HOSPITALIZED WITH CARDIORENAL SYNDROMES

Objective: Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, is an entity characterized by high morbidity and mortality. The aim of this study was to evaluate the prognostic role of risk factors and biomarkers in patients hospitalized for CRS. Design and method: In this prospective, observational cohort study, 113 consecutive patients hospitalized for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers were measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. Results: Patients were classified into two groups; Group 1 (N = 59): discharged being dialysis-independent, Group 2 (N = 54): death/dialysis dependence at discharge. No major differences were detected in baseline characteristics between the two groups. Group 2 patients used renin-angiotensin-aldosterone system blockers (RAASb) less often (Group 1: 69.5% vs. Group 2: 46.3%, p = 0.01) and more frequently presented with oliguria/anuria (Group 1: 28.8% vs. Group 2: 70.4%, p < 0.001) and any infection (Group 1: 33.9% vs. Group 2: 55.6%, p = 0.02). No dissimilarities were noted in echocardiographic markers. Group 2 patients had significantly lower hemoglobin, serum albumin, bicarbonate, and 25-hydroxy-vitamin D (25OHD). At the same time, N-terminal prohormone brain natriuretic peptide, serum potassium, and parathyroid hormone (PTH) were significantly higher in Group 2 patients (Figure 1). In a multivariate regression analysis, lack of RAASb was independently associated with a 17.7-fold increased risk of death or dialysis dependence at discharge, while the decreasing 25OHD/PTH ratio (beta coefficient -0.01, p = 0.007) and increasing admission serum potassium levels (beta coefficient 0.82, p = 0.03) increased the possibility of facing the composite endpoint. Following a receiver operating characteristic curve analysis, 25OHD/PTH ratio emerged as the most accurate predictor of facing the composite endpoint, with an ideal cutoff of 103.7 (sensitivity 81%, specificity 74%) (Figure 2). Conclusions: Lack of prior RAASb use, high admission serum potassium, and a low 25OHD/PTH ratio are associated with poor prognosis in patients hospitalized for CRS.

Natriuretic Peptides as Biomarkers: Narrative Review and Considerations in Cardiovascular and Respiratory Dysfunctions.

Natriuretic peptides (NPs) encompass a family of structurally related hormone/paracrine factors acting through the natriuretic peptide system regulating cell proliferation, vessel tone, inflammatory processes, neurohumoral pathways, fluids, and electrolyte balance. The three most studied peptides are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-Type natriuretic peptide (CNP). ANP and BNP are the most relevant NPs as biomarkers for the diagnosis and prognosis of heart failure and underlying cardiovascular diseases, such as cardiac valvular dysfunction, hypertension, coronary artery disease, myocardial infarction, persistent arrhythmias, and cardiomyopathies. Cardiac dysfunctions related to cardiomyocytes stretching in the atria and ventricles are primary elicitors of ANP and BNP release, respectively. ANP and BNP would serve as biomarkers for differentiating cardiac versus noncardiac causes of dyspnea and as a tool for measuring the prognosis of patients with heart failure; nevertheless, BNP has been shown with the highest predictive value, particularly related to pulmonary disorders. Plasma BNP has been reported to help differentiate cardiac from pulmonary etiologies of dyspnea in adults and neonates. Studies have shown that COVID-19 infection also increases serum levels of N-terminal pro b-type natriuretic peptide (NT-proBNP) and BNP. This narrative review assesses aspects of ANP and BNP on their physiology, and predictive values as biomarkers. We present an overview of the NPs' synthesis, structure, storage, and release, as well as receptors and physiological roles. Following, considerations focus on ANP versus BNP, comparing their relevance in settings and diseases associated with respiratory dysfunctions. Finally, we compiled data from guidelines for using BNP as a biomarker in dyspneic patients with cardiac dysfunction, including its considerations in COVID-19.

Prognostic Significance of Risk Factors and Biomarkers in Patients Hospitalized for Cardiorenal Syndromes: A Pilot Study.

Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, are an entity characterized by high morbidity and mortality. To evaluate the prognostic role of risk factors and biomarkers in patients hospitalized for CRS. In this observational cohort study, 100 consecutive patients hospitalized for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers were measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. Patients were classified into two groups; Group 1 (N= 52): discharged being dialysis-independent, Group 2 (N=48): death/dialysis dependence at discharge. No significant differences were detected in baseline characteristics between the two groups. Group 2 patients used renin-angiotensin-aldosterone system blockers (RAASb) less often and more frequently presented with oliguria/anuria. Group 2 patients had significantly lower hemoglobin, serum albumin, and 25-hydroxy-vitamin D (25(OH)D). At the same time, serum phosphate, potassium, and parathyroid hormone (PTH) were significantly higher in Group 2 patients. In a multivariate regression analysis, lack of prior RAASb and lower 25(OH)D levels were independently associated with an increased risk of death or dialysis dependence at discharge. 25(OH)D/PTH ratio was the most accurate predictor of the composite endpoint (Sensitivity: 79.4%, Specificity: 70.4%). Lack of prior RAASb use, high PTH, low 25(OH)D levels, and low 25(OH) D/PTH ratio are associated with a poor prognosis in patients hospitalized for CRS.

A Personalized Approach to the Management of Congestion in Acute Heart Failure.

Heart failure (HF) is the common final pathway of several conditions and is characterized by hyperactivation of numerous neurohumoral pathways. Cardiorenal interaction plays an essential role in the progression of the disease, and the use of diuretics is a cornerstone in the treatment of hypervolemic patients, especially in acute decompensated HF (ADHF). The management of congestion is complex and, to avoid misinterpretations and errors, one must understand the interface between the heart and the kidneys in ADHF. Congestion itself may impair renal function and must be treated aggressively. Transitory elevations in serum creatinine during decongestion is not associated with worse outcomes and diuretics should be maintained in patients with clear hypervolemia. Monitoring urinary sodium after diuretic administration seems to improve the response to diuretics as it allows for adjustments in doses and a personalized approach. Adequate assessment of volemia and the introduction and titration of guideline-directed medical therapy are mandatory before discharge. An early visit after discharge is highly recommended, to assess for residual congestion and thus avoid readmissions.

C-reactive protein and statins in heart failure with reduced and preserved ejection fraction.

High C-reactive protein (CRP) levels are associated with poor outcomes of heart failure (HF), and statins are known to reduce CRP levels. We investigated the prognostic value of CRP and statin in patients with HF with reduced and preserved ejection fraction (EF). Altogether, 3,831 patients from the Korean Acute Heart Failure registry were included and stratified according to the tertiles of CRP levels (T1: CRP < 0.30 mg/dL, T2: 0.30-1.14 mg/dL, and T3: CRP > 1.14 mg/dL). HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF) were defined as left ventricular ejection fraction (LVEF) ≤ 40%, 41-49%, ≥50%, respectively. The primary endpoints were all-cause, in-hospital, and post-discharge mortality. No significant correlation was observed between CRP levels and LVEF (r = 0.02, P = 0.131). The prevalence of risk factors increased gradually from T1 to T3 in both the types of HF. Overall, 139 (3.6%) and 1,269 (34.4%) patients died during the index admission and follow-up (median: 995 days), respectively. After adjustment, each increase in the CRP tertiles was independently associated with in-hospital mortality (HFrEF: OR 1.58 and 95% CI 1.09-2.30, HFmrEF: OR 1.51 and 95% CI 0.72-3.52, and HFpEF: OR 2.98, 95% CI 1.46-6.73) and post-discharge mortality (HFrEF: HR 1.20, 95% CI 1.08-1.33, HFmrEF: HR 1.38 and 95% CI 1.12-1.70, and HFpEF: HR 1.37, 95% CI 1.02-1.85). In only patients with LVEF > 40% with highest CRP tertile, statin-users showed better survival trend than those without statins. CRP is an excellent prognostic marker for HFrEF, HFmrEF, and HFpEF, implying that the neurohumoral and inflammatory pathways might be independent pathways. Statins may be beneficial in HF patients with increased CRP levels. [https://clinicaltrials.gov/], identifier [NCT013 89843].

Vasovagal Syncope Is Associated with Variants in Genes Involved in Neurohumoral Signaling Pathways.

Vasovagal syncope (VVS) is the most common cause of sudden loss of consciousness. VVS results from cerebral hypoperfusion, due to abnormal autonomic control of blood circulation, leading to arterial hypotension. It is a complex disease, and its development is largely associated with genetic susceptibility. Since abnormal neurohumoral regulation plays an important role in VVS development, we analyzed the association of VVS with polymorphic variants of ADRA1A, ADRB1, HTR1A, ADORA2A, COMT, and NOS3 genes, the products of which are involved in neurohumoral signaling, in patients with a confirmed VVS diagnosis (157 subjects) and individuals without a history of syncope (161 subjects). We were able to identify the associations between VVS and alleles/genotypes ADRA1A rs1048101, ADRB1 rs1801253, ADORA2A rs5751876, and COMT rs4680, as well as NOS3 rs2070744 in biallelic combination with COMT rs4680. Thus, we are the first to observe, within a single study, the role of the genes that encode α- and β-adrenergic receptors, catechol-O-methyltransferase, adenosine receptors and nitric oxide synthase in VVS development. These findings demonstrate that the genes involved in neurohumoral signaling pathways contribute to the formation of a genetic susceptibility to VVS.

Evaluation of the intestinal microbiota in operational staff of the Russian EMERCOM working in the Arctic zone of Russia

Relevance. Professional activity of operational staff of the Russian EMERCOM in the Arctic zone is associated with adaptive changes in the body resulting in changes in all types of metabolism, appearance of functional abnormalities and, without proper correction, development of various diseases. The complex system of metabolic interaction between humans and the microbiota is well described by the “microbiota-gut-brain” axis, which includes endocrine, immune, and neurohumoral pathways. Dysfunction of this axis in humans may be involved in pathogenesis of various diseases and somatic psychoneurological disorders.Intention is to study features of the intestinal microbiota in operational staff of the Russian EMERCOM working in the adverse conditions of the Arctic zone.Methodology. A study group included 94 firefighters and rescuers of the Russian EMERCOM working in the Arctic zone of Russia and was divided into subgroups depending on relevant work experience (0–5 years, 6–10 years, 11 years and more), as well as on age (22–35 years and 36–56 years). A control group included 98 rescue workers from the North-West regional search and rescue team and employees of the territorial fire departments of St. Petersburg (males aged 32.1 ± 0.5 years). Quantity and composition of the parietal intestinal microbiota were assessed based on microbial markers in the blood plasma using gas chromatography-mass spectrometry.Results and Discussion. Negative changes in the quantity and structure of the parietal intestinal microbiota were revealed in operational staff of the Russian EMERCOM working in the Arctic zone of Russia as compared with the control group: the total number of microbial markers was reduced by 34 %, beneficial flora – by 44 %, opportunistic flora – by 10 %, aerobes – by 25 %, anaerobes – by 32 %. In the structure of beneficial microflora, the proportion of Lactobacillus was 1.5 times greater and the proportion of Bifidobacterium was 3 times fewer. The most pronounced changes in the intestinal microbiota with increase of work experience were found in rescuer workers (a decrease in opportunistic flora and aerobes, an increase in the ratio of anaerobic to aerobic flora). According to the Kruskal–Wallace test, the amount of microbial markers of Bifidobacterium, Propionibacterium/Cl. Subterminale, aerobes, endotoxin, as well as the ratio of anaerobic to aerobic flora depends on the work experience of operational staff of the Russian EMERCOM working in the Arctic zone of Russia.Conclusion. Ecological and professional stress in operational staff of the Russian EMERCOM working in the Arctic zone disturbs trophism of various types of endogenous microflora and its regulatory relationships with the human body and, hence, results in quantitative and qualitative changes in the composition of the microflora.

Obesity-Related Chronic Kidney Disease: Principal Mechanisms and New Approaches in Nutritional Management.

Obesity is the epidemic of our era and its incidence is supposed to increase by more than 30% by 2030. It is commonly defined as a chronic and metabolic disease with an excessive accumulation of body fat in relation to fat-free mass, both in terms of quantity and distribution at specific points on the body. The effects of obesity have an important impact on different clinical areas, particularly endocrinology, cardiology, and nephrology. Indeed, increased rates of obesity have been associated with increased risk of cardiovascular disease (CVD), cancer, type 2 diabetes (T2D), dyslipidemia, hypertension, renal diseases, and neurocognitive impairment. Obesity-related chronic kidney disease (CKD) has been ascribed to intrarenal fat accumulation along the proximal tubule, glomeruli, renal sinus, and around the kidney capsule, and to hemodynamic changes with hyperfiltration, albuminuria, and impaired glomerular filtration rate. In addition, hypertension, dyslipidemia, and diabetes, which arise as a consequence of overweight, contribute to amplifying renal dysfunction in both the native and transplanted kidney. Overall, several mechanisms are closely related to the onset and progression of CKD in the general population, including changes in renal hemodynamics, neurohumoral pathways, renal adiposity, local and systemic inflammation, dysbiosis of microbiota, insulin resistance, and fibrotic process. Unfortunately, there are no clinical practice guidelines for the management of patients with obesity-related CKD. Therefore, dietary management is based on the clinical practice guidelines for the nutritional care of adults with CKD, developed and published by the National Kidney Foundation, Kidney Disease Outcome Quality Initiative and common recommendations for the healthy population. Optimal nutritional management of these patients should follow the guidelines of the Mediterranean diet, which is known to be associated with a lower incidence of CVD and beneficial effects on chronic diseases such as diabetes, obesity, and cognitive health. Mediterranean-style diets are often unsuccessful in promoting efficient weight loss, especially in patients with altered glucose metabolism. For this purpose, this review also discusses the use of non-classical weight loss approaches in CKD, including intermittent fasting and ketogenic diet to contrast the onset and progression of obesity-related CKD.

Biomarkers of Volume Overload and Edema in Heart Failure With Reduced Ejection Fraction.

From a pathogenetic point of view, heart failure (HF) is characterized by the activation of several neurohumoral pathways with a role in maintaining the cardiac output and the adequate perfusion pressure in target organs and tissues. Decreased cardiac output in HF with reduced ejection fraction causes activation of the sympathetic nervous system, the renin angiotensin aldosterone system, arginine-vasopressin system, natriuretic peptides, and endothelin, all of which cause water and salt retention in the body. As a result, patients will present clinically as the main symptoms: dyspnea and peripheral edema caused by fluid redistribution to the lungs and/or by fluid overload. By studying these pathophysiological mechanisms, biomarkers with a prognostic and therapeutic role in the management of edema were identified in patients with HF with low ejection fraction. This review aims to summarize the current data from the specialty literature of such biomarkers with a role in the pathogenesis of edema in HF with low ejection fraction. These biomarkers may be the basis for risk stratification and the development of new therapeutic means in the treatment of edema in these patients.

Benefits of SGLT2i for the Treatment of Heart Failure Irrespective of Diabetes Diagnosis: A State-of-the-Art Review.

Morbidity and mortality associated with heart failure (HF) has remained high despite advances in therapy. Furthermore, HF-associated risk in patients with type 2 diabetes mellitus (T2D) is even higher than in patients without T2D owing to the strong reciprocal relationship between conditions. However, until recently, no therapy to treat patients with diabetes also reduced cardiovascular risks related to HF. Recent clinical studies (DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved, SOLOIST-WHF trial) and meta-analysis have demonstrated that sodium–glucose cotransporter-2 inhibitors (SGLT2i) are among the first antidiabetic drugs capable of reducing cardiovascular risks related to HF and improving the prognosis of patients with and without diabetes. Their pleiotropic mechanisms of action place them at the intersection of hemodynamic, metabolic, and neurohumoral pathways, with clear advantages for treating these patients independent of its glucose-lowering effect. Moreover, the benefits of SGLT2i were consistent across the cardiorenal continuum in different populations and clinical settings, which has led to different guidelines introducing SGLT2i as a first-line treatment for HF.

PROGNOSTIC SIGNIFICANCE OF RISK FACTORS AND BIOMARKERS IN PATIENTS HOSPITALIZED FOR CARDIORENAL SYNDROMES

Objective: Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, is an entity characterized by high morbidity and mortality. Our study aimed to evaluate the prognostic role of risk factors and biomarkers in patients ospitalised for CRS. Design and method: In this observational cohort study, 100 consecutive patients ospitalised for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers was measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. Results: Patients were classified into two groups; Group 1 (N = 52): discharged being dialysis-independent, Group 2 (N = 48): death/dialysis dependence at discharge. No significant differences were detected in baseline characteristics between the two groups. Group 2 patients used ospit-angiotensin-aldosterone system blockers (RAASb) less often (Group 1: 71.2% vs. Group 2: 41.7%, p = .003) and more frequently presented with oliguria/anuria (Group 1: 28.8% vs. Group 2: 66.7%, p &lt; .001). Group 2 patients had significantly lower hemoglobin, serum albumin, and 25-hydroxy-vitamin D [25(OH)D] (Figure). At the same time, serum phosphate, potassium, N-terminal-pro hormone brain natriuretic peptide, and parathyroid hormone (PTH) were significantly higher in Group 2 patients (Figure). In a multivariate regression analysis, lack of prior RAASb (Odds ratio: 22.0, 95% confidence interval: 2.7–179.5, p = .004) and lower 25(OH)D levels (Odds ratio: 0.90, 95% confidence interval: 0.82–0.99, p = .03) were independently associated with an increased risk of death or dialysis dependence at discharge. 25(OH)D/PTH ratio was the most accurate predictor of the composite endpoint (area under receiver operating characteristics curve: 0.81), with a cutoff of equal or less than 97.9 having a sensitivity and specificity of 79.4% and 70.4%, respectively. Conclusions: Lack of prior RAASb use, high PTH, low 25(OH)D levels, and low 25(OH)D/PTH ratio are associated with a poor prognosis in patients ospitalised for CRS.

Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis—two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD.

Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities.

In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.

ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ.

ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium–calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII.

The Links of Ghrelin to Incretins, Insulin, Glucagon, and Leptin After Bariatric Surgery.

Type 2 diabetes mellitus (T2DM) is one of the most prominent and socially significant problems. The present study aimed to identify the mechanisms of interaction of critical regulators of carbohydrate metabolism using bioinformatics and experimental methods and to assess their influence on the development of T2DM. We conducted an in silico search for the relationship of hormones and adipokines and performed functional annotation of the receptors for ghrelin and incretins. Hormones and adipokines were assessed in the plasma of obese patients with and without T2DM as well as after laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) surgeries. Incretin- and ghrelin-associated functions and metabolic processes were discovered. Low ghrelin levels were observed in obese patients without T2DM compared with healthy volunteers and the other groups. The highest ghrelin levels were observed in obese patients with T2DM. This defense mechanism against insulin resistance could be realized through the receptors G-protein-coupled receptor (GPCR), growth hormone secretagogue receptor (GHSR), and growth hormone-releasing hormone receptor (GHRHR). These receptors are associated with proliferative, inflammatory, and neurohumoral signaling pathways and regulate responses to nutrient intake. Signaling through the GPCR class unites ghrelin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide (GLP)-1. Ghrelin impairs carbohydrate and lipid metabolism in obese patients. Ghrelin is associated with elevated plasma levels of insulin, glucagon, and leptin. Specific activation of receptors and modulation by posttranslational modifications of ghrelin can control IR’s development in obesity, which is a promising area for research.

Epidemiology, Pathophysiology, Diagnosis and Treatment of Heart Failure in Diabetes.

The cardiovascular disease continuum begins with risk factors such as diabetes mellitus (DM), progresses to vasculopathy and myocardial dysfunction, and finally ends with cardiovascular death. Diabetes is associated with a 2- to 4-fold increased risk for heart failure (HF). Moreover, HF patients with DM have a worse prognosis than those without DM. Diabetes can cause myocardial ischemia via micro- and macrovasculopathy and can directly exert deleterious effects on the myocardium. Hyperglycemia, hyperinsulinemia, and insulin resistance can cause alterations in vascular homeostasis. Then, reduced nitric oxide and increased reactive oxygen species levels favor inflammation leading to atherothrombotic progression and myocardial dysfunction. The classification, diagnosis, and treatment of HF for a patient with and without DM remain the same. Until now, drugs targeting neurohumoral and metabolic pathways improved mortality and morbidity in HF with reduced ejection fraction (HFrEF). Therefore, all HFrEF patients should receive guideline-directed medical therapy. By contrast, drugs modulating neurohumoral activity did not improve survival in HF with preserved ejection fraction (HFpEF) patients. Trials investigating whether sodium-glucose cotransporter-2 inhibitors are effective in HFpEF are on-going. This review will summarize the epidemiology, pathophysiology, and treatment of HF in diabetes.

Cholinergic receptors play a role in the cardioprotective effects of anesthetic preconditioning: Roles of nitric oxide and the CaMKKβ/AMPK pathway.

Vagus nerve activation may have important therapeutic significance for myocardial ischemia-reperfusion (IR) injury. Nitric oxide (NO) plays a vital role in the cardioprotective effects of anesthetic preconditioning (APC). Moreover, acetylcholine (ACh) prevents cardiomyocyte damage by activating AMP-activated protein kinase (AMPK) and increasing the phosphorylation of Ca2+/calmodulin-dependent protein kinase β (CaMKKβ). The aim of the present study was to determine whether APC could protect heart function by antagonizing IR damage via the cholinergic system. It was hypothesized that the NO synthase (NOS)/CaMKKβ/AMPK pathway might be involved in the cardioprotective effects induced by cholinergic receptor activation. Isolated rat hearts were subjected to ischemia for 30 min followed by 120 min of reperfusion. Volatile anesthetic sevoflurane (3.5%) was administered for 15 min before ischemia, then rinsed for 15 min. The muscarinic acetylcholine receptor (mAChR) antagonist atropine (ATR; 100 nM) and the nicotinic acetylcholine receptor (nAChR) antagonist hexamethonium (HEM; 50 µM) were administered 10 min before APC. Both mAChR and nAChR were involved in APC-induced cardioprotection. ATR and HEM treatment both abolished the protective effects of APC on IR damage in isolated hearts, demonstrating the importance of cholinergic receptors in the protection mechanism of APC. The present study thus suggests that APC plays a cardioprotective role, in part, by regulating neurohumoral pathways. In addition, there may be functional coupling between the two cholinergic receptors, and the NOS and CaMKKβ/AMPK pathways may play roles in shared pathways that mediate the cardioprotective effects of APC. These findings may provide insight into potential new mechanisms of APC-induced cardioprotection against IR injury.

Cardiac fibrosis.

Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.