Renin-angiotensin-aldosterone System Activation Research Articles

Mechanisms of violations of water-electrolyte metabolism under the influence of unfavorable factors of hyperbaria and promising possibilities of their correction

The purpose of the work: to identify the mechanisms of changes in kidney function and water-electrolyte metabolism in divers with different initial resistance to adverse factors of hyperbaria using oral stress renal tests.Materials and methods. 44 men were examined. Initial resistance to adverse factors of hyperbaria was assessed in all subjects. To determine the state of kidney function, oral stress renal tests were performed under the influence of hypoxia, hyperoxia, toxic nitrogen concentrations and decompression gas formation.Results and their discussion. Changes in kidney function and water-electrolyte metabolism occurring under the action of hyperbaria factors are largely determined by hormonal mechanisms implemented through the renin — angiotensin-aldosterone system (RAAS). Under the action of hypoxia, hyperoxia, toxic nitrogen concentrations and decompression gas formation on unstable subjects, the vector of changes in the activity of RAAS will mainly be directed towards increasing the secretion of antidiuretic hormone and aldosterone.

Renin-Angiotensin-Aldosterone System Activation and Diuretic Response in Ambulatory Patients With Heart Failure

Rationale & ObjectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study DesignObservational cohort.Setting & PopulationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical ApproachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = −0.41 [−0.76, −0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = −0.48 [−0.83, −0.14] and β = −0.51 [−0.95, −0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

The relation of RAAS activity and endothelin-1 levels to coronary atherosclerotic burden and microvascular dysfunction in chest pain patients

Background and aimsIn this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD). MethodsIn a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [15O]H2O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85). ResultsAfter correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups. ConclusionsOur report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.

Circulating renin-angiotensin-aldosterone system activity in cats with systemic hypertension or cardiomyopathy.

BackgroundActivity of the circulating renin‐angiotensin‐aldosterone system (RAAS) has not been comprehensively characterized in cats with systemic hypertension (SH) or cardiomyopathy (CM), and the effects of furosemide or amlodipine treatment on the RAAS have not been fully evaluated in cats.Hypothesis/ObjectivesTo document RAAS activity in cats with SH or CM compared to healthy cats and determine how RAAS profiles change with furosemide or amlodipine treatment.AnimalsSixty‐six client‐owned cats: 15 with SH (7 amlodipine‐treated, 8 untreated), 17 with advanced CM (7 furosemide‐treated, 10 not furosemide‐treated), and 34 healthy cats.MethodsEquilibrium concentrations of RAAS peptides and aldosterone were quantified in serum samples by liquid chromatography‐mass spectrometry. Variables were compared between groups using Kruskal‐Wallis analysis with post hoc Holms‐corrected Dunn's testing.ResultsCompared with healthy cats, cats with CM had higher concentrations of angiotensin I, aldosterone, and plasma renin activity (all P < .01), and these differences remained significant (P < .03) after considering subgroups of untreated or furosemide‐treated cats. Compared with healthy cats, untreated cats with SH showed no differences in RAAS biomarkers, whereas amlodipine‐treated cats had higher concentrations of angiotensins I, II, III, IV, and 1‐7, aldosterone, and plasma renin activity (all P < .03). Multivariable analysis determined that furosemide and amlodipine treatments were independent predictors of increased RAAS biomarker concentrations.Conclusions and Clinical ImportanceCats with CM had increased RAAS activity, whereas cats with untreated SH did not. Furosemide and amlodipine both led to nonspecific activation of both classical and alternative RAAS pathways in cats.

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart.

Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

Pre-dialytic Systolic Blood Pressure is an Independent Predictor of Intradialytic Hypertension

BACKGROUND: Since endothelial dysfunction and activation of renin-angiotensin aldosterone system are the primary mechanism of intradialytic hypertension (IDHT), the assessment of pre dialytic blood pressure might provide an important information for the prediction of IDHT.&#x0D; OBJECTIVES: To assess the association between pre dialytic blood pressure and the risk of IDHT.&#x0D; METHODS: We conducted a cross-sectional study in Universitas Muhammadiyah Malang Hospital. The inclusion criteria were all hemodialysis patients aged more than 18 years, and the exclusion criteria were patients with hemodialysis duration of less than three months, patients with poor compliance to consume antihypertensive drugs, and hemodynamically unstable. The predictor variable was pre dialytic systolic blood pressure and the outcome was the incidence of IDHT. The association between pre dialytic blood pressure and the risk of IDHT was assessed using multiple logistic regression.&#x0D; RESULTS: A total of 36 patients with IDHT and 60 patients without IDHT was enrolled in our study. Our study identified that pre dialytic systolic blood pressure was associated with the risk of IDHT, with mean difference was 10.90 mmHg between patients with IDHT and without IDHT. Our study confirmed that the levels of pre dialytic systolic blood pressure 135 mmHg was the optimal cut off, and we found that patients with pre dialytic systolic blood pressure ≥ 135 mmHg had 4.60-fold to develop IDHT compared to patients with pre dialytic systolic blood pressure &lt; 135 mmHg.&#x0D; CONCLUSION: Our study reveals that pre dialytic systolic blood pressure is an important predictor of IDHT.

First-trimester maternal renin–angiotensin–aldosterone system activation and fetal growth and birthweight: the Rotterdam Periconceptional Cohort

Research questionDoes first-trimester maternal renin–angiotensin–aldosterone system (RAAS) activity determine early and late fetal growth and birthweight? DesignA total of 201 ongoing pregnancies, of which 104 were conceived naturally, seven following single intrauterine insemination (IUI), eight after IUI with ovulation induction and 82 after IVF or intracytoplasmic sperm injection treatment were selected from the Rotterdam Periconceptional Cohort. Renin, prorenin and aldosterone concentrations were determined in blood plasma at 9 and 11 weeks of gestational age. Serial crown–rump length and embryonic volume at 7, 9 and 11 weeks of gestational age were measured using virtual reality software to assess early fetal growth. Estimated fetal weight at 22 and 32 weeks of gestational age and birthweight were measured to assess late fetal growth trajectories. Pregnancy outcomes, small for gestational age (SGA) (<p10) and birthweight were retrieved from medical records. ResultsProrenin concentrations at 11 weeks of gestation showed significant negative associations with late fetal growth (beta –0.07, 95% CI –0.11 to –0.03, P < 0.001) and birthweight (betaz-scores –0.28, 95% CI –0.55 to –0.01, P=0.03), and an increased risk of SGA (<p10) (OR 10.47, 95% CI 2.49 to 53.21, P=0.002). The aldosterone/renin ratio associated negatively with the risk of SGA (OR 0.38, 95% CI 0.15 to 0.91, P=0.03). In addition, adjusted linear regression models using the total Rotterdam Periconceptional Cohort (n=1401) confirmed decreased birthweight percentiles in pregnancies with >1 corpus luteum versus pregnancies with 1 corpus luteum (betaz-scores –0.17, 95% CI –0.32 to –0.01, P=0.04). ConclusionThis study shows that excessive first-trimester prorenin release, resulting in angiotensin up-regulation, can explain why pregnancies with >1 corpus luteum are at risk for offspring with decreased birthweight and SGA. Simultaneously, high concentrations of aldosterone, independent of renin, seem to have a beneficial influence.

Hemosiderin Accumulation in Liver Decreases Iron Availability in Tachycardia-Induced Porcine Congestive Heart Failure Model.

Despite advances in the management of iron deficiency in heart failure (HF), the mechanisms underlying the effects of treatment remain to be established. Iron distribution and metabolism in HF pathogenesis need to be clarified. We used a porcine tachycardia-induced cardiomyopathy model to find out how HF development influences hepatic and myocardial iron storing, focusing on ferritin, the main iron storage protein. We found that cumulative liver congestion (due to the decrease of heart function) overwhelms its capacity to recycle iron from erythrocytes. As a consequence, iron is trapped in the liver as poorly mobilized hemosiderin. What is more, the ferritin-bound Fe3+ (reflecting bioavailable iron stores), and assembled ferritin (reflecting ability to store iron) are decreased in HF progression in the liver. We demonstrate that while HF pigs show iron deficiency indices, erythropoiesis is enhanced. Renin–angiotensin–aldosterone system activation and hepatic hepcidin suppression might indicate stress erythropoiesisinduced in HF. Furthermore, assembled ferritin increases but ferritin-bound Fe3+ is reduced in myocardium, indicating that a failing heart increases the iron storage reserve but iron deficiency leads to a drop in myocardial iron stores. Together, HF in pigs leads to down-regulated iron bioavailability and reduced hepatic iron storage making iron unavailable for systemic/cardiac needs.

The Role of Aldosterone in OSA and OSA-Related Hypertension.

Obstructive sleep apnea (OSA) is regarded as an independent risk factor for hypertension. The possible mechanism includes oxidative stress, endothelial injury, sympathetic excitement, renin–angiotensin–aldosterone system activation, etc. Clinical studies have found that there is a high coexistence of OSA and primary aldosteronism in patients with hypertension and that elevated aldosterone levels are independently associated with OSA severity in resistant hypertension. The underlying mechanism is that aldosterone excess can exacerbate OSA through increasing overnight fluid shift and affecting the mass and function of upper airway muscles during the sleep period. Thus, a bidirectional influence between OSA and aldosterone exists and contributes to hypertension in OSA patients, especially resistant hypertension.

Stimulation of Angiotensin Converting Enzyme 2: A Novel Treatment Strategy for Diabetic Nephropathy.

Despite current therapies for diabetic nephropathy, many patients continue to progress to end-stage renal disease requiring renal replacement therapy. While the precise mechanisms underlying diabetic nephropathy remain to be determined, it is well established that chronic activation of the renin angiotensin aldosterone system (RAAS) plays a substantial role in the pathogenesis of diabetic nephropathy. Angiotensin converting enzyme 2 (ACE2), the enzyme responsible for activating the reno-protective arm of the RAAS converts angiotensin (Ang) II into Ang 1-7 which exerts reno-protective effects. Chronic RAAS activation leads to kidney inflammation and fibrosis, and ultimately lead to end-stage kidney disease. Currently, angiotensin converting enzyme inhibitors and Ang II receptor blockers are approved for renal fibrosis and inflammation. Targeting the reno-protective arm of the RAAS should therefore, provide further treatment options for kidney fibrosis and inflammation. In this review, we examine how targeting the reno-protective arm of the RAAS can ameliorate kidney inflammation and fibrosis and rescue kidney function in diabetic nephropathy. We argue tissue ACE2 stimulation provides a unique and promising therapeutic approach for diabetic nephropathy.

Changes in renin-angiotensin-aldosterone system during cardiac remodeling after mitral valvuloplasty in dogs.

BackgroundInformation regarding changes in renin‐angiotensin‐aldosterone system (RAAS) during cardiac remodeling after mitral valvuloplasty (MVP) in dogs remains lacking.Hypothesis/ObjectivesTo assess the longitudinal effects of MVP on circulating RAAS activity.AnimalsEight client‐owned dogs receiving MVP for myxomatous mitral valve disease (MMVD).MethodsThis is a cohort study. Plasma renin activity (PRA), angiotensin II (AT2), aldosterone (PAC), blood urea nitrogen (BUN), and creatinine concentrations, were measured in these dogs before (baseline) and at 3 consecutive monthly follow‐ups (Post‐1M, Post‐2M, Post‐3M). Echocardiography was concomitantly used to assess the process of cardiac recovery after MVP.ResultsThe echocardiography revealed a significant decrease in LVIDDN, LA/Ao, FS, E velocity, E/A, E′ sep, S′ lat, E′ lat, and A′ lat after MVP compared with baseline (P < .05). There was a significant reduction in the PRA (2.45, 3.05, 2.74 vs 8.8 ng/mL/h; P = .002), AT2 (466, 315, 235 vs 1200 pg/mL; P = .009), and PAC (39.88, 47, 54.62 vs 179.5 pg/mL; P = .01), respectively at Post‐1M, Post‐2M, Post‐3M compared to the baseline. Additionally, BUN and creatinine concentrations decreased from Post‐1M. The RAAS variables showed significant, weak to moderate, relationship with selected echocardiographic variables.Conclusions and Clinical ImportanceMitral valvuloplasty contributes to decreased RAAS activity in MMVD dogs, which paralleled the process of cardiac reverse remodeling up to Post‐3M. This information facilitates formulating strategies to optimize clinical outcomes for dogs after MVP.

Role and Mechanism of the Renin-Angiotensin-Aldosterone System in the Onset and Development of Cardiorenal Syndrome.

Cardiorenal syndrome (CRS), a clinical syndrome involving multiple pathological mechanisms, exhibits high morbidity and mortality. According to the primary activity of the disease, CRS can be divided into cardiorenal syndrome (type I and type II), renal heart syndrome (type III and type IV), and secondary heart and kidney disease (type V). The renin-angiotensin-aldosterone system (RAAS) is an important humoral regulatory system of the body that exists widely in various tissues and organs. As a compensatory mechanism, the RAAS is typically activated to participate in the regulation of target organ function. RAAS activation plays a key role in the pathogenesis of CRS. The RAAS induces the onset and development of CRS by mediating oxidative stress, uremic toxin overload, and asymmetric dimethylarginine production. Research on the mechanism of RAAS-induced CRS can provide multiple intervention methods that are of great significance for reducing end-stage organ damage and further improving the quality of life of patients with CRS.

Sex influences the effect of adiposity on arterial stiffness and renin‐angiotensin aldosterone system activity in young adults

IntroductionSex influences the cardiovascular risk associated with body mass index (BMI) in older adults. Whether this risk differs by sex in younger adults is unknown. We aimed to evaluate the association between measures of adiposity and arterial stiffness and reninangiotensin‐aldosterone system (RAAS) activity in younger adults, stratified by sex.MethodsBody mass index (BMI), waist circumference (WC), hip circumference (HC), waist‐to‐hip ratio (WHR), waist‐to‐height ratio (WHtR) and fat mass% (FM%) were measured in healthy participants in a fasting, high‐salt state. Arterial stiffness [pulse wave velocity (PWV) and aortic augmentation index (AIx)] were measured at baseline and in response to angiotensin II challenge, a validated marker of RAAS activity. Associations were evaluated using linear regression analysis and stratified by sex.ResultsNinety‐five healthy, normotensive, non‐diabetic females (n = 67, 37 ± 2 y, BMI 25 ± 1 kg/m2) and males (n = 28, 39 ± 3 y, BMI 27 ± 1 kg/m2) participated in the study. No association was observed between any measure of adiposity and PWV, either at baseline or in response to angiotensin II challenge in premenopausal females. In contrast, all measures of adiposity except HC were associated with PWV at baseline (BMI r = 0.32; WC r = 0.18; WHtR r = 0.34; FM r = 0.21; all values p < .05) and in response to AngII (BMI r = −0.39; WC r = −0.42; WHR r = −0.39; and WHtR r = −0.55) in males. Most adiposity measures were positively associated with baseline AIx (BMI r = 0.33; WC r = 0.27; WHtR r = 0.35; FM% r = 0.25; p < .05) in females, while only WHtR was associated with baseline AIx (r = 0.39; p = .04) in males. All measures of adiposity were positively associated with a blunted Aix response to Ang II (all values p < .001) in females. BMI, WC, WHR and WHtR were associated with a blunted AIx response to Ang II (ΔAIx: BMI r = −0.37; WC r = −0.31; WHR r = −0.16; and WHtR r = −0.22; all values p < .05) in males.ConclusionThe associations between adiposity measures and cardiovascular risk differ by sex in a young population. These factors should be considered when managing cardiovascular risk.

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

Changes of FGF23 and the Renin-Angiotensin-System in Male Mouse Models of Chronic Kidney Disease and Cardiac Hypertrophy.

Serum fibroblast growth factor 23 (FGF23) levels and the renin-angiotensin-aldosterone system (RAAS) are elevated in chronic kidney disease (CKD) patients, and their association with left ventricular hypertrophy (LVH) has been reported. However, whether the FGF23 elevation is the cause or result of LVH remains unclear. At 10 weeks, male C57BL/6J mice were divided into 4 groups: sham, CKD (5/6 nephrectomy), LVH (transaortic constriction), and CKD/LVH group. At 16 weeks, the mice were euthanized, and blood and urine, cardiac expressions of FGF23 and RAAS-related factors, and cardiac histological analyses were performed. Heart weight, serum FGF23 levels, and cardiac expression of FGF23 and RAAS-related factors, except for angiotensin-converting enzyme 2, were more increased in the CKD/LVH group compared to the other groups. A significant correlation between LVH and cardiac expressions of FGF23 and RAAS-related factors was observed. Furthermore, there was a significantly close correlation of the cardiac expression of FGF23 with LVH and RAAS-related factors. The coexisting CKD and LVH increased serum and cardiac FGF23 and RAAS-related factors, and there was a significant correlation between them. A close correlation of cardiac, but not serum FGF23, with LVH and RAAS suggests that local FGF23 levels may be associated with LVH and RAAS activation.

545 Cardiac protection by pirfenidone after myocardial infarction: a bioinformatic analysis

Abstract Aims Left ventricular (LV) remodelling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by an anti-fibrotic drug such as pirfenidone. Methods and results We explored the relationship between protein modulation by pirfenidone and post-MI remodelling, based on publicly available molecular information and transcriptomic data from a swine model of MI. We also compared the effects of pirfenidone and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), mineralocorticoid receptor blockers (MRA) and beta-blockers. We identified six causative motives of post-MI remodelling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodelling and fibrosis, hypertrophy, renin–angiotensin–aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). When considering both targets and bioflags, pirfenidone showed a broad relationship encompassing all six motives. p38γ-MAPK12 blockade inhibits cardiomyocyte apoptosis, cardiomyocyte hypertrophy and inflammation. Furthermore, pirfenidone can modulate extracellular matrix remodelling and cardiac fibrosis by targeting the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1, which promote myocardial fibrosis, cardiomyocyte hypertrophy and impaired contractility. All the gold standard drugs were found to be important for specific clinical motives, but pirfenidone had a more widespread action on the molecular pathways active in the post-MI setting. Conclusions A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodelling, and suggests additional effects over guideline-recommended therapies. These findings support clinical studies evaluating the beneficial effects of pirfenidone in patients with MI.

Cirrhosis-Associated RAS-Inflammation-Coagulation Axis Anomalies: Parallels to Severe COVID-19.

(1) Background: Cirrhotic patients have an increased risk for severe COVID-19. We investigated the renin-angiotensin-aldosterone system (RAS), parameters of endothelial dysfunction, inflammation, and coagulation/fibrinolysis in cirrhotic patients and in COVID-19 patients. (2) Methods: 127 prospectively characterized cirrhotic patients (CIRR), along with nine patients with mild COVID-19 (mild-COVID), 11 patients with COVID-19 acute respiratory distress syndrome (ARDS; ARDS-COVID), and 10 healthy subjects (HS) were included in the study. Portal hypertension (PH) in cirrhotic patients was characterized by hepatic venous pressure gradient (HVPG). (3) Results: With increased liver disease severity (Child−Pugh stage A vs. B vs. C) and compared to HS, CIRR patients exhibited higher RAS activity (angiotensin-converting enzyme (ACE), renin, aldosterone), endothelial dysfunction (von Willebrand-factor (VWF) antigen), inflammation (C-reactive protein (CRP), interleukin-6 (IL-6)), and a disturbed coagulation/fibrinolysis profile (prothrombin fragment F1,2, D-dimer, plasminogen activity, antiplasmin activity). Increased RAS activity (renin), endothelial dysfunction (vWF), coagulation parameters (D-dimer, prothrombin fragment F1,2) and inflammation (CRP, IL-6) were significantly altered in COVID patients and followed similar trends from mild-COVID to ARDS-COVID. In CIRR patients, ACE activity was linked to IL-6 (ρ = 0.26; p = 0.003), independently correlated with VWF antigen (aB: 0.10; p = 0.001), and was inversely associated with prothrombin fragment F1,2 (aB: −0.03; p = 0.023) and antiplasmin activity (aB: −0.58; p = 0.006), after adjusting for liver disease severity. (4) Conclusions: The considerable upregulation of the RAS in Child−Pugh B/C cirrhosis is linked to systemic inflammation, endothelial dysfunction, and abnormal coagulation profile. The cirrhosis-associated abnormalities of ACE, IL-6, VWF antigen, and antiplasmin parallel those observed in severe COVID-19.

Abstract 11071: Increased Circulating Raas Activity is Related to Functionally Significant Coronary Artery Disease as Defined by Ffr and [ 15 O]h2o Pet Perfusion as Well as Vulnerable Plaque Characteristics on CT Angiography

Introduction: Renin-angiotensin-aldosterone-system (RAAS) activity has been linked to coronary artery disease (CAD) and coronary microvascular dysfunction (CMD), opening potential frontiers for treatment. In this study we investigated if increased RAAS activation is related to CAD, high risk plaque (HRP), myocardial perfusion, and CMD in chest pain patients. Methods: Renin as a measure for RAAS activation, was quantified by immunoradiometric assay in 205 patients (64% men; age 58 ± 9 years) with suspected CAD. Patients underwent 256-slice coronary CT angiography for (quantitative) plaque analysis and coronary artery calcium (CAC) scoring, [ 15 O]H2O PET perfusion imaging and invasive FFR measurements in all coronary arteries. A total of 585 vessels were stratified upon four categories based on [ 15 O]H2O PET perfusion and invasive pressure measurements. Vessels with a FFR &gt;0.80 but with an ischemic hyperemic MBF below 2.3 ml/min/g were defined as CMD. Results: In univariable analysis, renin associated positively with the CAC score, total plaque volume (TPV) and impaired perfusion (p&lt;0.01 for all). Patients with HRP displayed higher levels of renin (p=0.04). As expected, renin (p&lt;0.01) was elevated in males. After correction for baseline characteristics including sex, renin associated positively with CAC score and TPV (p&lt;0.01 and p=0.03), but not with HRP and perfusion (p=0.14 and p=0.40). Figure 1 shows that vessels with a significant flow limiting stenosis (FFR+, PET+; p=0.04) occur in patient with elevated renin levels, while vessels defined as CMD (FFR-, PET+) do not, except for patient without RAAS inhibition. Conclusion: RAAS activation is associated with CAD defined by FFR and [ 15 O]H2O PET and HRP. Future studies should clarify whether RAAS activation and CAD are causally related and represent modifiable targets. Figure 1. Intergroup p values are depicted for significant p values only. The upper and lower whiskers represent the 10 th and 90 th percentile.

Abstract 11991: Effects of Clozapine at Different Doses on Blood Pressure and Renal Sodium Transporters in Mice

Introduction: one of major side effects of clozapine (common antipsychotic drug) is hypertension. Kidney regulates blood pressure by initiating and responding to renin-angiotensin-aldosterone system (RAAS) physiologically and pathophysiologically;the pathogenesis of hypertension is linked to, generally, the increases in the protein expressions and functions of renal sodium transport proteins along the nephron with or without RAAS activation. Methods: we examined the blood pressures (BP) and protein expressions of major sodium transport proteins profiled along the renal tubules in the C57Bl6/J male mice (9 weeks old, n=4-5/group) treated with clozapine at three doses of 5,10 and 20 mg/ kg for 1 week via intraperitoneal injection. Result: blood pressures (tail-cuff, BP98A, softron, Japan) were higher in clozapine at 20mg/kg/day than vehicle (SBP: 130±1.64 vs 109±1.39, DBP: 87 ±4.12 vs 69±2.10 mmHg, n=5/group) and not altered at 5 &amp; 10 mg/kg/day. BW was similar between groups. There were no differences in serum/urine creatinine and electrolytes except for a slight increase in serum sodium at dose of 20 mg/kg (152.8±0.71 vs 150.6±0.40, mmol/L).The renal protein expressions of NaPi2 (western blotting, 199±26 , % of vehicle), NKCC2(184±20), NCC(213±14), and ENaC-α(217±47)were higher at 20 mg/kg than vehicle. No increases were found in protein expressions of NHE3, αNKA, ENaC-β and ENaC-γ. The expressions of renin, AT1R and ACE at 20mg/kg were similar between groups while ACE2 was decreased (42±10). Renal protein expression of NKCC2 was increased in 5mg/kg (360±80, % of vehicle) and 10mg/kg (247±50) groups; NCC was increased at 5 mg/kg (175±9); α NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. Additional mice were treated with clozapine at 20mg/kg/day via osmotic mini-pump for 1 week (mini-pump) or administrated by intraperitoneal injection for 2 weeks (2wks). Increases of renal NKCC2 (mini-pump:180±21, 2wks:153±18) and NCC (mini-pump:171±22, 2 wks:160±23) were also found in those models. Conclusions: increases of renal sodium transport proteins, mainly NCC and NKCC2, contribute to the dose-related increase of BP in mice treated with clozapine and may play an important role in the pathogenesis of theclozapine-induced hypertension.

Abstract 12660: Novel Model of Oxalate Diet Induced Chronic Kidney Disease in Dahl-Salt-Sensitive Rats

Background: Diet induced models of chronic kidney disease (CKD) may offer several advantages vs surgical models in terms of clinical relevance and animal welfare. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. Increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction and eventually CKD. Dahl-salt-sensitive rats (Dahl-S) are a common strain used to study for hypertensive renal disease however characterization of other diet induced models on this background would allow for comparative studies of CKD within the same strain. We hypothesized that Dahl-S rats on a low-salt, oxalate rich diet would have increased renal injury and will serve as a novel rat model to study CKD. Methods/Results: Ten week-old male Dahl-S rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks (n=6-8/group). Real-time PCR demonstrated increased expression of inflammatory marker IL-6 (235% vs SS-NC, p&lt;0.0001) and fibrotic marker Timp-1 metalloproteinase (142% vs SS-NC, p&lt;0.0001) in the renal cortex of SS-OX rat kidneys compared to SS-NC. Immunohistochemistry of kidney tissue demonstrated increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats (275% vs SS-NC, p&lt;0.001). In addition, SS-OX rats displayed increased 24-hour urinary protein excretion (UPE) (97% vs SS-NC, p&lt;0.01) as well as significant elevations of plasma Cystatin C (135% vs SS-NC, p&lt;0.01). Furthermore, oxalate diet induced hypertension (23% increase in systolic blood pressure vs. SS-NC, p&lt;0.05) and renin-angiotensin-aldosterone system (RAAS) profiling (via LC-MS/MS) in the SS-OX plasma showed significant (p&lt;0.05) increases in angiotensin [1-5] (128% vs SS-NC) and angiotensin I (56% vs SS-NC) as well as suppression of the steroid aldosterone (-54% vs SS-NC). Conclusion: Oxalate diet induces significant renal inflammation, fibrosis, renal dysfunction, decreased aldosterone secretion as well as RAAS activation and hypertension in Dahl-S rats and provides a novel diet-induced model to study hypertension and CKD.