Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age.

Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP's contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP.

Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis.

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme. A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested. These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis.

Circulating Biomarkers Predict Symptomatic but Not Asymptomatic Carotid Artery Stenosis.

BACKGROUND: Subjects exposed to risk factors such as age, gender, hypertension, diabetes mellitus, and smoking are prone to atherosclerotic events. AIMS: The main aim of this longitudinal cohort study was to determine whether the role of novel plasma biomarkers for atherosclerotic carotid artery disease is different in subjects developing symptomatic carotid artery stenosis (CAS), as opposed to those with incident asymptomatic CAS. METHODS: The following biomarkers were measured in 5,550 middle-aged subjects in a population-based cohort study: C-reactive protein (CRP), lipoprotein-associated phospholipase A2 mass and activity, proneurotensin, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT pro-BNP), copeptin, and cystatin C. After exclusion of those with prevalent CAS, subjects were thereafter followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident symptomatic and asymptomatic CAS. RESULTS: Among 110 patients with confirmed incident CAS, 56 were symptomatic and 54 were asymptomatic. When including conventional risk markers in a Cox regression analysis, NT pro-BNP (hazard ratio [HR] 1.59; 95% confidence interval [CI]: 1.20-2.11), MR-proADM (HR 1.40; CI: 1.13-1.73), cystatin C (HR 1.21; CI: 1.02-1.43), and CRP (HR 1.53; CI: 1.13-1.73) were independently associated with incident symptomatic CAS, whereas no plasma biomarker was associated with incident asymptomatic CAS. CONCLUSION: Plasma biomarkers NT pro-BNP, MR-proADM, cystatin C, and CRP were independently associated with incident symptomatic CAS, whereas no such association could be demonstrated with incident asymptomatic CAS. As these biomarkers indicate future development of clinically relevant atherosclerotic CAS, their potential utility in relation to intensified preventive measures and selection of potential candidates for carotid surgery should be further evaluated.

The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria.

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin-low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

MR-proANP and NT-proBNP During Targeted Temperature Management Following Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the TTH48 Trial.

We aimed to evaluate the effect of prolonged targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA) on the levels of midregional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) and assess their potential as prognostic biomarkers. A preplanned post hoc analysis of "Targeted temperature management for 48 h vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial (TTH48 trial)," where patients were randomized to TTM at 33°C ± 1°C of standard duration (24 hours) versus prolonged (48 hours). Blood samples were drawn from patients with OHCA at two Scandinavian university hospitals at admission to the ICU and at 24, 48, and 72 hours after reaching the target temperature. Primary outcome was levels of MR-proANP and NT-proBNP. Secondary outcome was cerebral performance category (CPC 1-5) at 6 months. Samples from 114 patients were analyzed. Prolonged TTM significantly decreased the levels of MR-proANP and NT-proBNP at 48 hours compared with standard 24 hours-TTM (p < 0.01). However, there were no significant differences at other time points. Patients with poor outcome (CPC 3-5) had a statistically significantly increased MR-proANP level at 24 hours (p < 0.01) and 72 hours (p < 0.01) compared with the good outcome group (CPC 1-2). Prognostic performance was best at 24 hours for both MR-proANP and NT-proBNP; with an AUC of 0.73 (confidence interval [95% CI]: 0.63-0.83) and 0.72 (95 % CI: 0.59-0.85), respectively. Prolonged TTM lowered the levels of both MR-proANP and NT-proBNP at 48 hours. MR-proANP may add prognostic information in postcardiac arrest patients. ClinicalTrials.gov ID: NCT01689077.

Flow reduction of a high-flow arteriovenous fistula in a hemodialysis patient reveals changes in natriuretic and renin-angiotensin system hormones of relevance for kidney function.

Arteriovenous fistulas (AVFs) are iatrogenic vascular connections established to allow high-flow intravascular access for patients with chronic kidney disease requiring hemodialysis. The left-right flow shunt results in changes in extracellular fluid volume and blood pressure-controlling hormones that could affect the residual kidney function. We present a case where a female patient with a brachiocephalic AVF had a fistula flow of >4 L/min. To reduce the flow, a banding procedure was performed. The patient was examined prior to banding and 1 and 2 weeks thereafter. Banding resulted in a marked decrease in AVF flow from >4 to 1 L/min and was associated with reductions in N-terminal pro-brain natriuretic peptide of 51% and 67% at 1- and 2-weeks post-banding, respectively. Mid-regional pro-atrial natriuretic peptide concentrations were reduced post-banding by 17% after 1 week and 25% after 2 weeks. After 1 week, renin, angiotensin II, and aldosterone levels in plasma decreased transiently by 44%, 47%, and >86%, respectively, and returned to pre-banding levels after 2 weeks. Creatinine clearance tended to decrease while blood pressure and total body water increased 2 weeks after banding. This indicates that high-flow AVF is associated with increased natriuretic peptides and hormones of the renin-angiotensin-aldosterone system, that may balance each other regarding fluid retention and hypertension and support remaining kidney function.

Deterioration of diabetic nephropathy via stimulating secretion of cytokines by atrial natriuretic peptide.

BACKGROUND: Atrial natriuretic peptide (ANP) is a cardiovascular and metabolic hormone that has been identified recently as being associated with chronic kidney disease (CKD) without diabetes. Cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin (ADP) contribute to the development of type 2 diabetes (T2DM). The aim here was to investigate the relationships of ANP with cytokine levels and clinical variables in T2DM nephropathy patients. METHODS: A total of 81 participants with T2DM were recruited, including 37 patients with normoalbuminuria, 23 patients with microalbuminuria and 21 patients with macroalbuminuria. Serum concentrations of ANP and cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANP and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANP and the severity and presence of albuminuria. RESULTS: The macroalbuminuria patients exhibited higher plasma levels of ANP, TNF-α, IL-6, and ADP; higher serum creatinine (Cr) and blood urea nitrogen (BUN); and longer duration of diabetes mellitus (DM) than the patients with normoalbuminuria and microalbuminuria. Plasma ANP level was significantly associated with TNF-α (r = 0.876, p < 0.001), IL-6 (r = 0.816, p < 0.001) and ADP (r = 0.772, p < 0.001), independent of the duration of DM or the BUN concentration. CONCLUSION: ANP is higher in type 2 diabetes mellitus nephropathy subjects, especially those who have macroalbuminuria, which is associated with compensatory responses to inflammation.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

Characterization of the spontaneous degenerative mitral valve disease in FVB mice.

BACKGROUND: The development of new non-surgical treatments dedicated to mitral valve degeneration is limited by the absence of relevant spontaneous and rapidly progressing animal experimental models. ANIMALS: We characterized the spontaneous mitral valve degeneration in two inbred FVB mouse strains compared to C57BL/6J and investigated a contribution of the serotonergic system. METHODS: Males and females FVB/NJ and FVB/NRj were compared to the putative C57BL/6J control at 12, 16, 20 and 24 weeks of age. Body weight, systolic blood pressure, heart rate, urinary 5-hydroxyindoleacetic acid (5-HIAA), whole blood and plasma serotonin, tail bleeding time, blood cell count, plasma TGF-ß1 and plasma natriuretic peptide concentrations were measured. Myocardium and mitral valves were characterized by histology. mRNA mitral expression of 5-HT2A and 5-HT2B receptors was measured in the anterior leaflet. Cardiac anatomy and function were assessed by echocardiography. RESULTS: Compared to C57BL/6J, FVB mice strains did not significantly differ regarding body weight increase, arterial blood pressure and heart rate. A progressive augmentation of plasma pro-ANP was observed in FVB mice. Nevertheless, no cardiac hypertrophy or left-ventricular fibrosis were observed. Accordingly, plasma TGF-ß1 was not different among the three strains. Conversely, FVB mice demonstrated a high prevalence of fibromyxoid highly cellularized and enriched in glycosaminoglycans lesions, inducing major mitral leaflets thickening without increase in length. The increased thickness was correlated with urinary 5-HIAA and blood platelet count. Whole blood serotonin concentration was similar in the two strains but, in FVB, a reduction of plasma serotonin was observed together with an increase of the bleeding time. Finally, echocardiography identified left atrial and left ventricular remodeling associated with thickening of both mitral leaflets and mitral insufficient in 30% of FVB mice but no systolic protrusion of mitral leaflets towards the atrium. CONCLUSION: The FVB mouse strain is highly prone to spontaneous mitral myxomatous degeneration. A contribution of the peripheral serotonergic system is suggested.

An NP-led pilot telehealth programme to facilitate guideline-directed medical therapy for heart failure with reduced ejection fraction during the COVID-19 pandemic.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is associated with poor outcomes. While several medications are beneficial, achieving optimal guideline-directed medical therapy (GDMT) is challenging. COVID-19 created a need to explore new ways to deliver care. METHODS: Fifty consecutive patients were taught to identify fluid congestion and monitor their vital signs using BP monitors and electronic scales with NP-led telephone support. Quantitative data were collected and a patient experience interview was performed. RESULTS: The majority (76%) of the cohort (male, 76%; Maori/Pacific, 58%) had a new diagnosis of HFrEF, with 90% having severe left ventricular (LV) dysfunction. There were 216 contacts (129 (60%) by telephone), which eliminated travelling, (time saved, 2.12 hours per patient), petrol costs ($58.17 per patient), traffic pollution (607 Kg of CO2) and time off work. Most (75%) received contact within two weeks and 75% were optimally titrated within two months. Improvements in systolic BP (SBP) (124mmHg to 116mmHg), pulse (78 bpm to 70 bpm) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (292 to 65) were identified. Of the 43 patients who had a follow-up transthoracic echocardiogram (TTE), 33 (77%) showed important improvement in left ventricular ejection fraction (LVEF). CONCLUSIONS: Patients found the process acceptable and experienced rapid titration with less need for clinic review with titration rates comparable with most real-world reports.

Impact of Midregional N-Terminal Pro-Atrial Natriuretic Peptide and Soluble Suppression of Tumorigenicity 2 Levels on Heart Rhythm in Patients Treated With Catheter Ablation for Atrial Fibrillation: The Biorhythm Study.

Background We assessed the impact of preprocedural plasma levels of MRproANP (midregional N-terminal pro-atrial natriuretic peptide) and sST2 (soluble suppression of tumorigenicity 2) on recurrence of atrial fibrillation (AF) at 1 year after catheter ablation of AF. Methods and Results This was a prospective, multicenter, observational study including patients undergoing catheter ablation of AF. MRproANP and sST2 were measured in a peripheral venous blood preprocedure, and MRproANP was assessed in the right and left atrial blood during ablation. The primary end point was recurrent AF between 3 and 12 months postablation, defined as a documented (>30 seconds) episode of AF, flutter, or atrial tachycardia. We included 106 patients from December 2017 to March 2019; 105 had complete follow-up, and the mean age was 63 years with 74.2% males. Overall, 34 patients (32.1%) had recurrent AF. In peripheral venous blood, MRproANP was significantly higher in patients with recurrent AF (median, 192.2; [quartile 1-quartile 3, 155.9-263.9] versus 97.1 [60.9-150.7] pmol/L; P<0.0001), as was sST2 (median, 30.3 [quartile 1-quartile 3, 23.3-39.3] versus 23.4 [95% CI, 17.4-33.0] ng/mL; P=0.0033). In the atria, MRproANP was significantly higher than in peripheral blood and was higher during AF than during sinus rhythm. Receiver operating characteristic curve analysis identified a threshold of MRproANP>107.9 pmol/L to predict AF recurrence at 1 year and a threshold of >26.7 ng/mL for sST2. By multivariate analysis, MRproANP>107.9 pmol/L was the only independent predictor of recurrent AF (OR, 24.27; 95% CI, 4.23-139.18). MRproANP<107.9 pmol/L identified subjects at very low risk of recurrence (negative predictive value >95%). Conclusions Elevated MRproANP level independently predicts recurrent AF, whereas sST2 levels do not appear to have any prognostic value in assessing the risk of recurrence of AF up to 1 year after catheter ablation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351816.

Intensive Lifestyle Intervention Increases Plasma Midregional Proatrial Natriuretic Peptide Concentrations in Overweight Children.

Background Overweight adults have low circulating concentrations of ANP (atrial natriuretic peptide) and proANP fragments. We tested the hypothesis that an intensive lifestyle intervention with an intended weight loss would increase plasma concentrations of a proANP fragment in overweight children. Methods and Results We measured MR-proANP (midregional proANP) concentrations in plasma from overweight children who participated in the OOIS (Odense Overweight Intervention Study). OOIS randomized 115 overweight children (11-13 years, 55% girls) to an intensive day-camp intervention arm with increased physical activity and healthy diet or to a less intensive standard intervention arm for 6 weeks. We used linear mixed-effects modeling for repeated measures to estimate the difference in the mean change with 95% CIs in fasting plasma MR-proANP concentrations between the 2 arms, and we used partial least squares regression analysis to identify candidate mediators. Differences in weight, fitness, and metabolic factors were also analyzed. At baseline, fasting plasma MR-proANP concentrations were (median [interquartile range]) 35.0 pmol/L (26.8-42.0) in the day-camp intervention arm and 37.2 pmol/L (31.7-44.7) in standard intervention arm participants, respectively. After 6 weeks intervention, children in the day-camp intervention arm had increased their MR-proANP (5.4 pmol/L [0.8-10.0], P=0.022) and their fitness (2.33 mL O2/min per kg [0.52-4.14], P=0.012) and they had deceased their body mass index (-2.12 kg/m2 [-2.59 to -1.65], P<0.001) as compared with children in standard intervention arm. In the partial least squares analysis, decreases in fasting insulin and in estimated insulin resistance were associated with the observed increase in MR-proANP concentrations. Conclusions An intensive lifestyle intervention increases plasma MR-proANP among overweight children. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01574352.

The Protective Role of the Long Pentraxin PTX3 in Spontaneously Hypertensive Rats with Heart Failure.

Pentraxin 3 (PTX3) is synthesized locally and released into the circulation, reflecting local inflammation in the cardiovascular system. Therefore, we conducted a study to explore the effect of PTX3 in spontaneously hypertensive heart failure (SHHF) rats. Sprague Dawley (SD) and SHHF rats were treated with recombinant PTX3 protein, and the blood pressure (BP) and echocardiographic parameters were collected. Radioimmunoassay, enzyme immunoassay and enzyme-linked immunosorbent assay (ELISA) were applied to detect plasma levels of atrial/B-type natriuretic peptide (ANP/BNP) and PTX3. The pathological changes in the myocardial tissues were observed by hematoxylin and eosin (HE) and Masson stainings. The mRNA and protein expressions were detected by quantitative real-time reverse-transcription polymerase chain reaction (qPCR) and western blotting. Cardiomyocyte apoptosis was evaluated by TUNEL staining and DNA fragmentation test. Increased plasma concentrations of PTX3 were found in SHHF rats compared with SD rats, which was further enhanced by recombinant PTX3 protein. After injection with recombinant PTX3 protein, the heart function was improved in SHHF rats with the decreased systolic and diastolic BP, and the reduced plasma levels of ANP and BNP. Moreover, PTX3 improved the myocardial damage and interstitial fibrosis in SHHF rats with reduced cardiomyocyte apoptosis and decreased mRNA expressions of pro-inflammatory factors in myocardial tissues. PTX3 could decrease the BP and plasma levels of ANP and BNP in SHHF rats, as well as improve the inflammation, cardiomyocyte apoptosis, and pathological changes of myocardial tissues, suggesting it may be a useful intervention in the treatment of SHHF.

Plasma adrenomedullin level and year-by-year variability of body mass index in the general population.

Plasma levels of the hypotensive peptides of adrenomedullin and atrial and B-type natriuretic peptides (AM, ANP, BNP) are possible biomarkers for cardiovascular diseases. Increased variability of body mass index (BMI) over a certain period of time has been reported to be associated with cardiovascular morbidity or mortality. The aim of this study is to examine clinical significance of those hypotensive peptides as biomarkers by analyzing the relationship between plasma levels of the peptides and year-by-year variability of BMI in the general population without overt cardiovascular diseases. The subjects were 427 local residents (141 males and 286 females) attending their annual health check-up, who had been examined at least 5 times over the preceding period of 10 years. They were divided into two groups of low or high variability by the median of coefficient of variation (CV) of BMI values for each gender. Plasma AM levels of those with high year-by-year variability of BMI were significantly increased, as compared to the group with low variability, in both genders; meanwhile, such a difference was not noted in plasma levels of the natriuretic peptides. No significant differences were found in the basal parameters, which could affect plasma AM level, such as age, BMI, blood pressure or serum creatinine, between two groups. In conclusion, increase in plasma AM was associated with high year-by-year variability of BMI in the general population without overt heart disease. This relationship between the two suggests that increased plasma AM level is a cardiovascular risk marker.

Maternal plasma pro-atrial and C-type natriuretic peptide levels and their associations with cardiovascular and renal function in the second half of normal pregnancy: a longitudinal study.

BACKGROUND: Physiological adaptation in pregnancy is characterized by remodeling of endocrine, cardiovascular and renal functions leading to fluid retention, volume expansion, altered cardiac loading conditions and hyperdynamic circulation. Natriuretic peptides have been used as biomarkers of cardiovascular function, but their associations with gestational age-related changes in maternal cardiac, endothelial and renal function have not been elucidated. The aim of this study was to establish longitudinal reference values for maternal plasma atrial natriuretic peptide (proANP) and C-type natriuretic peptide (CNP) and investigate their temporal association with cardiovascular and renal function in the second half of pregnancy. METHODS: This study was a prospective longitudinal study of 53 low-risk pregnancies. Women were examined every 3-5 weeks during 22-40 weeks of gestation (252 observations). Fasting maternal blood samples were obtained to measure proANP, CNP, creatinine, cystatin C, uric acid, and fibrinogen levels. Cardiac function and systemic hemodynamics were assessed noninvasively by impedance cardiography (ICG) and vascular endothelial function by flow-mediated vasodilation of brachial artery (FMD). RESULTS: The plasma proANP (R2adj = 0.79; P = 0.007), CNP (R2adj = 0.54; P = 0.005) decreased between 22 and 40 weeks. The creatinine (R2adj = 0.90; P < 0.001), cystatin C (R2adj = 0.93; P = < 0.001) and uric acid (R2adj = 0.83; P < 0.001) increased significantly, whereas the estimated glomerular filtration rate (R2adj = 0.93; P < 0.001) decreased with gestational age. The FMD did not change significantly but fibrinogen (R2adj = 0.79; P < 0.001) increased with advancing gestation. The maternal systemic vascular resistance index (R2adj = 0.50; P < 0.001) increased, stroke index (R2adj = 0.62; P < 0.001) decreased, whereas the cardiac index (R2adj = 0.62; P = 0.438) and thoracic fluid content (R2adj = 0.72; P = 0.132) did not change significantly with gestation. The proANP was associated with thoracic fluid content (R2adj = 0.74; P < 0.001) and fibrinogen (R2adj = 0.78; P = 0.034) but not with other variables of systemic hemodynamics, endothelial function, or renal function. The CNP was not associated significantly with parameters of cardiovascular or renal function. CONCLUSION: Longitudinal reference values for maternal plasma proANP and CNP were established. These natriuretic peptides decreased slightly with advancing gestation, but they did not reflect the temporal physiological changes in maternal systemic hemodynamics, vascular endothelial function and renal function during the second half of pregnancy. The proANP correlated with the thoracic fluid content reflecting volume load in pregnancy.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

[Figure: see text].

Copeptin, pro-atrial natriuretic peptide and pro-adrenomedullin as markers of hypoxic stress in patients with obstructive sleep apnea-a prospective intervention study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) might lead to oxidative stress, inflammation and elevated circulating copeptin, proANP and proADM levels. We aimed to evaluate whether the levels of these prohormones are higher in patients with OSA and whether they might change under continuous positive airway pressure (CPAP) therapy, serving as potential proxies for the diagnosis and therapy-response in OSA. METHODS: A total of 310 patients with suspicion of OSA were recruited. Screening for OSA was performed using overnight pulse oximetry followed by polygraphy and a venous puncture in the morning. All patients diagnosed with OSA underwent CPAP adaptation. A venous puncture was conducted in the night before CPAP and in the following morning. At 1 and 6 months of treatment, polygraphy was performed, followed by a venous puncture in the morning. In the acquired blood, copeptin, proANP and proADM levels were measured. RESULTS: We analyzed 232 patients with OSA and 30 patients without OSA. Our results indicated that only copeptin levels differed significantly among patients with and without OSA at baseline. In OSA patients, the levels of proADM significantly changed after 1 and 6 months on CPAP therapy, when compared to baseline (p < 0.001 and p = 0.020). Additionally, proANP levels significantly decreased after 12 h on CPAP therapy, as compared to baseline levels (p < 0.001). CONCLUSIONS: Copeptin is significantly associated with the presence of OSA. ProANP levels might serve as a potential proxy for the acute response to non-invasive ventilation (12 h), while proADM reflects the long-term response (1 and 6 months).

Mid-regional pro-atrial natriuretic peptide independently predicts short-term mortality in COVID-19.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID-19 yet. METHODS: This prospective, observational study of patients with COVID-19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28-day mortality. RESULTS: A total of 213 eligible patients with COVID-19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR-proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 - 532] vs 75 pmol/L [IQR, 43 - 153], P < .001) compared to survivors and increased with disease severity and level of hypoxaemia. The area under the ROC curve for MR-proANP predicting 28-day mortality was 0.832 (95% CI 0.753 - 0.912, P < .001). An optimal cut-off point of 160 pmol/L yielded a sensitivity of 82.1% and a specificity of 76.2%. MR-proANP was a significant predictor of 28-day mortality independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (HR 2.77, 95% CI 1.21 - 6.37; P = .016), while NT-proBNP failed to independently predict 28-day mortality and had a numerically lower AUC compared to MR-proANP. CONCLUSION: Higher levels of MR-proANP at admission are associated with disease severity of COVID-19 and act as a powerful and independent prognostic marker of 28-day mortality.

The Prognostic Potential of Atrial Natriuretic Peptide on the Development of Postoperative Atrial Fibrillation after Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) represents a common complication after cardiac surgery associated with major adverse events and poor patient outcome. Tools for risk stratification of this arrhythmia remain scarce. Atrial natriuretic peptide (ANP) represents an easily assessable biomarker picturing atrial function and strain; however, its prognostic potential on the development of POAF has not been investigated so far. METHODS: Within the present investigation, 314 patients undergoing elective cardiac surgery were prospectively enrolled. Preoperative mid-region proANP (MR-proANP) values were assessed before the surgical intervention. Patients were followed prospectively and continuously screened for the development of arrhythmic events. RESULTS: A total of 138 individuals (43.9%) developed POAF. Median concentrations of MR-proANP were significantly higher within the POAF group (p < 0.001). MR-proANP showed a strong association with the development of POAF with a crude odds ratio (OR) of 1.68 per 1 standard deviation (1-SD; 95% confidence interval [CI]: 1.31-2.15; p < 0.001), which remained stable after comprehensive adjustment for confounders with an adjusted OR of 1.74 per 1-SD (95% CI: 1.17-2.58; p = 0.006). The discriminatory power of MR-proANP for the development of POAF was validated by the category-free net reclassification improvement (0.23 [95% CI: 0.0349-0.4193]; p = 0.022) and integrated discrimination increment (0.02 [95% CI: 0.0046-0.0397], p = 0.013). CONCLUSION: MR-proANP proved to be a strong and independent predictor of the development of POAF. Considering a personalized diagnostic and prognostic preoperative work-up, a standardized preoperative evaluation of MR-proANP levels might help to identify patients at risk for development of POAF after cardiac surgery.

Plasma volume contraction reduces atrial natriuretic peptide after four days of hypobaric hypoxia exposure.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L (P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL (P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 (P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 (P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L (P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.