Renin-angiotensin-aldosterone system dynamics after targeted blood pressure control using angiotensin II or norepinephrine in cardiac surgery: mechanistic randomised controlled trial.

BACKGROUND: The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels. METHODS: In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70-80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery. RESULTS: In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3-88] µU ml-1; P<0.001) but angiotensin II did not (MD -3 [IQR -62 to 35] µU ml-1; P=0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD -0.01 [IQR -0.14 to 0.03] µU ml-1 per ng dl-1, P=0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004-0.26] µU ml-1 per ng dl-1, P<0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points. CONCLUSIONS: Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry-ACTRN12621000195853 23/02/2021.

Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk.

BACKGROUND: Despite cardiovascular diseases and thrombosis being major causes of death in patients with chronic kidney disease (CKD), there remains no effective biomarker to predict thrombotic risk in this population. OBJECTIVE: To evaluate global coagulation assays in patients with CKD and correlate the biomarkers to clinical outcomes. MATERIAL AND METHODS: Patients with eGFR<30 mL/min/1.73m2 were recruited (n = 90) in this prospective observational study. Blood samples were collected for global coagulation assays, including thromboelastography, calibrated automated thrombogram (CAT), overall hemostatic potential (OHP) and tissue factor pathway inhibitor (TFPI). RESULTS: Following adjustment for age and gender, CKD subjects (mean age 66 years, 36 % female) had increased maximum amplitude on thromboelastography (70.1 vs 60.2 mm, p < 0.001), higher peak thrombin (233.2 vs 219.7 mm, p = 0.030) and increased OHP (16.1 vs 6.4 units, p < 0.001) compared to healthy controls (n = 153). TFPI was also increased in CKD patients (36.4 vs 14.5 ng/mL, p < 0.001). Compared to hemodialysis patients (n = 43), peritoneal-dialysis patients (n = 25) had more hypercoagulable parameters. Thirty-five CKD patients reported thrombotic complications - key predictors included dialysis, higher fibrinogen, reduced endogenous thrombin potential, elevated D-dimer and increased TFPI. Using the dialysis cohort, the predictive risk model based on the key predictors performed better than Framingham heart score and number of cardiovascular risk factors (Harrell's C-stat 0.862 vs 0.585 vs 0.565). CONCLUSION: CKD appears to confer a hypercoagulable state compared to healthy controls. Interestingly, reduced thrombin generation and raised TFPI was paradoxically associated with increased thrombotic risks, highlighting possible complex compensatory mechanisms within the coagulation system, which may be important in predicting clinical outcomes.

Retinal microvascular function predicts chronic kidney disease in patients with cardiovascular risk factors.

BACKGROUND AND AIMS: Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. METHODS: In a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). RESULTS: Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2) (1.0 [0.4-2.1]% vs. 2.0 [0.8-3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2. CONCLUSIONS: Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.

Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?

OBJECTIVE: We evaluated the influence of the renin-angiotensin system (RAS) on intestinal inflammation and fibrosis. DESIGN: Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1-7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies. RESULTS: Human colonic myofibroblast proliferation was reduced by Ang (1-7) in a dose-dependent manner (p<0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p<0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1-7) (p<0.05) and captopril (p<0.001), and was increased by Ang II (p<0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson's trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=-0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation. CONCLUSIONS: The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.

Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis.

OBJECTIVES: This study investigated the relationship between plasma angiotensin-converting enzyme 2 (ACE2) activity levels and the severity of stenosis and myocardial remodeling in patients with aortic stenosis (AS) and determined if plasma ACE2 levels offered incremental prognostic usefulness to predict all-cause mortality. BACKGROUND: ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of cardiovascular disease. METHODS: Plasma ACE2 activity was measured in 127 patients with AS; a subgroup had myocardial tissue collected at the time of aortic valve replacement. RESULTS: The median plasma ACE2 activity was 34.0 pmol/ml/min, and levels correlated with increased valvular calcification (p = 0.023) and the left ventricular (LV) mass index (r = 0.34; p < 0.001). Patients with above-median plasma ACE2 had higher LV end-diastolic volume (57 ml/m2 vs. 48 ml/m2; p = 0.021). Over a median follow-up of 5 years, elevated plasma ACE2 activity was an independent predictor of all-cause mortality after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06; p = 0.042), including brain natriuretic peptide activation (integrated discrimination improvement: 0.08; p < 0.001). In 22 patients with plasma and tissue, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression (0.7-fold; p = 0.033) and severe myocardial fibrosis (p = 0.027). CONCLUSIONS: In patients with AS, elevated plasma ACE2 was a marker of myocardial structural abnormalities and an independent predictor of mortality with incremental value over traditional prognostic markers. Loss of ACE2 from the myocardium was associated with increased fibrosis and higher circulating ACE2 levels.

Development of Acute Decompensated Heart Failure Among Hospital Inpatients: Incidence, Causes and Outcomes.

BACKGROUND: We aimed to investigate the incidence, precipitants, and outcomes of acute decompensated heart failure (ADHF) that develops during the inpatient stay. METHODS: We undertook a case-control study in the medical, oncology, surgical, and orthopaedic wards of a tertiary referral hospital (February-May, 2016). Patients aged ≥18 years who developed ADHF during their inpatient stay were enrolled as cases. One control patient was matched to each case by age, gender, presenting complaint/surgery performed and co-morbidities. Multivariate regression was employed to determine variables associated with ADHF. RESULTS: The incidence of ADHF was 1.0% of patients. Eighty cases were well-matched to 80 controls (p>0.05). ADHF precipitants comprised infection (30%), inappropriate intravenous (IV) fluid and medication management (23.8% and 8.8%, respectively), tachyarrhythmia (12.5%), ischaemic heart disease (8.8%), renal failure (1.3%), and other/unclear causes (15%). Three variables were associated with ADHF: not having English as the preferred language (OR 3.5, 95%CI 1.2-9.8), a history of ischaemic heart disease (OR 3.3, 95%CI 1.2-9.1), and the administration of >2000ml of IV fluid on the day before the ADHF (OR 8.3, 95%CI 1.5-48.0). The day before the ADHF, cases were administered significantly more IV fluids than controls (median 2,757.5 versus 975ml, p=0.001). Medication errors mostly related to failure to restart regular diuretics. Cases had significantly greater length of stay (median 15 versus 6 days, p<0.001) and mortality (12.5% versus 1.3%, p=0.01). CONCLUSIONS: New onset ADHF is common and a substantial proportion of cases are iatrogenic. Cases experience significantly increased length of hospital stay, morbidity, and mortality.

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.

MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury.

Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and microRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-ß, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes.

Emerging markers in cardiovascular disease: where does angiotensin-converting enzyme 2 fit in?

The renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease (CVD). The enzyme angiotensin-converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor AngII and was thought, until recently, to be the main effector of the system. The enzyme ACE2, discovered in 2000, can counterbalance the effects of ACE through degradation of AngII and generation of Ang-(1-7). Angiotensin-converting enzyme 2 is abundantly expressed in the heart and localized to the endothelial cells of coronary vessels and smooth muscle cells. Its catalytically active ectodomain undergoes shedding, resulting in ACE2 in the circulation. There are 10 studies to date that have measured circulating ACE2 activity in humans, including in healthy subjects and those with heart failure, Type 1 diabetes, implantable cardioverter/defibrillator, elderly subjects undergoing emergency orthopaedic surgery and kidney transplant patients. The results suggest that circulating ACE2 activity may be a marker of CVD, with low levels in healthy individuals and increased levels in those with cardiovascular risk factors or disease. Whether increased plasma ACE2 activity reflects increased synthesis from tissue ACE2 mRNA or increased shedding of tissue ACE2 remains to be determined. Angiotensin-converting enzyme 2 is located on the X-chromosome and circulating ACE2 levels are higher in men than in women. Large clinical studies in CVD are needed to more precisely clarify the role of ACE2 as a biomarker of CVD, determine the prognostic significance of circulating ACE2 activity and assess whether the measurement of ACE2 will improve CVD risk prediction.