Low- and High-renin Heart Failure Phenotypes with Clinical Implications

Pávó, Noémi; Goliasch, Georg; Wurm, Raphael; Novák, J; Strunk, Guido; Gyöngyösi, Mariann; Poglitsch, Marko; Säemann, Marcus D.; Hülsmann, Martin

doi:10.1373/clinchem.2017.278705

Cited by 56 publications

(65 citation statements)

References 35 publications

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“…Briefly, serum conditioning for equilibrium analysis was performed at 37°C followed by stabilization through the addition of an enzyme inhibitor cocktail (Waters, Milford, Massachusetts), as described previously . Previous results have shown similar qualitative outcomes when comparing the quantification of circulating (stabilized immediately at blood drawing) and equilibrium angiotensin peptide levels . Stabilized equilibrated serum samples were further spiked with stable isotope labeled internal standards for each angiotensin metabolite as well as with the deuterated internal standard for aldosterone (aldosterone D4) at a concentration of 200 pg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…The ratio of angiotensin II to angiotensin I was calculated as a marker for ACE activity (ACE‐S). Angiotensin I and angiotensin II were summed as a marker for plasma renin concentration (PRA‐S) . The ratio of angiotensin 1‐5 to angiotensin 1‐7 (Ang 1‐5/Ang 1‐7) was calculated as an indicator of ACE activity driven by its N‐domain .…”

Section: Methodsmentioning

confidence: 99%

“…The equilibrium concentrations of 6 different RAAS angiotensin peptide metabolites and aldosterone in canine serum samples were quantified by liquid chromatography-mass spectrometry/massspectroscopy performed at a service provider laboratory (Attoquant Diagnostics, Vienna, Austria), using previously validated and described methods. 8,10,17 Briefly, serum conditioning for equilibrium analysis was performed at 37 C followed by stabilization through the addition of an enzyme inhibitor cocktail (Waters, Milford, Massachusetts), as described previously. 8,10,17 Previous results have shown similar qualitative outcomes when comparing the quantification of circulating (stabilized immediately at blood drawing) and equilibrium angiotensin peptide levels.…”

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

“…8,10,17 Briefly, serum conditioning for equilibrium analysis was performed at 37 C followed by stabilization through the addition of an enzyme inhibitor cocktail (Waters, Milford, Massachusetts), as described previously. 8,10,17 Previous results have shown similar qualitative outcomes when comparing the quantification of circulating (stabilized immediately at blood drawing) and equilibrium angiotensin peptide levels. 8 The ratio of angiotensin II to angiotensin I was calculated as a marker for ACE activity (ACE-S).…”

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

“…Angiotensin I and angiotensin II were summed as a marker for plasma renin concentration (PRA-S). 17 The ratio of angiotensin 1-5 to angiotensin 1-7 (Ang 1-5/Ang 1-7) was calculated as an indicator of ACE activity driven by its N-domain. 15 The ratio of aldosterone to angiotensin II (AA2) was calculated as an indicator of adrenal responsiveness to angiotensin II stimulation of aldosterone release.…”

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

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Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Adin

Atkins

Domenig³

et al. 2020

Veterinary Internal Medicne

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Background An angiotensin‐converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied. Hypothesis We hypothesized that dogs with the polymorphism would show alternative renin‐angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE‐inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE‐inhibitor administration. Animals Twenty‐one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism. Methods This retrospective study utilized stored samples from 8 ACE gene polymorphism‐negative (PN) dogs and 13 ACE gene polymorphism‐positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups. Results The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85‐184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00‐33.92) after enalapril. Conclusions and Clinical Importance The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE‐inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

Section: Equilibrium Analysis Of Raas Componentsmentioning

confidence: 99%

See 3 more Smart Citations

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Adin

Atkins

Domenig³

et al. 2020

Veterinary Internal Medicne

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Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure

et al. 2020

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Aims Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. Methods and results We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile 25-75 = 28-247) μIU/mL and 9.4 (percentile 25-75 = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. Conclusions Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.Categorical variables are described as frequencies (percentages), and continuous variables are described as means ± 954 M. Kobayashi et al. ESC Heart Failure 2020; 7: 953-963

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Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure

Bosch

Poglitsch²,

Kannenkeril

et al. 2023

ESC Heart Failure

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Aims Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin-angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme-angiotensin II-angiotensin-1 receptor axis (Ang I-ACE-Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2angiotensin-(1-7)-Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects. Methods We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II-III) in a randomized placebo-controlled clinical trial 'Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)'. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication. Results Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3-324.2) vs. 131.5 pmol/L (34.9-564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5-236.6) vs. 125.9 pmol/L (52.6-512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0-15.0) vs. 10.1 pmol/L (3.0-31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0-22.9) vs. 9.9 pmol/L (2.8-36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2-750.6) vs. 568.2 pmol/L (164.7-1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0-14.1) vs. 15.0 pmol/L (3.0-31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8-46.6) vs. 36.4 pmol/L (11.1-90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0-60.8) vs. 26.4 pmol/L (10.7-63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0-20.7) vs. 10.5 pmol/L (3.0-50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0-8.4) vs. 2.8 pmol/L (2.0-6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment). Conclusions Our data indicate that empagliflozin might lead to an activation of both the Ang I-ACE-Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I-ACE-Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.

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Low- and High-renin Heart Failure Phenotypes with Clinical Implications

Abstract: In addition to NT-proBNP and NYHA stages, ARC enables classification of HFrEF patients receiving OMT into more distinguished neurohumoral HFrEF phenotypes, offering a rationale for adaptive therapeutic interventions.

Cited by 56 publications

References 35 publications

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Renin‐angiotensin aldosterone profile before and after angiotensin‐converting enzyme‐inhibitor administration in dogs with angiotensin‐converting enzyme gene polymorphism

Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure

Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure

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