Neurohumoral Pathways Research Articles

The Effect of Emergency Department Visits and Inflammatory Markers on One-Year Mortality in Patients with Heart Failure.

The neurohumoral and inflammatory pathways proposed for the development and progression of heart failure (HF) remain up-to-date. We aimed to investigate the effect of emergency department (ED) visits and inflammatory markers on mortality in HF patients. Two-hundred patients with stable chronic HF followed by the cardiology clinic were included in this study. The patients were divided into two groups as patients who had visited the ED due to worsening HF symptoms within the last 6 months (ED visit Group) and who had not (No ED visit Group). The demographical properties, clinical characteristics, and laboratory values including inflammatory markers of the patients were recorded. During the follow-up period, 38 patients (19%) died. In HF patients with previous ED visits, the mortality risk was 2.091 times higher (relative risk, RR). It was identified that the HF patients who died during the follow-up had higher initial NLR (p = 0.004), IG% (p = 0.029), hs-CRP (p = 0.001), and NT-proBNP (p = 0.004) values. It was observed that the area under the curve (AUC) values, NLR (AUC: 0.705, p < 0.001), IG% (AUC: 0.652, p = 0.003), and hs-CRP (AUC: 0.732, p < 0.001) were very strong predictors of the 1-year mortality. According to the cut-off points, the mortality risk (RR) was 3.39 times higher in patients with NLR > 3.7 (95% CI 1.783-6.444), 2.39 times higher when IG% > 0.4 (95% CI 1.16-4.957), and 4,2 times higher when hs-CRP > 9.9mg/dl (95% CI 2.16-8.16) (p < 0.05). The patients with chronic stable HF who visited the ED within the last six months and having increased NLR, IG%, and CRP levels among inflammatory markers were associated with a higher mortality risk at 1year.

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers.

Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.

Range of adiposity and cardiorenal syndrome.

Obesity and obesity-related co-morbidities, diabetes mellitus, and hypertension are among the fastest-growing risk factors of heart failure and kidney disease worldwide. Obesity, which is not a unitary concept, or a static process, ranges from alterations in distribution to the amount of adiposity. Visceral adiposity, which includes intraabdominal visceral fat mass and ectopic fat deposition such as hepatic, cardiac, or renal, was robustly associated with a greater risk for cardiorenal morbidity than subcutaneous adiposity. In addition, morbid obesity has also demonstrated a negative effect on cardiac and renal functioning. The mechanisms by which adipose tissue is linked with the cardiorenal syndrome (CRS) are hemodynamic and mechanical changes, as well neurohumoral pathways such as insulin resistance, endothelial dysfunction, nitric oxide bioavailability, renin-angiotensin-aldosterone, oxidative stress, sympathetic nervous systems, natriuretic peptides, adipokines and inflammation. Adiposity and other associated co-morbidities induce adverse cardiac remodeling and interstitial fibrosis. Heart failure with preserved ejection fraction has been associated with obesity-related functional and structural abnormalities. Obesity might also impair kidney function through hyperfiltration, increased glomerular capillary wall tension, and podocyte dysfunction, which leads to tubulointerstitial fibrosis and loss of nephrons and, finally, chronic kidney disease. The development of new treatments with renal and cardiac effects in the context of type 2 diabetes, which improves mortality outcome, has highlighted the importance of CRS and its prevalence. Increased body fat triggers cellular, neuro-humoral and metabolic pathways, which create a phenotype of the CRS with specific cellular and biochemical biomarkers. Obesity has become a single cardiorenal umbrella or type of cardiorenal metabolic syndrome. This review article provides a clinical overview of the available data on the relationship between a range of adiposity and CRS, the support for obesity as a single cardiorenal umbrella, and the most relevant studies on the recent therapeutic approaches.

Role of Leptin in Cardiovascular Diseases.

The adipocyte-derived adipokine leptin exerts pleiotropic effects, which are essential for the regulation of energy balance and cell metabolism, for controlling inflammatory and immune responses, and for the maintenance of homeostasis of the cardiovascular system. Leptin resistance in obese or type 2 diabetes mellitus (T2DM) patients is defined as a decrease in tissue response to leptin. In the cardiovascular system, leptin resistance exhibits the adverse effect on the heart's response to stress conditions and promoting cardiac remodeling due to impaired cardiac metabolism, increased fibrosis, vascular dysfunction, and enhanced inflammation. Leptin resistance or leptin signaling deficiency results in the risk increase of cardiac dysfunction and heart failure, which is a leading cause of obesity- and T2DM-related morbidity and mortality. Animal studies using leptin- and leptin receptor- (Lepr) deficient rodents have provided many useful insights into the underlying molecular and pathophysiological mechanisms of obese- and T2DM-associated metabolic and cardiovascular diseases. However, none of the animal models used so far can fully recapitulate the phenotypes of patients with obese or T2DM. Therefore, the role of leptin in the human cardiovascular system, and whether leptin affects cardiac function directly or acts through a leptin-regulated neurohumoral pathway, remain elusive. As the prevalence of obesity and diabetes is continuously increasing, strategies are needed to develop and apply human cell-based models to better understand the precise role of leptin directly in different cardiac cell types and to overcome the existing translational barriers. The purpose of this review is to discuss the mechanisms associated with leptin signaling deficiency or leptin resistance in the development of metabolic and cardiovascular diseases. We analyzed and comprehensively addressed substantial findings in pathophysiological mechanisms in commonly used leptin- or Lepr-deficient rodent models and highlighted the differences between rodents and humans. This may open up new strategies to develop directly and reliably applicable models, which resemble the human pathophysiology in order to advance health care management of obesity- and T2DM-related cardiovascular complications.

A MULTI-MARKER MODEL FOR PREDICTING DECOMPENSATED HEART FAILURE IN PATIENTS WITH PRIOR ACUTE MYOCARDIAL INFARCTION

The aim of the study was to assess the prognostic value of determining the plasma concentration of NT-proBNP and ST2 in the patients with decompensated HF and prior acute myocardial infarction and their combination in this category of patients. Materials and methods. There were examined 120 patients with acute myocardial infarction and stage II A-B decompensated chronic HF according to the classification proposed by Vasylenko V. Kh. and Strazhesko M.D., NYHA functional class (FC) III-IV. The patients with Q-QS wave MI (60 individuals) and non Q MI (60 individuals) were divided into 4 groups depending on the treatment methods. Study groups were homogenous by age, gender, disease severity, duration of the post-infarction period, clinical signs of decompensation, which served as a basis for inclusion of the patients in the study. All the patients underwent the six-minute walk test in a quiet 30-50-m long hospital corridor in the morning. N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) and ST-2 were analyzed in all patients. Results. Promising biomarkers of HF decompensation in the post-infarction period were studied. In the patients with prior Q-QS MI and decompensated HF, NT-proBNP level was (950.38±3.15) pmol/l (p&lt;0.05); in the patients with prior MI without signs of decompensated HF, it was (580.15±3.03) pmol/l (p˂0.05); in apparently healthy individuals, the level of NT-proBNP was found to be (111.20±3.47) pmol/l. ST2 level was (14.80±1.61) ng/ml, (36.00±1.43) ng/ml and (49.22±1.40) ng/ml in the patients of Group 1, Group 2 and Group 3, respectively (p˂0.05). Similar changes were found in patients with decompensated HF in postinfarction period after non Q MI. Conclusions. The increase in plasma concentration of sST2 is associated with the activation of both neurohumoral and fibrous pathways and can help in detecting the patients with decompensated HF in the post-infarction period and predicting the risk of its development. Our results confirmed the results of other multiple studies reporting ST2 in combination with NT-proBNP to be valuable tools for prognosing the development of decompensated HF in the patients with prior MI. ST2, alongside with NT-proBNP, is a promising biomarker to be included in the diagnostic panel for detecting acute HF and can provide additional information on risk stratification for such patients during hospitalization and at the time of discharge from the hospital.

The Role of Nicotinic Anti-Inflammatory Pathway in Prostaglandin Mediated Inflammatory Response in Sepsis: A Short Review

Sepsis is a severe and multifaceted condition of body in response to an infection, which affects multiple organs systems that makes it difficult to treat and enhances the mortality rates. Release of inflammatory cytokines can initiate an inflammatory response during sepsis. However, the response can be modified by the control mechanism inside the body that are essential for the keeping the balance and survival. The cholinergic anti-inflammatory pathway is defined as a comprehensive neurohumoral pathway that diminishes pro-inflammatory cytokine release through the vagus nerve and cholinergic receptors, predominantly α7 nicotinic acetylcholine receptors (α7nAChR) that expressed on inflammatory mononuclear cells. Thus, cholinergic agonists might be a part of prospective treatment approach in inflammatory diseases such as sepsis. This review covers the role of cholinergic system in prostaglandin mediated inflammatory response.

Phenotyping progression of secondary mitral regurgitation in chronic systolic heart failure.

BackgroundSecondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR.MethodsA total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow‐up.ResultsOf 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR‐proADM (adj.OR 2.25, 95% CI 1.29‐3.93; P = .004), MR‐proANP (adj.OR 1.84, 95% CI 1.14‐3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04‐2.67; P = .035) and CT‐pro‐ET1 (adj.OR 1.68, 95% CI 1.06‐2.68; P = .027) but not with NT‐proBNP (P = .54).ConclusionIncreased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT‐proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR‐proANP, primarily produced in the atria, copeptin partly triggered by intra‐cardiac and intra‐arterial pressures and MR‐proADM, a marker of forward failure and peripheral released vasoactive CT‐proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.

Neurohumoral Pathway in Heart Failure

Heart Failure is now considered as one of the leading cause for mortality and morbidity. It is affecting several organs and cause organ damages due to the myocardial failure to pump inadequate oxygenated blood to the body including metabolites, to end organs and peripheral tissues. Heart failure results from multifactorial mechanism including neurohumoral activations including increased activity of the sympathetic nervous system, renin-angiotensin aldosteron system, vasopression and the atrial natriuretic peptide. This neurohumoral pathway has significant contribution to the development of myocardial dysfunction that lead to clinical manifestation of heart failure. Some of the markers in these pathways have now been considered as an independent predictors of prognosis in heart failure patient.

Abstract 082: Intrarenal Nacl Boli Cause Longlasting Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long-lasting tonic sympatho-inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro-humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho-depressory mechanism. Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) &amp; heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec superperfusion to 4.5 % NaCl or equiosmotic mannitol. solution Results are given in mean±SEM. IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p&lt;0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p&lt;0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1-blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p&lt;0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p&lt;0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p&lt;0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (-10708.8±3546.5 pA*, from baseline, p&lt;0.05). No responses to equiosmolar mannitol. Increased intrarenal sodium concentrations might induce long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho-depressory mechanism could be involved in salt sensitive hypertension.

Experimental Spinal Cord Injury Causes Left-Ventricular Atrophy and Is Associated with an Upregulation of Proteolytic Pathways.

Spinal cord injury (SCI) causes autonomic dysfunction, altered neurohumoral control, profound hemodynamic changes, and an increased risk of heart disease. In this prospective study, we investigated the cardiac consequences of chronic experimental SCI in rats by combining cutting edge in vivo techniques (magnetic resonance imaging [MRI] and left-ventricular [LV] pressure-volume catheterization) with histological and molecular assessments. Twelve weeks post-SCI, MRI-derived structural indices and in vivo LV catheterization-derived functional indices indicated the presence of LV atrophy (LV mass in Control vs. SCI = 525 ± 38.8 vs. 413 ± 28.6 mg, respectively; p = 0.0009), reduced ventricular volumes (left-ventricular end-diastolic volume in Control vs. SCI = 364 ± 44 vs. 221 ± 35 μL, respectively; p = 0.0004), and contractile dysfunction (end-systolic pressure-volume relationship in Control vs. SCI = 1.31 ± 0.31 vs. 0.76 ± 0.11 mm Hg/μL, respectively; p = 0.0045). Cardiac atrophy and contractile dysfunction in SCI were accompanied by significantly lower blood pressure, reduced circulatory norepinephrine, and increased angiotensin II. At the cellular level, we found the presence of reduced cardiomyocyte size and increased expression of angiotensin II type 1 receptors and transforming growth factor-beta receptors (TGF-β receptor 1 and 2) post-SCI. Importantly, we found more than a two-fold increase in muscle ring finger-1 and Beclin-1 protein level following SCI, indicating the upregulation of the ubiquitin-proteasome system and autophagy-lysosomal machinery. Our data provide novel evidence that SCI-induced cardiomyocyte atrophy and systolic cardiac dysfunction are accompanied by an upregulation of proteolytic pathways, the activation of which is likely due to loss of trophic support from the sympathetic nervous system, neuromechanical unloading, and altered neurohumoral pathways.

Intrarenal High Salt Administration Causes Tonic Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long‐lasting tonic sympatho‐inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro‐humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho‐depressory mechanism.Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) &amp; heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10–7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10–3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec exposure to 4.5 % NaCl or equi‐osmotic 20% mannitol. Results are given in mean±SEM.IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p&lt;0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p&lt;0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1‐blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p&lt;0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p&lt;0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p&lt;0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (−10708.8±3546.5 pA*, from baseline, p&lt;0.05). No responses to mannitol 20%.Increased intrarenal sodium concentrations might induce long‐lasting sympatho‐depression via a neuro‐humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho‐depressory mechanism could be involved in salt sensitive hypertension.Support or Funding InformationDFG Deutsche Forschungsgemeinschaft VE 104/4‐1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evolution of secondary mitral regurgitation.

Secondary mitral regurgitation (MR) drives adverse remodelling towards late heart failure stages. Little is known about the evolution of MR under guideline-directed therapy (GDT) and its relation to cardiac remodelling and outcome. We therefore aimed to assess incidence, impact, and predictors of progressive secondary MR in patients under GDT. We prospectively enrolled 249 patients with chronic heart failure and reduced ejection fraction receiving GDT in this long-term observational study. Of patients with non-severe MR at baseline 81% remained stable whereas 19% had progressive MR. Those patients were more symptomatic (P < 0.001), had higher neurohumoral activation (encompassing various neurohumoral pathways in heart failure, all P < 0.05), larger left atrial size (P = 0.004) and more tricuspid regurgitation (TR, P = 0.02). During a median follow-up of 61 months (IQR 50-72), 61 patients died. Progression of MR conveyed an increased risk of mortality-univariately (HR 2.33; 95% CI 1.34-4.08; P = 0.003), that persisted after multivariate adjustment using a bootstrap-selected confounder model (adjusted HR 2.48; 95% CI 1.40-4.39; P = 0.002). In contrast, regression of MR was not associated with a beneficiary effect on outcome (crude HR 0.84; 95% CI 0.30-2.30; P = 0.73). Every fifth patient with chronic heart failure suffers from MR progression. This entity is associated with a more than two-fold increased risk of death even after careful multivariable adjustment. Symptomatic status, left atrial size, TR, and neurohumoral pathways help to identify patients at risk for progressive secondary MR in an early disease process and open the possibility for closer follow-up and timely intervention.

Acupuncture and Cardiovascular Disease: Focus on Heart Failure.

Symptomatic heart failure is managed with interdisciplinary approaches to reduce acute exacerbations and to improve mortality. Acupuncture is a standardized treatment of Traditional Chinese Medicine that has been shown to have beneficial effects on the cardiovascular system via a neurohumoral pathway known as the long-loop pathway. This article serves to examine recent evidence supporting the long-loop pathway as the physiologic mechanism of acupuncture and the sympatholytic, vasodilatory, and cardioprotective effects of acupuncture that could specifically improve cardiac function and quality of life measures in the management of congestive heart failure.

Prohormones in the Early Diagnosis of Cardiac Syncope.

BackgroundThe early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional–pro‐A‐type natriuretic peptide (MRproANP), C‐terminal proendothelin 1, copeptin, and midregional‐proadrenomedullin.Methods and ResultsWe prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1‐year follow‐up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C‐terminal proendothelin 1, copeptin, and midregional‐proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P<0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76–0.84), 0.69 (95% CI, 0.64–0.74), 0.58 (95% CI, 0.52–0.63), and 0.68 (95% CI, 0.63–0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82–0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87–0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of <77 pmol/L and an ED probability of <20% had a sensitivity and a negative predictive value of 99%.ConclusionsThe use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01548352.

Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond.

This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3-6mmHg) and body weight (∼2-4kg/m2). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubuloglomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.

Impact of HIV infection and antiretroviral treatment on N-terminal prohormone of brain natriuretic peptide as surrogate of myocardial function.

Vasoactive cardiovascular hormones such as the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are produced upon ventricular stretch and play a central role in neurohumoral pathways of the heart regulating cardiovascular remodeling and volume homeostasis. The impact of HIV infection on these neurohumoral pathways of the heart and its potential reversibility by combinations of antiretroviral therapies remain unclear. We assessed serum levels of NT-proBNP in 219 antiretroviral therapy-naïve HIV-infected patients with a normal cardiac and renal status at treatment initiation and after attainment of viremic control. Before antiretroviral therapy, NT-proBNP as a surrogate of myocardial function displayed a significant correlation with absolute CD4 cell count (r = -0.31; P < 0.001) as well as with HIV viral load (r = 0.26; P < 0.001). The median levels of NT-proBNP were 80 pg/ml (36-205) in patients with a CD4 cell count less than 200 cells/μl and 42 pg/ml (20-80; P < 0.001) with a CD4 cell count more than 500 cells/μl. After viremic control, no statistical correlation was present. Higher NT-proBNP levels were observed in treatment-naïve patients with low CD4 cell count and high HIV viral load, indicating a subclinical impact of HIV infection on myocardial function. This association is reversible by the initiation of antiretroviral therapy and subsequent viral suppression.

What constitutes optimal neurohumoral antagonism in chronic heart failure?

### Learning objectives Heart failure (HF) is a major global health problem with more than 23 million people affected worldwide.1 While a range of conditions can lead to the development...

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease.

Reduced smooth muscle (SM)-specific α2 Na+ pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensinII (AngII) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases AngII/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2R/R mice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2R/R mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by AngII and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na+ pump activity and Ca2+ transporter expression and, via Na+ /Ca2+ exchange, Ca2+ homeostasis. This regulates sensitivity to sympathetic activity, Ca2+ signalling and arterial and cardiac contraction.

PHYLOMETABOLIC CORE OF INTESTINAL MICROBIOTA

The authors discuss the theory of human superorganism and its microbiota (microbiome), whose mutualistic interactions is realized within the microbiota – gut – brain axis that includes endocrine, immune and neurohumoral pathways. The newest concepts of microbiome enterotypes and core microbiota are presented, which are important for understanding of the role of symbiotic microorganisms in human vital activities, for explanation of pathophysiology of many chronic human diseases (beyond gastrointestinal disorders), as well as for the search of effective therapeutic targets. As highly promising are considered the functional approaches to studies of microbiota that allowed to formulate the concept of phylometabolic (phylofunctional) core. This is a series of evolutionally stable microorganisms responsible for majority of the main microbiome functions, such as fermentation of polysaccharides (glycans), production of short-chain fatty acids (butyrate, propionate, acetate), hydrogen utilization, production of lactate, metabolism of aminoacids, bile acids, choline, production of vitamins and some biologically active substances – anti-inflammatory, anti-microbial, immunostimulatory. The authors are first to describe the main functional groups of microorganisms of gut microbiota phylometabolic core, providing key metabolic functions, as well as the leading characteristics of the phylometabolic core as such. The perspectives of modification of composition and functions of phylometabolic microbiota core are discussed based on metabiotics as a virtually new class of therapeutic agents. A hypothesis has been proposed that the ratios between main components of the key gut microbiota may reflect fundamental processed related to a mutualistic interactions between microbiota and human body, as well as they may serve as effective biological markers of dysbiotic states determining the development of various pathologic conditions. For example, the ratio between Bacteroides spp. and butyrate producing bacteria that indirectly indicates total numbers of microbial genes can be used both for assessment of chronic inflammation of various localization (starting from inflammatory bowel disease to fat tissue inflammation related to metabolic syndrome), and for control of treatment efficacy.

Why isn't endogenous ouabain more widely accepted?

A new idea is the most quickly acting antigen known to science . —Wilfred Trotter During the past few years, several distinguished senior colleagues who visited our department and inquired about the status of endogenous ouabain (EO) have asked, “How come I didn't know about these [published]