Increase In Atrial Natriuretic Peptide Research Articles

Effect of sacubitril/valsartan on natriuretic peptide in patients with compensated heart failure.

The time-dependent changes in the natriuretic peptide families during sacubitril/valsartan (S/V) treatment remain obscure in the Asian heart failure (HF) cohort. Eighty-one outpatients with compensated HF were analyzed. The patients were divided into two groups based on the administration of S/V (n = 42) or angiotensin converting enzyme inhibitor (ACE-I; n = 39). Changes to the natriuretic peptide families and the daily dose of loop diuretics were evaluated 3 and 6months after the intervention. The atrial natriuretic peptide (ANP) level was significantly increased (102 [63-160] pg/mL to 283 [171-614] pg/mL [3months]; 409 [210-726] pg/mL [6months]) in the S/V group but not in the ACE-I group. The dose of furosemide was significantly decreased during the six-month follow-up period in the S/V group (40 [20-40] mg to 20 [10-20] mg) but not in the ACE-I group. A multivariate logistic regression model showed that the presence of persistent atrial fibrillation (AF) and HF with a preserved left ventricular ejection fraction (HFpEF) was independently associated with a high delta-ANP ratio (≥ 4.5 ANP value on the start date/ANP value at 6months; the mean value was used as the cutoff value) (odds ratio [OR]: 4.649, 95% CI 1.032-20.952 and OR: 7.558, 95% CI 1.427-40.042). The plasma level of ANP was increased, and the loop diuretic dose was decreased by the addition of neprilysin inhibitor therapy in patients with compensated HF. In patients with HFpEF and complicated persistent AF, neprilysin inhibitor therapy was associated with an increase in ANP.

Diagnostic value of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and their correlation with lipoproteins in dogs with myxomatous mitral valve disease

BackgroundMyxomatous mitral valve disease (MMVD) is the most common diagnosed cardiovascular disease in dogs. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) tests are used to diagnose congestive heart failure, but there are conflicting reports about their value in diagnosing the subclinical stages of MMVD in dogs. Moreover, the diagnostic value of blood lipoproteins in dogs with MMVD is still unclear. The purpose of this study was to assess the serum concentrations of ANP, BNP and lipoproteins of dogs with MMVD and to evaluate the correlation of the levels of ANP and BNP with lipoproteins.ResultsThis study was performed on 24 dogs with MMVD and 10 healthy dogs. Dogs with MMVD were classified in to stages B1 (n = 11), B2 (n = 6), C (n = 4) and D (n = 3) groups according to the classification suggested by American College of Veterinary Internal Medicine guidelines. Our results showed that the mean serum BNP levels were significantly increased for all MMVD groups compared to control dogs. The mean serum ANP levels for the stage B2, C and D groups were significantly higher than the control group, while the mean serum ANP concentrations did not differ significantly between the stage B1 and control groups. An increase in BNP level was observed in 87.5% of patients. Although BNP concentrations were elevated in 100% of dogs with stages C, D and B2, high BNP was observed in 72.72% of dogs with stage B1. Regarding ANP, 58.33% of patients had an increase in ANP. However, elevated ANP levels were found in only 27.27% of patients in stage B1, while increased ANP levels were observed in 66.66 and 100% of patients in stage B2 and C/D groups respectively. Also, in all patients with MMVD, the mean serum concentrations of high-density lipoprotein cholesterol (HDL-C) were approximately 1.7 to 2 times significantly lower than the control group. Additionally, the mean serum low-density lipoprotein cholesterol (LDL-C) increased significantly (1.9-2.7 times) compared to the control group.There was a significant inverse correlation between HDL-C and BNP, and HDL-C and ANP. LDL-C showed a significant positive correlation with BNP, and ANP. Also, LDL-C, but not HDL-C, had a significant positive correlation with LA/AO ratio, LVIDd, LVIDdN and VHS. BNP and ANP showed a significant positive correlation with LA/AO, LVIDd, LVIDdN and VHS.ConclusionsSerum BNP has a greater diagnostic value than serum ANP in dogs with MMVD. In addition, serum BNP can be used to determine the subclinical stages of B1 and B2 MMVD. This study also suggests that dogs with subclinical MMVD, showed an increase in BNP along with a decrease in HDL-C and an increase in LDL-C, which are known to be risk factors for cardiovascular diseases in human. However, it seems that high LDL-C is more involved in the pathogenesis of MMVD than low HDL-C. Therefore, periodic testing of serum lipoproteins is recommended in high-risk patients, even if total cholesterol levels are normal.

Exogenous 8-hydroxydeoxyguanosine attenuates doxorubicin-induced cardiotoxicity by decreasing pyroptosis in H9c2 cardiomyocytes

Doxorubicin (DOX), which is widely used in cancer treatment, can induce cardiomyopathy. One of the main mechanisms whereby DOX induces cardiotoxicity involves pyroptosis through the NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD). Increased NAPDH oxidase (NOX) and oxidative stress trigger pyroptosis. Exogenous 8-hydroxydeoxyguanosine (8-OHdG) decreases reactive oxygen species (ROS) production by inactivating NOX. Here, we examined whether 8-OHdG treatment can attenuate DOX-induced pyroptosis in H9c2 cardiomyocytes. Exposure to DOX increased the peroxidative glutathione redox status and NOX1/2/4, toll-like receptor (TLR)2/4, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, while an additional 8-OHdG treatment attenuated these effects. Furthermore, DOX induced higher expression of NLRP3 inflammasome components, including NLRP3, apoptosis-associated speck-like protein containing a c-terminal caspase recruitment domain (ASC), and pro-caspase-1. Moreover, it increased caspase-1 activity, a marker of pyroptosis, and interleukin (IL)-1β expression. All these effects were attenuated by 8-OHdG treatment. In addition, the expression of the cardiotoxicity markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was increased by DOX, whereas the increase of ANP and BNP induced by DOX treatment was reversed by 8-OHdG. In conclusion, exogenous 8-OHdG attenuated DOX-induced pyroptosis by decreasing the expression of NOX1/2/3, TLR2/4, and NF-κB. Thus, 8-OHdG may attenuate DOX-induced cardiotoxicity through the inhibition of pyroptosis.

The effect of resistance training on blood pressure, apelin, ANP, PON1, adiponectin, H2O2, and ET-1 in hypertensive men

Background and aims: Primary hypertension, an unexplained increase in blood pressure (BP), accounts for 90% of the cases of hypertension and remains a critical public health challenge. This study aimed to investigate the effects of 12-week resistance training (RT) on some vasodilators and vasoconstrictors in hypertensive men. Methods: This is a semi-experimental study. A total of 40 middle-aged men (45.3±3.2 years) with moderate hypertension (systolic BP [SBP] 140.5±0.3 and diastolic BP [DBP] 90.7±0.0 mm Hg) were randomly divided into the RT (n=20) and non-exercise control (n=20) groups. The 12-week dynamic RT program was performed at an intensity of 80% of one repetition maximum for 3 days per week (3 sets of 8 repetitions/3 days a week). Blood samples were taken from both groups at baseline and weeks 4, 8, and 12. Results: SBP and DBP decreased by -8.19±2.46 mm Hg (P=0.039) and -1.19±0.02 mm Hg (P=0.033) from baseline at week 12 in the RT group, respectively, compared to the control group (SBP; 8.22±2.49, P=0.04; DBP; -1.19±0.03, P=0.032). Adiponectin, apelin, atrial natriuretic peptide (ANP), and paraoxonase-1 (PON-1) serum levels increased from baseline at weeks 8 (P=0.01) and 12 (P=0.01), while endothelin-1 (ET-1) and H2 O2 decreased from baseline at weeks 8 (P=0.01) and 12 (P=0.01) in the RT in comparison to the control group. Conclusion: Overall, 12-week RT led to an increase in apelin, ANP, PON-1, and adiponectin. Increasing these markers reduces H2 O2 and ET-1, thus decreasing SBP and DBP in hypertensive men.

B-Type Natriuretic Peptide (BNP) Revisited—Is BNP Still a Biomarker for Heart Failure in the Angiotensin Receptor/Neprilysin Inhibitor Era?

Simple SummaryActive BNP-32, less active proBNP-108, and inactive N-terminal proBNP-76 all circulate in the blood. The circulating protease neprilysin has lower substrate specificity for BNP than ANP, while proBNP and N-terminal proBNP are not degraded by neprilysin. Currently available BNP immunoassays react with both mature BNP and proBNP; therefore, measured plasma BNP is mature BNP + proBNP. Because ARNI administration increases mature BNP, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI administration reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase of mature BNP due to inhibition of degradation by neprilysin, resulting in lower plasma BNP levels. In the ARNI era, BNP remains a useful biomarker for heart failure, though mild increases early during ARNI administration should be taken into consideration.Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the glycosylation status. As a result, active BNP, less active proBNP, and inactive N-terminal proBNP all circulate in the blood. There are three major pathways for BNP clearance: (1) cellular internalization via natriuretic peptide receptor (NPR)-A and NPR-C; (2) degradation by proteases in the blood, including neprilysin, dipeptidyl-peptidase-IV, insulin degrading enzyme, etc.; and (3) excretion in the urine. Because neprilysin has lower substrate specificity for BNP than atrial natriuretic peptide (ANP), the increase in plasma BNP after angiotensin receptor neprilysin inhibitor (ARNI) administration is much smaller than the increase in plasma ANP. Currently available BNP immunoassays react with both mature BNP and proBNP. Therefore, BNP measured with an immunoassay is mature BNP + proBNP. ARNI administration increases mature BNP but not proBNP, as the latter is not degraded by neprilysin. Consequently, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase in mature BNP mediated by inhibiting degradation by neprilysin, which lowers plasma BNP levels. These results suggest that even in the ARNI era, BNP can be used for diagnosis and assessment of the pathophysiology and prognosis of heart failure, though the mild increases early during ARNI administration should be taken into consideration.

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

BackgroundPulmonary hypertension is associated with an increase in pulmonary vascular resistance leading to pulmonary vascular changes, right ventricular hypertrophy, and heart failure. Pulmonary hypertension can be induced in animal models similar to humans where the changes are comparable. Monocrotaline (MCT), an alkaloid derived from a toxic plant, can be used to induce pulmonary hypertension in animals. Sildenafil has been used to treat patients with pulmonary hypertension since it induces smooth muscle relaxation. Atrial natriuretic peptide (ANP) is a hormone secreted naturally from the atria of the heart. An increase in ANP in hypervolemia and hypertension is beneficial since it induces a significant decrease in blood volume, therefore, lowers blood pressure. Studies showed that atrial natriuretic peptide combined with sildenafil reduces pulmonary arterial hypertension significantly. Cardiac hypertrophy due to pulmonary hypertension increases expression of myosin heavy chain β in the right ventricle of the heart.AimsTo explore the ability of sildenafil to alleviate PH induced by Monocrotaline (MCT) in rats and explore the ANP level before and after induction of PH, and the administration of sildenafil.MethodsSixty four male Wister rats, were divided randomly into 4 groups: Control A, (7 Rats). Group received MCT only (14 rats), at dose 60mg /kg body weight subcutaneously. Group C received a single injection of MCT subcutaneously at a dose of 60mg /kg for 3 weeks and then sildenafil at a dose of 50mg/kg/day from the beginning of the fourth week to the end of the sixth week (The reversal group) counted 23 rats. Group D received a single injection of MCT subcutaneously at a dose of 60mg /kg for 3 weeks at the same time sildenafil was given at a dose of 50mg/kg from day 1 to the end of day 21 (The prevention group) consisting of 20 rats.ResultsThe survival rate of the prevention group was the highest compared to other groups. The results revealed that MCT‐ treated rats and the reversal group showed a significant increase in ANP levels compared to the control one. The prevention group rats showed a significant decrease in ANP levels compared to both the reversal and the MCT‐ treated group. Fulton index ratio shows a significant increase in MCT treated rats and the reversal group compared to the control group, also it has an increasingly significant level to the reversal group compared to the prevention group. The percent of β‐ myosin heavy chain (MHC) is decreased significantly in the reversal group compared to both the MCT treated group and the control group. Nitric oxide (NO) levels were increased significantly in the reversal group compared to both the MCT treated group and the control group.ConclusionSildenafil significantly decreases ANP levels in rats treated with MCT, and it also decreases cardiac hypertrophy induced by MCT.

ProANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action.

Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

Resuscitation of hemorrhagic shock using normal saline does not damage the glycocalyx in the immediate resuscitation phase.

OBJECTIVES:The objectives were to study the effect of aggressive resuscitation using normal saline on hemodynamics, serum atrial natriuretic peptide (ANP), syndecan-1 (marker of endothelial glycocalyx shedding), and extravascular lung water index (ELWI) following hemorrhagic shock.METHODS:Eleven male piglets (Sus scrofa) underwent blood drawing to create 20% drop in mean arterial pressure (MAP). Two-phase resuscitation was performed: Phase 1 using normal saline of an equal volume of blood drawn to create shock and Phase 2 using 40 ml/kg BW of normal saline to simulate hypervolemia and hemodilution. Heart rate, MAP, cardiac index (CI), systemic vascular resistance index, oxygen delivery (DO2), global end-diastolic volume index, ELWI, hemoglobin (Hb), lactate, ANP, and syndecan-1 at each phase and up to 60 min following Phase 2 resuscitation were recorded.RESULTS:Phase 2 resuscitation significantly decreased Hb concentration (P = 0.006), however, DO2 was maintained (P = 1.000). CI increased from shock to Phase 1 (P = 0.029) and further increase in Phase 2 resuscitation (P = 0.001). Overall, there was a transient increase of ANP following Phase 1 resuscitation, from 85.20 ± 40.86 ng/L at baseline to 106.42 ± 33.71 ng/L (P = 0.260). Serum syndecan-1 and ELWI change at all phases were not significant.CONCLUSIONS:We demonstrate compensatory protective mechanism despite overzealous fluid resuscitation. Compensatory increased CI despite decreased Hb maintained DO2. In the absence of inflammation, serum ANP did not increase significantly, no glycocalyx shedding occurred, subsequently no change in ELWI. We show that factors other than volume overload are more dominant in causing glycocalyx shedding.

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein.

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

63 Nocturia—An Underappreciated “Symptom” of Obstructive Sleep Apnoea?

Abstract Nocturia (>2 per night) is the most frequent cause of disturbed sleep in older people. Poor sleep results in reduced health related QoL, and is linked to the development of cognitive impairment. Nocturia can result in an increase risk of falls and fractures, and is also an independent risk factor for mortality. The prevalence of norturia is high in the elderly, and it has been reported to be around 77.1% in elderly women and 93% in men. Historically, this bothersome symptom is thought to be mainly a result of bladder outflow obstruction due to prostatic hypertrophy or overactive bladder. More recently, nocturia has been associated witsh nocturnal polyuria (NPu) and obstructive sleep apnoea (OSA). The relationship between OSA and NPu is not fully understood but it is thought that the negative intrathoracic pressure generated by OSA causes an increase in Atrial Natriuretic Peptide (ANP) secretion, resulting in NPu. Nocturia is highly prevalent in patients with severe OSA. However, patients are usually unaware that they have sleep apnoea, and are therefore more likely to present to urology or geriatric services. It is important that OSA is not overlooked in these clinics as intervention with CPAP is highly effective in reducing symptoms. Here, we present the result of using the STOP-Bang questionnaire in 71 consecutive patients presenting to our urology service with nocturia. The average age was 73 years (range 34-88), male-to-female ratio 14:1 and median nocturia frequency of 4. 42 patients were at risk of undiagnosed sleep apnoea (median STOP-Bang Score of 5)—35 were referred for sleep studies, 4 patients declined and 3 patients were not referred. Overall, 31 out of 35 sleep studies (88.6%) demonstrated the presence of OSA; of these 23 (74.2%) confirmed moderate or severe OSA. All patients with OSA were seen and treated by the respiratory service. Overall, median nocturia frequency decreased from 4 to 1 across the whole cohort, from a combination of CPAP therapy, bladder outlet procedures and desmopressin. Conclusion At least a third of patients (32%) with bothersome nocturia have an undiagnosed clinically-significant OSA. Identification of OSA improves outcomes across the whole cohort, because nocturia in patients without OSA is more likely to respond to bladder outlet procedures and desmopressin.

Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload.

RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/–) mice and absent in homozygous (GqI–/–) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 h after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels.ConclusionCardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but not for LVH induced by mechanical pressure overload (TAC). Rather, TAC-induced LVH is associated with activation of the CaMKII-HDAC4-MEF2 pathway.

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

ObjectivesThis study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). BackgroundNeprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP. MethodsIn a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment. ResultsAmong 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both). ConclusionsConcentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)

Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism

ObjectivePancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC...

Atrial Natriuretic Peptide Mediates Reverse Cardiac Remodeling During Treatment with Sacubitril/Valsartan in Patients with Heart Failure with Reduced Ejection Fraction

Introduction Sacubitril/valsartan (S/V) promotes reverse cardiac remodeling in patients with HFrEF. Neprilysin inhibition results in increase of several vasoactive peptides that may mediate effects of S/V, however its effects on atrial natriuretic peptide (ANP) are largely unknown. Effects of ANP are mediated by cyclic guanosine monophosphate (cGMP). Hypothesis Longitudinal change in ANP concentration following initiation of S/V is associated with reverse cardiac remodeling. Methods Within a prospective open-label study of initiation and titration of S/V in patients with HFrEF, this pre-specified sub-study included patients in whom ANP was measured from samples collected in protease inhibitors to minimize its degradation. Concentrations of ANP and cGMP were measured at baseline and serially through 12 months of treatment. Echocardiographic assessment of LVEF and left atrial volume index (LAVi) was performed at baseline, 6 and 12 months. Results Among 144 participants (mean age 64.5 years; LVEF 30.8%), median ANP concentration at baseline was 102 pg/mL. Following initiation of S/V, ANP increased steeply and consistently during the first 2 months, with a significant increase in log-transformed ANP concentration at Day 14 (from 4.60 pg/mL to 5.05 pg/mL; Δ = 0.453; P Conclusions Concentrations of ANP increase substantially after initiation of S/V in patients with HFrEF. Larger early increases in ANP after S/V initiation were associated with greater magnitude of reverse cardiac remodeling (PROVE-HF; NCT02887183).

Sustained increased CaMKII phosphorylation is involved in the impaired regression of isoproterenol-induced cardiac hypertrophy in rats

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the CaV1.2 channel and amounts of CaMKII bound with HDAC4 and CaV1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with CaV1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.

Abstract C47: Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis

Abstract Cancer-associated thrombosis/thromboembolism (CAT) is a serious clinical complication and leads to occasional cause of death in patients with cancers, including pancreatic ductal adenocarcinoma (PDAC). However, diagnostic and inhibitory approach for CAT is still unestablished. We found that CAT with cardiomegaly and increase of plasma atrial natriuretic peptide (ANP) were frequently observed in the PDAC mice containing conditional KrasG12D mutation and knockout of TGF-β receptor type II (Tgfbr2) (PKF mice). Similar to usual thrombotic patients without cancer, high plasma level of cytokines including soluble cell adhesion molecule X was detected in the mice. Molecule-X was immunohistochemically observed in activated endothelium and thrombi. Injection of neutralized anti-molecule-X antibody reduced onset of CAT and cardiac weight in the PKF mice. Meanwhile, high plasma levels of ANP and/or molecule-X were detected in PDAC patients before and after diagnosis of CAT. Taken together, increase of ANP and/or molecule-X is a new risk factor of CAT in PDAC patients. Blocking molecule-X, at least in part, would be an inhibitory approach for CAT in PDAC. Citation Format: Makoto Sano, Hideaki Ijichi, Kazunaga Ishigaki, Ryota Takahashi, Koji Miyabayashi, Keisuke Tateishi, Hiroyuki Isayama, Kazuhiko Koike. Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C47.

Arbutin Attenuates Isoproterenol-Induced Cardiac Hypertrophy by Inhibiting TLR-4/NF-κB Pathway in Mice.

Arbutin is a glycoside reported for its anti-oxidant, anti-inflammatory and anti-tumor properties. However, the cardioprotective effect of Arbutin is not well established. The study aims to understand the effect of arbutin on isoproterenol (ISO)-induced cardiac hypertrophy in mice. The animals were pretreated with Arbutin for a week and ISO was administered for 10 days and then sacrificed. Cardiac injury markers such as creatinine kinase and lactate dehydrogenase concentrations were measured in the serum. The mRNA expression of cardiac hypertrophy markers namely atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured using qRT-PCR. The levels of pro-inflammatory cytokines TNF-α and IL-6 were quantified by ELISA in isolated tissues and serum. Other tissue anti-oxidant parameters such as GST, GSH, SOD and TBARS were also measured. TUNEL assay was performed to detect apoptosis. Histology studies were performed using H & E and Masson trichome staining. Immunoblot analysis was used to quantify the protein expression of TLR-4 and NF-κB. ISO-alone-treated group showed significant increase in CK-MB, LDH along with increase in hypertrophic markers ANP and BNP, TNF-α and IL-6 levels in serum and tissues andincreased cardiomyocyte apoptosis. Anti-oxidant parameters were significantly decreased and TLR-4 and NF-κB protein expression was found to be upregulated in comparison to the control group. Pretreatment with Arbutin-exhibited significant inhibition of TLR-4/NF-κB pathway with decreased levels of pro-inflammatory cytokines and enhanced myocardial anti-oxidant status. Our study demonstrated that pretreatment with Arbutin exhibits marked protective effects on ISO-induced cardiac hypertrophy in mice. Thus, Arbutin may be used as potential pharmacological interventions in the management of cardiac hypertrophy.

Abstract P158: Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An In Silico Analysis

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

Effect of Neprilysin Inhibition on VariousNatriuretic Peptide Assays.

With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood. This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays. Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits. Average time to 3 follow-up visits was 22, 46, and 84days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change. Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.