The prognostic value of hypoxia biomarkers in older patients with chronic heart failure

Chronic kidney disease (CKD) worsens the prognosis of chronic heart failure (CHF). Hypoxia is the leading link in pathogenesis, especially in older patients with comorbidity. The aim of this study was to investigate the prognostic value of biomarkers of myocardial, renal dysfunction and hypoxia in older patients with CHF. Materials and methods 80 older hypertensive patients with CHF (48 females, mean age 70.7±8.7 years) were examined. CHF was defined according to ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, 2016. CKD was diagnosed and classified according to the KDIGO guidelines (2012). Serum levels of hypoxia-inducible factor 1-alpha (HIF-1α), endogenous erythropoietin (eEPO), N-terminal propeptide of type B natriuretic hormone (NT-proBNP), cystatin C were assessed. The follow-up period was 12 months; the primary endpoint was total mortality. Results CKD was diagnosed in 49 (61.3%) older patients with CHF. The HIF-1α level was significantly higher in the group of deceased patients than in the survivors (0.08 (IQR 0.06; 0.11) and 0.05 (IQR 0.04; 0.07) ng/ml, p=0.02), as well as the level of NT-proBNP (1126.3 (IQR 551.8; 2750.0) and 164.4 (IQR 135.5; 1100.9) pg/ml, p<0.0001), eEPO (16.92 (ICR 5.43; 64.57) and 5.36 (IQR 1.65; 8.85) mIU/ml, p<0.0001), cystatin C (1.49 (ICR 0.86; 2.13) and 0.99 (IQR 0.82; 1.32) Mg/l, p=0.0005). Cox regression analysis adjusted for sex, age and comorbidity (χ2=36.8, p<0.0001) showed that endogenous erythropoietin, independently of other factors and biomarkers, determined the prognosis of annual mortality in patients with chronic heart failure (HR 3.27 (95% CI 1.08–9.91, p=0.03); χ2=30.7, p=0.0002). When constructing classification trees, in older patients with CHF in the presence of eEPO less than 16.19 mIU/ml NT-proBNP more than 232.5 pg/ml is an unfavorable factor (in patients with NT-proBNP <232.5 pg/ml the risk decreased to 0) (for model: sensitivity – 57.1%; specificity – 92.3% (AUC=0.87); p=0.0015). Conclusions The level of eEPO in older patients with CHF has an independent and closer relationship with the annual mortality of patients than the NT-proBNP – currently accepted biomarker of the severity and prognosis of CHF. FUNDunding Acknowledgement Type of funding sources: None.

Possibilities of predicting the risk of cardiorenal syndrome in patients with chronic kidney disease on the background of congenital malformations of the urinary system

BACKGROUND. Currently, there is no doubt that there is a close relationship between the condition of the kidneys and the cardiovascular system. Neurohormonal systems various parts long-term hyperactivation is important in the development of pathological processes. Natriuretic peptides provide cardio and renoprotective effects, inhibit the activity of the renin-angiotensin-aldosterone system (RAAS). AIM. To establish the prognostic significance of determining the concentration of natriuretic peptides in comparison with the activity of RAAS in children with congenital malformations of the urinary system to assess the risk of cardiovascular complications.PATIENTS AND METHODS. 76 patients with congenital malformations OUS aged 3 to 18 years were examined: – 40 children with congenital vesicoureteral reflux, – 18 children with hydronephrosis, 18 children with other forms of OUS dysembryogenesis ( 10 patients with renal agenesis, 8-with hypoplasia). The control group consisted of 10 clinically healthy children of the appropriate age. The following parameters were determined in the blood by the enzyme immunoassay: renin, aldosterone, n-terminal propeptide of natriuretic hormone (NТ-рroВNР).RESULTS. Hyperproduction of NТ-рroВNР was observed in 61.8 % of patients, stimulation of renin and/or aldosterone production in 39.5 % of cases. Elevated levels of natriuretic peptides were found in 32.8 % of cases in 25 children with congenital OUS defects without signs of arterial hypertension (AH) and left ventricular hypertrophy (LVH). Significantly higher concentrations of (NТ-рroВNР), renin, and aldosterone are recorded in patients with AH and LVH.CONCLUSION. The increased level of natriuretic peptides is noted earlier than the clinical and instrumental signs of heart dysfunction are noticeable, it is important in identifying early stages of cardiovascular complications, evaluating the prognosis, and in justifying renoprotective treatment in pediatric Nephrology practice.

Prediction role of a novel biomarker ST2 in risk assessment of adverse cardiovascular events in chronic heart failure with preserved and intermediate ejection fraction after myocardial revascularization

Aim. To evaluate prediction role of the biomarkers soluble ST2 (sST2) and natriuretic hormone N-terminal propeptide (NT-proBNP) in risk assessment of adverse cardiovascular events (ACVE) in coronary heart disease patients (CHD) with chronic heart failure (CHF) after myocardial revascularization.Material and methods. Totally, 87 patients included (72 males) with CHD and CHF I-III functional class by NYHA with ejection fraction of the left ventricle (LVEF) 63 [55; 65]%, mean age 63 [57; 69] y.o. Levels of sST2 and NT-proBNP in plasma were measured by immune enzyme assay before myocardial revascularization.Results. In 12 months of prospective follow-up, patients were selected to 2 groups according to clinical course of CHF. To the group I the patients included (n=35) with ACVE, group II (b=52) — with none. It was found that in the group I the level of sST2 was higher by 41,5% (p<0,001) and reached 46,78 [37,88; 64,96] ng/mL, and in the group II — 27,39 [23,02; 35,4] ng/mL. Concentration of NT-proBNP in the group with ACVE was 2,5 times (p=0,004) higher comparing with group II and reached 189,21 [74,46; 580,79] and 73,58 [26,64; 155,77] pg/mL, respectively. In ROC-analysis it was found that the level of sST2 ≥34,18 ng/mL (sensitivity — 90,6%, specificity — 75,0%, AUC — 0,88, р<0,0001) and level of NT-proBNP ≥276,96 pg/mL (sensitivity — 88,4%, specificity — 43,7%, AUC — 0,64, р<0,004) can be regarded as markers of ACVE during 12 months in CHD and CHF patients after revascularization. Also, together these two markers increase predictive significance of the analysis (sensitivity — 92,6%, specificity — 77,1%, AUC — 0,90, р<0,0001).Conclusion. Therefore, the preprocedural level of sST2 can be regarded as non-invasive marker for prediction of ACVE. Combination of sST2 and NT-proBNP shows higher diagnostic sensitvity and specificity for prediction of adverse CHF course.

NATRIURETIC PEPTIDES LEVEL AND THE STATUS OF THE RENIN – ANGIOTENSIN-ALDOSTERONE SYSTEM IN CHRONIC KIDNEY DISEASE IN PATIENTS WITH CONGENITAL MALFORMATIONS OF THE URINARY SYSTEM

THE AIM. To determine the concentration of natriuretic peptide in the blood serum in children with congenital malformations of the urinary system (CM US) and to compare with the activity of renin-angiotensin-aldosterone system (RAAS).MATERIALS AND METHODS.119 patients with CM US aged 3 to 18 years were examined. A control group of 10 clinically healthy children. 3 groups were assigned: group I – 55 children with congenital vesicoureteral reflux, and group II – 34 children with congenital hydronephrosis and ureterohydronephrosis, III group – 30 children with other forms of dysembryogenesis of the US. Following indicators were identified by ELISA in the blood: renin, aldosterone, N – terminal propeptide natriuretic hormone (NT-рroВNР). RESULTS.NT-рroВNР, renin and aldosterone hyperproduction were diagnosed in 59,6%, 69,7%, 54.6 % of sick children relatively. Concentrations were higher in all variants of malformations in comparison with the control group. Significant differences were revealed in obstructive species, where arterial hypertension (AH) was diagnosed more often. Patients with AH recorded significantly higher concentrations of NT-proВNР and renin.CONCLUSION.The key point in pathological processes developmentand progression in the cardiovascular system and kidneys is the activation of RAAS. The system of natriuretic factors is important in maintaining the compensated state of patients due to the blockade of RAAS.

Role of endogenous digitalis-like factors in the clinical manifestations of severe preeclampsia: a systematic review

Endogenous digitalis-like factor(s), originally proposed as a vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it cross-reacts with antidigoxin antibodies (ADAs). Early studies using immunoassays with ADA identified the digoxin-like immuno-reactive factor(s) (EDLF) in maternal blood as well, and suggested it originated in the feto–placental unit. Mammalian digoxin-like factors have recently been identified as at least two classes of steroid compounds, plant derived ouabain (O), and several toad derived bufodienolides, most prominent being marinobufagenin (MBG). A synthetic pathway for MBG has been identified in mammalian placental tissue. Elevated maternal and fetal EDLF, O and MBG have been demonstrated in preeclampsia (PE), and inhibition of red cell membrane sodium, potassium ATPase (Na, K ATPase (NKA)) by EDLF is reversed by ADA fragments (ADA-FAB). Accordingly, maternal administration of a commercial ADA-antibody fragment (FAB) was tested in several anecdotal cases of PE, and two, small randomized, prospective, double-blind clinical trials. In the first randomized trial, ADA-FAB was administered post-partum, in the second antepartum. In the post-partum trial, ADA-FAB reduced use of antihypertensive drugs. In the second trial, there was no effect of ADA-FAB on blood pressure, but the fall in maternal creatinine clearance (CrCl) was prevented. In a secondary analysis using the pre-treatment maternal level of circulating Na, K ATPase (NKA) inhibitory activity (NKAI), ADA-FAB reduced the incidence of pulmonary edema and, unexpectedly, that of severe neonatal intraventricular hemorrhage (IVH). The fall in CrCl in patients given placebo was proportional to the circulating level of NKAI. The implications of these findings on the pathophysiology of the clinical manifestations PE are discussed, and a new model of the respective roles of placenta derived anti-angiogenic (AAG) factors (AAGFs) and EDLF is proposed.

The pump, the exchanger, and the holy spirit: origins and 40-year evolution of ideas about the ouabain-Na+pump endocrine system

Two prescient 1953 publications set the stage for the elucidation of a novel endocrine system: Schatzmann’s report that cardiotonic steroids (CTSs) are all Na+pump inhibitors, and Szent-Gyorgi’s suggestion that there is an endogenous “missing screw” in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na+pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na+pumps and salt reabsorption. The hormone also inhibits arterial Na+pumps, elevates myocyte Na+and promotes Na/Ca exchanger-mediated Ca2+gain. This enhances vasoconstriction and arterial tone—the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na+pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1) cloning the Na+pump isoforms and physiological studies of mutated pumps in mice; 2) discovery that Na+pumps are also EO-triggered signaling molecules; 3) demonstration that ouabain, but not digoxin, is hypertensinogenic; 4) elucidation of EO’s roles in kidney development and cardiovascular and renal physiology and pathophysiology; 5) discovery of “brain ouabain”, a component of a novel hypothalamic neuromodulatory pathway; and 6) finding that EO and its brain receptors modulate behavior and learning.

Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis

The natriuretic hormone CCK exhibits its gene transcripts in total kidney extracts. To test the possibility of CCK acting as an intrarenal mediator of sodium excretion, we examined mouse kidneys by 1) an in situ hybridization technique for CCK mRNA in animals fed a normal- or a high-sodium diet; 2) immuno-electron microscopy for the CCK peptide, 3) an in situ hybridization method and immunohistochemistry for the CCK-specific receptor CCKAR; 4) confocal image analysis of receptor-mediated Ca2+ responses in isolated renal tubules; and 5) metabolic cage experiments for the measurement of urinary sodium excretion in high-salt-fed mice either treated or untreated with the CCKAR antagonist lorglumide. Results showed the CCK gene to be expressed intensely in the inner medulla and moderately in the inner stripe of the outer medulla, with the expression in the latter being enhanced by high sodium intake. Immunoreactivity for the CCK peptide was localized to the rough endoplasmic reticulum of the medullary interstitial cells in corresponding renal regions, confirming it to be a secretory protein. Gene transcripts, protein products, and the functional activity for CCKAR were consistently localized to the late proximal tubule segments (S2 and S3) in the medullary rays, and the outer stripe of the outer medulla. Lorglumide significantly diminished natriuretic responses of mice to a dietary sodium load without altering the glomerular filtration rate. These findings suggest that the medullary interstitial cells respond to body fluid expansion by CCK release for feedback regulation of the late proximal tubular reabsorption.

Cardiotonic steroids: main effects, therapeutic applications

For last few decades 'putative natriuretic hormone' have been considered as very important therapeutic target for developing novel therapies for cardiovascular diseases. The present review discusses the pathophysiological role of endogenous cardiotonic steroids with main focus on marinobufagenin (MBG). Recent studies has established that MBG plays a vital role in regulation of electrolyte homeostasis in humans and rodents. Additionally, it has been reported that elevated MBG plasma levels are associated with number of pathological states such as arterial hypertension, chronic kidney disease, preeclampsia and heart failure. It has been demonstrated that MBG-Na/K-ATPase interaction in kidneys regulates renal sodium excretion inducing natriuresis. Further, it has been reported that MBG-Na/K-ATPase interaction in vascular smooth muscle cells could induce vasoconstriction and cardiovascular fibrosis. Thus these facts have established MBG as a potential therapeutic target. Several therapies such as immunoneutralization of MBG with specific monoclonal antibodies and antagonism with aldosterone antagonists have already been proposed. Further studies providing understanding of pathophysiological implications of MBG and signaling pathways could contribute in establishing new therapies for cardiovascular diseases.