Atrial Natriuretic Peptide Research Articles

Endocrinological disorders in acute kidney injury: an often overlooked field of clinical research.

Acute kidney injury (AKI) is a common comorbidity, affecting approximately one in five hospitalized adults. The kidney is the site for the production, metabolism or excretion of most hormones, including the production of erythropoietin (EPO), the active form of vitamin D, renin, thrombopoietin, and the excretion of insulin, catecholamines, gastrin and many other hormones. Therefore, it is reasonable to say that AKI can have a considerable impact on the endocrine system. Although the effects of AKI on various parameters, including cardiovascular parameters, serum electrolytes and acid-base disorders, neuro-humoral mechanisms and neurological outcomes have been extensively studied, the endocrinological consequences of AKI are understudied. Thyroid dysfunction, mainly euthyroid sick syndrome, hypo/hyperglycemia, bone mineral disorders, changes in EPO and atrial natriuretic peptide (ANP) levels are commonly found in AKI. EPO, thyroxine and ANP administration have been evaluated as potential tools to prevent or treat AKI with varying success, while the effects of AKI on some key hormones, including cortisol and insulin, have never been studied. Aim of this narrative review is to illustrate what is known and what is not known about the endocrinological outcomes of AKI. Few clinical trials are ongoing: however, there is a clear need for large-scale randomized controlled trials investigating the endocrinological consequences of AKI.

The prognostic role of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio and its relationship with NT-proANP plasma level in systemic sclerosis.

The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio is an echocardiographic estimation of the right ventricle to pulmonary artery (RV/PA) coupling, with a validated prognostic role in different clinical settings. Systemic sclerosis (SSc) patients without evident cardiovascular involvement frequently display subtle RV impairment. The amino-terminal atrial natriuretic peptide (NT-proANP) plasma level relates to SSc disease progression and mortality. We aimed to assess the prognostic value of the TAPSE/sPAP ratio and its relationship with NT-proANP plasma level in SSc patients without overt cardiovascular involvement. We retrospectively analysed 70 SSc consecutive patients, with no clinical evidence of cardiovascular involvement or pulmonary hypertension (PH), and 30 healthy controls (HC) in a retrospective, single-centre study. All SSc patients underwent recurrent clinical and echocardiographic assessments and NT-proANP plasma level was assessed at baseline. SSc-related cardiovascular events and deaths were extracted during a 6-year follow-up. The complete work-up for the diagnosis, treatment and management of PH performed along the 6 years of follow-up referred to the 2015 European Society of Cardiology guidelines. Systemic sclerosis patients showed lower TAPSE/sPAP ratio at baseline compared to HC [SSc median value = 0.71 mm/mmHg, (IQR 0.62-0.88) vs. HC median value = 1.00 mm/mmHg, (IQR 0.96-1.05); p < 0.001]. Multivariable Cox analysis revealed TAPSE/sPAP ratio as an independent predictor for SSc-related cardiovascular events [HR = 3.436 (95% CI 1.577-7.448); p = 0.002] and mortality [HR = 3.653 (95% CI 1.712-8.892); p = 0.014]. The value of TAPSE/sPAP ratio < 0.7 mm/mmHg was identified as an optimal cut-off for predicting adverse outcomes (p < 0.001) by receiver operating characteristic (ROC) analyses. NT-proANP level significantly related to TAPSE/sPAP ratio (r = 0.52, p < 0.001). TAPSE/sPAP ratio combined with NT-proANP showed an overall significant prognostic role in this SSc population, confirmed by Kaplan-Meier analysis (Log rank p < 0.001). The TAPSE/sPAP ratio, as an index of RV/PA coupling, is an affordable predictor of cardiovascular events and mortality in SSc and, combined with NT-proANP level, may improve the clinical phenotyping and prognostic stratification of SSc patients.

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations-higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Māori or Pacifica ethnicity) participating in the original CHALICE study-free of history of heart or renal disease at age 50 years and who consented to further study-will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. The study will commence in 2022 and be completed in 2024. Proving our hypothesis-that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively-opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. PRR1-10.2196/37011.

Isoalantolactone Regulates the Activity of Mitogen-Activated Protein Kinases and Nuclear-Factor Erythroid 2-Related Factor 2 Pathways to Attenue Angiotensin II-Induced Cardiomyocyte Hypertrophy and Oxidative Stress

While isoalantolactone is a sesquiterpene lactone known for its anti-inflammatory and antioxidant activities, its role in cardiac hypertrophy is unknown. This study aimed to explore the role and mechanism of isoalantolactone in cardiomyocyte hypertrophy using angiotensin II-treated H9C2 cells as a model. The Western blot analysis was used to evaluate changes in the cardiac hypertrophy marker proteins atrial natriuretic peptide and brain natriuretic peptide and the activity of nuclear-factor erythroid 2-related factor 2/mitogen-activated protein kinase signaling pathway. Rhodamine-phalloidin staining was used to measure the surface area of cardiomyocytes. Apoptosis and intracellular reactive oxygen species levels were measured by flow cytometry. The results showed that isoalantolactone inhibited angiotensin II-induced H9C2 cell hypertrophy and cardiomyocyte apoptosis and reduced intracellular reactive oxygen species and cytochrome C levels in a dose-dependent manner. Furthermore, isoalantolactone upregulated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and inhibited extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 (a stress-stimulated kinase) activation. Collectively, the findings suggest that isoalantolactone can enhance the antioxidant capacity of H9C2 cells, reduce apoptosis, and inhibit cardiac hypertrophy, and these protective effects may be related to the regulation of nuclear-factor erythroid 2-related factor 2 and mitogen-activated protein kinase pathway activity by isoalantolactone.

Guanylyl cyclase/natriuretic peptide receptor-A: Identification, molecular characterization, and physiological genomics.

The natriuretic peptides (NPs) hormone family, which consists mainly of atrial, brain, and C-type NPs (ANP, BNP, and CNP), play diverse roles in mammalian species, ranging from renal, cardiac, endocrine, neural, and vascular hemodynamics to metabolic regulations, immune responsiveness, and energy distributions. Over the last four decades, new data has transpired regarding the biochemical and molecular compositions, signaling mechanisms, and physiological and pathophysiological functions of NPs and their receptors. NPs are incremented mainly in eliciting natriuretic, diuretic, endocrine, vasodilatory, and neurological activities, along with antiproliferative, antimitogenic, antiinflammatory, and antifibrotic responses. The main locus responsible in the biological and physiological regulatory actions of NPs (ANP and BNP) is the plasma membrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), a member of the growing multi-limbed GC family of receptors. Advances in this field have provided tremendous insights into the critical role of Npr1 (encoding GC-A/NPRA) in the reduction of fluid volume and blood pressure homeostasis, protection against renal and cardiac remodeling, and moderation and mediation of neurological disorders. The generation and use of genetically engineered animals, including gene-targeted (gene-knockout and gene-duplication) and transgenic mutant mouse models has revealed and clarified the varied roles and pleiotropic functions of GC-A/NPRA in vivo in intact animals. This review provides a chronological development of the biochemical, molecular, physiological, and pathophysiological functions of GC-A/NPRA, including signaling pathways, genomics, and gene regulation in both normal and disease states.

S-27-5: DELETION OF AT1A RECEPTORS IN THE PROXIMAL TUBULES AUGMENTS NATRIURETIC RESPONSE TO ATRIAL NATRIURETIC PEPTIDE VIA NPR/CGMP/NO SIGNALING

Objective: The proximal tubules of the kidney play a critical role in maintaining normal body salt and fluid balance and blood pressure homeostasis in part by interactions between two key vasoactive hormone receptors. In the proximal tubules, angiotensin II (Ang II) binds and activate AT1a receptors to stimulate proximal tubule Na+ reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates NPRA receptors to inhibit Ang II-induced proximal tubule Na+ reabsorption. These two vasoactive systems play important counteracting roles in the proximal tubules to control proximal tubule Na+ reabsorption in the kidney and maintain blood pressure homeostasis. However, it is not known whether the hypotensive and natriuretic responses to ANP may be augmented by deletion of AT1 (AT1a) receptors selectively in the proximal tubules of the kidney. Design and Methods: The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors in the kidney, PT-Agtr1a -/-, to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules indeed augments the hypotensive and natriuretic responses to ANP. Four groups (n = 9–12 per group) of adult male wild-type and PT-Agtr1a -/- mice were infused without (served as time controls) or with ANP via osmotic minipump (10 ng/min, i.p.) continuously for 2 weeks. Results: Basal blood pressure was about 16 ± 3 mmHg lower (P &lt; 0.01), fractional proximal tubule Na+ reabsorption was significantly lower (P &lt; 0.05), whereas 24 h urinary Na+ excretion was significantly higher in PT-Agtr1a -/- mice (P &lt; 0.01), compared with age-matched wild-type mice. ANP infusion significantly decreased blood pressure and increased the natriuretic response in PT-Agtr1a -/- mice further by inhibiting proximal tubule Na+ reabsorption, compared with wild-type controls (P &lt; 0.01). The augmented hypotensive and natriuretic responses to ANP infusion in PT-Agtr1a -/- mice was associated with increased plasma and kidney cGMP levels (P &lt; 0.01), kidney cortical NPRA and NPRC mRNA expression (P &lt; 0.05), total endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS proteins (P &lt; 0.01), and urinary nitric oxide (NO) excretion (P &lt; 0.01), respectively. Conclusions: Taken together, the results of the present study provide further new insights into the important physiological roles for intratubular Ang II/AT1a and ANP/NPRA in the proximal tubules to regulate proximal tubule Na+ reabsorption and help maintain blood pressure homeostasis. Supported by 2R01DK067299-10A1, 2R01DK102429-03A1, and 1 R01DK123144-01.

PS-C22-4: ASSOCIATION OF ATRIAL NATRIURETIC PEPTIDE GENETIC POLYMORPHISMS WITH ARTERIAL HYPERTENSION IN MONGOLIAN POPULATION

Objective of the present study was to evaluate the association between polymorphisms of atrial natriuretic peptide(ANP) gene and arterial hypertension. Design and method: This study was conducted in Ulaanbaatar between October 2018 and November 2019 years. A case-control study was performed in 123 subjects including 82 hypertensives and 41 normotensive subjects, aged 20–60 years. The family history of cardiovascular disease and risk factors of hypertension were taken by questionnaires and body mass index, systolic and diastolic pressures were evaluated by physical examination. Hypertension was defined as systolic BP ≧ 130 mm Hg and/or diastolic BP ≧ 80 mm Hg. After isolation DNA from peripheral blood, specific primers were used for PCR to detect the mutations of gene by using ThermoFisher dream Tag DNA Polymerase. QIAGEN QIAquick PCR purification kit and QIAquick Gel extraction kit were used to establish nucleic acid sequence. The study was approved by the Ethics Committee of Mongolian National University of Medical Sciences and all subjects participated in the study after making signed informed consents. Results: The mean age of the participants was 40.2 years and 56.1% were men. The T2325C variant of ANP gene was identified in 4.9% of all participants. According to the genotype results, the frequencies of T2325C polymorphism of the ANP gene were 1.2% in hypertensive patients and 12.2% in normotensive subjects respectively. The partial DNA sequence in ANP gene was shown in Figure 1. DNA sequencing showed a thymine to serine substitution at nucleotide 2325. Compared with individuals without T2325C polymorphism, individuals with T2325C polymorphism had higher percentage of family history of cardiovascular disease. Conclusion: The genetic polymorphism in ANP gene identified for the first time in the Mongolia. This case-control study indicated that the ANP T2325C gene polymorphism may have no relationship with arterial hypertension.

Retracted: The Clinical Efficacy of Cedilanid and Isosorbide Dinitrate plus Pericardial Dissection for Chronic Constrictive Pericarditis in the Elderly and Its Influence on Plasma Endothelin, Atrial Natriuretic Peptide, and Systemic Immune-Inflammation Index.

[This retracts the article DOI: 10.1155/2022/5406649.].

PS-BPR02-7: SACUBITRIL VALSARTAN FOR REFRACTORY HYPERTENSION CAUSED BY PRIMARY ALDOSTERONISM: A CASE SERIES

Introduction: Primary aldosteronism (PA) is the disease characterized by inappropriately elevated autonomous adrenal aldosterone secretion, leading to the development of refractory hypertension. Patients with PA show higher nighttime blood pressure (BP) and lower nocturnal BP decline than those with essential hypertension. Angiotensin receptor neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the renin angiotensin system and the natriuretic peptide system. Atrial natriuretic peptide has been shown to inhibit basal aldosterone secretion from adrenal cells in vitro. Case Presentation: A man in his 50 s was referred to our hospital due to vision loss and diagnosed with hypertensive retinopathy. His serum potassium level was below 3.5 mEq/L. A captopril test confirmed the diagnosis of PA, though a CT image revealed no adrenal adenoma. According to his discretion, medical treatment including a mineralocorticoid receptor antagonist, a calcium channel blocker, an angiotensin receptor blocker (ARB), an angiotensin converting enzyme inhibitor (ACEI), an alpha blocker and a beta blocker, were commenced. However, the result of ambulatory bloop pressure monitoring (ABPM) revealed his mean BP of 143/91 mmHg and his mean nighttime BP of 148/89 mmHg, indicating riser pattern. Switching from an ACEI, imidapril (10 mg per day), and an ARB, azilsartan (40 mg per day), to sacubitril/valsartan (200 mg per day) decreased his mean BP to 138/89 mmHg. Furthermore, his mean nighttime BP decreased to 122/79 mmHg, indicating that his nocturnal hypertension was improved by sacubitril/valsartan. Similar favorable effects of Sacubitril/valsartan on BP were found in three other patients with refractory hypertension caused by PA. Discussion: ARNIs are an appropriate treatment option for refractory hypertension caused by PA.

Vanillic Acid Alleviates Right Ventricular Function in Rats With MCT-Induced Pulmonary Arterial Hypertension

This study examined the molecular processes behind the effects of vanillic acid (VA) on right ventricular (RV) hypertrophy and function in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). There were 40 male Sprague‒Dawley (SD) rats that were separated into 4 groups: Control, PAH, MCT + VA (50 mg/kg/d), and MCT + VA (100 mg/kg/d). Male SD rats were injected with MCT once under the skin to create the PAH model (40 mg/kg). RV morphological properties were evaluated using Masson and hematoxylin and eosin (H&amp;E) staining. Echocardiography was used to evaluate RV functioning and right ventricle–pulmonary artery (RV-PA) coupling. In addition, Rho-associated protein kinase (ROCK) pathway-related factors were evaluated using Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory markers as well as atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP) in the blood of PAH rats. As a result, VA effectively reduced the development of RV cardiomyocyte hypertrophy and fibrosis in PAH rats; levels of ANP, BNP, and inflammatory markers in the blood of PAH rats were also significantly decreased by VA intervention. Additionally, VA enhanced RV functioning and RV-PA coupling in PAH rats. In response to VA, the expression of proteins related to the ROCK pathway (ROCK1, ROCK2, NFATc3, P-STAT3, and Bax) was downregulated, whereas Bcl-2 expression was elevated. This study found that VA could attenuate RV remodeling and improve RV-PA coupling in PAH rats. RV remodeling and dysfunction may be linked to the dysregulation of the ROCK pathway, and the protective action of VA on RV function may be due to a block in the ROCK signaling pathway or its downstream signaling molecules.

PS-R02-6: ASSOCIATION BETWEEN DE NOVO TYPICAL CLINICAL-SCENARIO-1 HEART FAILURE AND RENAL ARTERY STENOSIS

A 70-year-old man with sudden onset of dyspnea was referred to our emergency room. Over several years, he had received medical treatments for hypertension, diabetes mellitus, hypercholesterolemia, and obesity, and had a history of heavy smoking until the age of 60. In the past month, systolic blood pressure (BP) increased from around 120/- mmHg to 170/- mmHg or over and exertional dyspnea appeared. On admission, BP was 241/134 mmHg and pulse rate was 140 beats per minute. The chest X-ray showed severe pulmonary edema with butterfly shadow and blood gas analysis revealed the PO2 was 62.2 mmHg, the PCO2 57.7 mmHg, and the pH 7.208 with oxygen inhalation of 12 litters per minute. These were the typical manifestations of clinical scenario (CS) 1 of heart failure (HF). Chemical analysis showed total cholesterol of 240 mg/dl, LDL-cholesterol 159 mg/dl, triglyceride 127 mg/dl, creatinine 1.04 mg/dl, BNP 455.7 pg/ml, and plasma renin activity over 20 ng/ml/hr. Intravenous nitroglycerin, atrial natriuretic peptide and furosemide and noninvasive positive pressure ventilation with oxygen inhalation were consecutively administered. The symptom rapidly resolved thereafter. The left ventricular ejection fraction (EF) of 25–30 % on admission improved to 66 % 5 days later. Abdominal ultrasonography showed an atrophic left kidney (pole-to-pole length 77 mm, resistive index 0.61) compared with the right kidney (pole-to-pole length 96 mm, resistive index 0.71), which suggested the stenosis of the left renal artery and plain computed tomography showed severe calcification of the abdominal aorta and left renal artery. Contrast-enhanced magnetic resonance imaging and diagnostic angiography revealed severe left renal stenosis. There was no significant stenosis in any coronary arteries. After renal revascularization, BP decreased and antihypertensive agents were reduced, and there was no exacerbation of HF afterward. Renovascular hypertension (RH) is a rare disease in daily practice and is recognized as one of the causes of HF with unknown etiology. RH with recurrent exacerbation of HF is the indication for renal revascularization. However, renal artery stenosis is rarely identified even in HFpEF (HF with preserved EF) patients. We experienced a de novo HFpEF case with the typical features of CS 1 of hypertensive emergency complicated by RH with underlying multiple arteriosclerotic diseases. The association between de novo typical CS-1 heart failure of hypertensive emergency and renal artery stenosis might be closer and thus both conditions might more often coexist than expected, and once RH would be identified, the clinical course could be carefully observed thereafter.

The landscape of N6-methyladenosine modification patterns and altered transcript profiles in the cardiac-specific deletion of natriuretic peptide receptor A.

The atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) are critical biological makers and regulators of cardiac functions. Our previous results show that NPRA (natriuretic peptide receptor A)-deficient mice have distinct metabolic patterns and expression profiles compared with the control. Still, the molecular mechanism that could account for this observation remains to be elucidated. Here, methylation alterations were detected by mazF-digestion, and differentially expressed genes of transcriptomes were detected by a Genome Oligo Microarray using the myocardium from NPRA-deficient (NPRA-/-) mice and wild-type (NPRA+/+) mice as the control. Comprehensive analysis of m6A methylation data gave an altered landscape of m6A modification patterns and altered transcript profiles in cardiac-specific NPRA-deficient mice. The m6A "reader" igf2bp3 showed a clear trend of increase, suggesting a function in altered methylation and expression in cardiac-specific NPRA-deficient mice. Intriguingly, differentially m6A-methylated genes were enriched in the metabolic process and insulin resistance pathway, suggesting a regulatory role in cardiac metabolism of m6A modification regulated by NPRA. Notably, it was confirmed that the pyruvate dehydrogenase kinase 4 (Pdk4) gene upregulated the gene expression and the hypermethylation level simultaneously, which may be the key factor for the cardiac metabolic imbalance and insulin resistance caused by natriuretic peptide signal resistance. Taken together, cardiac metabolism might be regulated by natriuretic peptide signaling, with decreased m6A methylation and a decrease of Pdk4.

MORPHOLOGICAL CHARACTERISTICS OF THE ENDOCRINE FUNCTION OF THE HEART IN COMORBID PATHOLOGY.

Aim: To study the ultrastructural remodeling of atrial myoendocrine cells (AMC) of the atrial myocardium in streptozotocin-induced diabetes (SID) under chronic immobilization stress (CIS). Materials and methods: 40 sexually mature white male rats (body weight 150-180 g) were included in the study. Four groups were formed: group 1 - animals with comorbid pathology (SID and CIS), group 2 - animals with SID, group 3 - animals with CIS, group 4 - intact animals. Results: On the 14th day of the development of SID and CIS, an increase in the functional activity of AMC is noted, which is confirmed by hyperplasia and hypertrophy of the protein-synthesizing apparatus, an increase in the volume density of secretory granules (SG), especially diffusing ones, and indicates enhanced release of atrial natriuretic peptide (ANP) from cells during the experiment. On the 56th day of the experiment, in groups 1 and 2 of , destructive changes in AMC were noted, such as vacuolar and balloon dystrophy, colliquative and partial necrosis. At the same time, the functional activity of AMC of different regions of the myocardium significantly. In animals with CIS, the volume density of young and diffusing SG in AMC is decreased. Conclusions: Therefore, in the early stages of the development of SID and CIS, an increase in the morpho-functional activity of AMC is noted. The long course of SID and its combination with CIS lead to destructive changes in AMC and to decrease in their secretory activity.

S-20-3: PLASMA ATRIAL AND BRAIN NATRIURETIC PEPTIDES LEVELS AND THE RISK OF INCIDENT ATRIAL FIBRILLATION: THE SUITA STUDY

Background: Atrial fibrillation (AF), a common cardiac rhythm abnormality, is associated with significantly increased morbidity and mortality risk. We developed the risk prediction of incident AF using traditional risk factors. It is essential to consider the residual risk to increase risk predictions. Heart failure is not a factor that appeared in the Suita AF score but others. There is no prospective study on the relationship between plasma atrial and brain natriuretic peptide (ANP and BNP) levels and incident AF in non-Western residents. Objectives: We hypothesized the association between ANP, BNP, and incident AF in the Suita Study. Methods: A total of 2,828 participants (mean age 66.7 ± 10.4 years without AF at the baseline) have been prospectively followed-up for incident AF since November 2005. AF was diagnosed when AF or atrial flutter was present on ECG at a biannual health examination or when AF was indicated as a current illness or was in the medical records during follow-up. ANP and BNP were measured by the CLEIA methods at the baseline survey examination. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were analysed after adjusting for the risk components of the recently published Suita AF risk score. Statistical analyses were performed using Cox proportional hazards regression methods and evaluated using C statistics and net reclassification improvement. Results: The baseline prevalence of hypertension according to the BNP levels were 34.5%, 50.1%, and 78.8% in BNP &lt; 18.5 pg/dL, 18.5–99 pg/dL, and P ≧ 4100 pg/dL, respectively. During the 16,584 person-years of follow-up, we observed 65 incidents of AF. Compared to the subjects with ANP&lt; 42 pg/dL and BNP&lt; 18.4 pg/dL, the adjusted HRs (95% confidence intervals) of incident AF were 2.70 (1.53–4.78) for the subjects with ANP ≧ 42 pg/dL and 2.09 (1.09–4.01) and 9.75 (3.82–24.87) for the subjects with BNP = 18.5–99 pg/dL and BNPP ≧ 4100 pg/dL, respectively. The addition of ANP and BNP to variables recently combined in the Suita AF risk score showed an integrated discrimination improvement of 0.061 (0.035–0.087) and 0.068 (0.036–0.100), with 13.3% and 19.1% relative improvement in reclassification analysis, respectively. Furthermore, the addition of ANP to the Suita AF score with BNP showed a significant but slight integrated discrimination improvement of 0.007 (0.001–0.012) (P = 0.01). Conclusions: Each elevated ANP and BNP contributed significantly to the predictive for incident AF to calculate the Suita Risk Score, but adding ANP to the Suita AF score with BNP improved the risk prediction slightly.

Urinary neprilysin - Another marker to predict postoperative acute kidney injury.

Dear Editor, Perioperative acute kidney injury (AKI) is a serious complication which is multifactorial, which leads to increased hospital and intensive care unit stay, possibility of chronic kidney disease and hemodialysis, increased cost of treatment, significant morbidity, and mortality. Neprilysin or neutral endopeptidase (NEP) is a single-pass membrane glycoprotein with zinc-dependent endopeptidase activity and a short cytosolic tail. NEP is found predominantly within the kidneys, gastrointestinal tract, liver, male genital organs, lungs, adipose tissue, brain, and heart. The renal brush border of proximal tubule on the luminal side is rich in membrane-bound NEP. NEP is involved in the degradation of both atrial and B-type natriuretic peptides, adrenomedullin, endothelin-1 and angiotensin II, and also nonvasoactive peptides, such as glucagon, glucagon-like peptide, enkephalins, and somatostatin. Circulating NEP estimation in serum has been used as a biomarker in acute and chronic heart failure patients for predicting cardiovascular death and time-to-first admission for an acute event.[1] The prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin-converting enzyme (ACE) inhibitor (ACEi) to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF) study reported significant clinical benefits with the combination of an angiotensin receptor blocker valsartan with a neprilysin inhibitor sacubitril over ACEi in heart failure with reduced ejection fraction.[2] However, trends of serum NEP could never correlate NT-pro-BNP and even clinically. In AKI, NEP is flushed out from the kidneys due to shedding of the tubular brush border and thus is available for estimation in the urine as a marker. Bernardi et al.[3] conducted a prospective, observational cohort study involving 96 patients undergoing elective cardiac surgeries with cardiopulmonary bypass. They estimated urinary neprilysin levels in the immediate postoperative period and on day 1. The authors concluded that estimation of urinary neprilysin levels after cardiac surgeries has comparable discriminatory power to presently studied AKI biomarkers and has potential as a biomarker for the early detection of AKI after cardiac surgery. Pajenda et al.[4] analyzed urinary neprilysin levels of 90 critically ill patients admitted to intensive or intermediate care unit over 2–5 days. On analysis, they found that NEP levels who suffered AKI according to the KDIGO (Kidney Disease Improving Global Outcomes) criteria were significantly elevated in comparison to healthy controls. In a comparative study performed by Gutta et al.[5] between 20 nondiabetics and 40 diabetic patients, authors compared urinary ACE2, NEP, disintegrin and metalloproteinase 17 (ADAM17) between two groups. The authors concluded that urinary ACE2 and NEP can be used as early biomarkers to predict the incidence or progression of chronic kidney disease at early stages among individuals with type 2 diabetes. The normal values of urinary neprilysin derived from recent studies are in the range of 0.5–1 ng/mL. To conclude, urinary NEP needs to be validated with adequately powered randomized controlled studies in various postoperative scenarios like thoraco-abdominal aneurysm repair, major laparotomies including cytoreductive surgeries and heated intraperitoneal chemotherapy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Momordicine I alleviates isoproterenol-induced cardiomyocyte hypertrophy through suppression of PLA2G6 and DGK-ζ.

This study aimed to observe the protective effect of momordicine I, a triterpenoid compound extracted from momordica charantia L., on isoproterenol (ISO)-induced hypertrophy in rat H9c2 cardiomyocytes and investigate its potential mechanism. Treatment with 10 μM ISO induced cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein content as well as pronounced upregulation of fetal genes including atrial natriuretic peptide, β-myosin heavy chain, and α-skeletal actin; however, those responses were markedly attenuated by treatment with 12.5 μg/ml momordicine I. Transcriptome experiment results showed that there were 381 and 447 differentially expressed genes expressed in comparisons of model/control and momordicine I intervention/model, respectively. GO enrichment analysis suggested that the anti-cardiomyocyte hypertrophic effect of momordicine I may be mainly associated with the regulation of metabolic processes. Based on our transcriptome experiment results as well as literature reports, we selected glycerophospholipid metabolizing enzymes group VI phospholipase A2 (PLA2G6) and diacylglycerol kinase ζ (DGK-ζ) as targets to further explore the potential mechanism through which momordicine I inhibited ISO-induced cardiomyocyte hypertrophy. Our results demonstrated that momordicine I inhibited ISO-induced upregulations of mRNA levels and protein expressions of PLA2G6 and DGK-ζ. Collectively, momordicine I alleviated ISO-induced cardiomyocyte hypertrophy, which may be related to its inhibition of the expression of glycerophospholipid metabolizing enzymes PLA2G6 and DGK-ζ.

Роль генов систем натрийуретических пептидов и антиоксидантной защиты в формировании риска развития инфаркта миокарда (предварительные результаты пилотного исследования)

Aim: to reveal a relationship of single-nucleotide polymorphic variants of the genes of the natriuretic peptides, antioxidant defense systems and the endothelial function with the development of myocardial infarction. Patients and Methods: the study included 146 patients with myocardial infarction (MI) and maintained or moderately decreased left ventricular ejection fraction: 108 males and 38 females with a mean age of 57 (51; 64) years. The control group was composed of Kemerovo city residents without acute MI (n=300, 190 females and 110 males). To make the evaluation, genomic DNA was isolated from the peripheral blood by phenol- chloroform extraction according to the standard protocol. Real-time PCR method was used for genotyping. To conduct the study, 24 polymorphic variants of 14 genes (those of the natriuretic peptides, antioxidant defense systems and the endothelial function) were selected. Results: significant associations with the allelic variants of CBR1 and CBR3 genes (carbonyl reductase 1 and 3 genes) of the antioxidant defense system were found in the sample of studied patients with MI (not divided by gender or age). When the patients were divided by gender, the following associations were found: in males the single-nucleotide polymorphic variant (SNPV) genotypes CBR1 rs9024 and CBR3 rs1056892 had the protective effect against susceptibility to myocardial infarction (dominant inheritance pattern). It was demonstrated that allelic variants in the NPR2 gene (the gene of atrial natriuretic peptide receptor 2) comprised a risk factor for MI development. In females, a relationship between the assessed genetic factors and the MI development (dominant inheritance pattern) could be associated with SNPV genotypes NPR2 rs13288085 and rs7034957, CBR1 rs9024, and CBR3 rs1056892 which are characterized by the protective effect. Conclusion: some polymorphic variants of the genes of the natriuretic peptide and antioxidant defense systems are associated with the risk and the protective effect against MI susceptibility. The preliminary findings indicate that it is necessary to continue investigations of the identified single-nucleotide polymorphic variants and to assess their impact on the MI severity and the risk of recurrent cardiovascular events in the long-term perspective. KEYWORDS: myocardial infarction, gene, natriuretic peptides, antioxidant defense, polymorphic variants. FOR CITATION: Khutornaya M.V., Khryachkova O.N., Sinitskaya A.V. et al. Role of the genes of the natriuretic peptide and antioxidant defense systems in creating the risk of myocardial infarction development (the preliminary results of a pilot study). Russian Medical Inquiry. 2023;7(1):5–12 (in Russ.). DOI: 10.32364/2587-6821-2023-7-1-5-12.

Prognostic significance of atrial natriuretic peptide in patients undergoing cardiac surgery

Prognostic significance of atrial natriuretic peptide in patients undergoing cardiac surgery

Abstract 2500: The Effect of Sildenafil on Atrial Natriuretic Peptide Level in Rats Treated with Monocrotaline

Abstract 2500: The Effect of Sildenafil on Atrial Natriuretic Peptide Level in Rats Treated with Monocrotaline

PS-B02-10: MTOR INHIBITOR IMPROVES TESTOSTERONE-INDUCED MYOCARDIAL HYPERTROPHY IN HYPERTENSIVE RATS

Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy in postmenopausal women is significantly increased worldwide. Our team previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized spontaneously hypertensive rats aged 12 weeks were used to study the effects of testosterone T 2.85 mg/kg/weekly im on blood pressure and myocardial tissue. On the basis of antihypertensive therapy chlorthalidone 8 mg/kg/day ig, the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin 0.8 mg/kg/day Vs 1.5 mg/kg/day Vs 2 mg/kg/day ip in OVX+ estrogens E 9.6 mg/Kg/day, ig+T group was further evaluated. After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length, cross-sectional area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor mTOR, ribosomal protein S6 kinase S6K1, 4E-bindiong protein 1 4EBP1 and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive women with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.