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Fibrosis mechanistic phenotyping and antifibrotic response determination with biomarkers in heart failure: one single biomarker may not fit all settings

2018; Elsevier BV; Volume: 20; Issue: 9 Linguagem: Inglês

10.1002/ejhf.1214

1879-0844

Patrick Rossignol, João Pedro Ferreira, Faı̈ez Zannad,

Pulmonary Hypertension Research and Treatments

This article refers to 'Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial' by S. Ravassa et al., published in this issue on pages 1290–1299. Heart failure (HF) with preserved ejection fraction (HFpEF) affects a large proportion of patients with the clinical syndrome of HF.1 These patients share impaired quality of life and poor prognosis with their HF counterparts with reduced ejection fraction (HFrEF).2 To date, the only large outcome-driven randomized controlled trial using spironolactone vs. placebo in HFpEF was the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial.3 In TOPCAT, treatment with spironolactone did not reduce the primary outcome of cardiovascular death or HF hospitalization [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.77–1.04; P=0.14] but did reduce the pre-specified outcome of HF hospitalization (HR 0.83, 95% CI 0.69–0.99; P=0.04). However, marked geographical differences were found in TOPCAT whereby spironolactone was efficient in patients from 'the Americas' (and not in patients from Eastern Europe) and in those stratified with B-type natriuretic peptide (BNP) as entry criteria.4, 5 Aldo-DHF was a randomized controlled trial that enrolled 422 HFpEF patients (age ∼67 years; 52% female) to spironolactone or placebo for 12 months to test the efficacy of spironolactone for improving diastolic function (as assessed by echocardiographic E/e') and maximal exercise capacity [peak oxygen consumption (VO2)].6 After 12 months of therapy, spironolactone improved E/e' (adjusted mean difference –1.5, 95% CI –2.0 to –0.9; P<0.001) but not peak VO2 (adjusted mean difference +0.1, 95% CI –0.6 to +0.8 mL/min/kg; P=0.81). Spironolactone also reduced left ventricular mass and decreased N-terminal-proBNP (NT-proBNP) but did not improve HF symptoms or quality of life and slightly reduced 6-minute walking distance. Based on the TOPCAT findings and in the absence of more definitive data, it appears reasonable to treat HFpEF patients with spironolactone, as suggested by the class II indication in current US guidelines.7 However, it is possible that a more tailored approach identifying those patients more likely to benefit from spironolactone treatment may help clinicians to decide whom to treat.8 The 'antifibrotic' properties of spironolactone have been described in HFrEF and/or post-myocardial infarction (MI), and some reports suggest that patients with high cardiac collagen content respond better to spironolactone [and mineralocorticoid receptor antagonists (MRAs) in general].9, 10 In this issue of the Journal, Ravassa et al.11 present a post-hoc analysis in 381 patients of the Aldo-DHF trial investigating whether the effect of spironolactone on diastolic function (as assessed by medial E/e' ratio) is dependent on its effects on collagen cross-linking (CCL) or collagen type I deposition. For this purpose, the authors assessed the ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1) as an inverse index of myocardial CCL, and serum carboxy-terminal propeptide of procollagen type I (PICP) as a direct index of myocardial collagen deposition. The authors observed that spironolactone therapy reduced serum levels of PICP, but did not modify the ratio of serum levels of CITP over MMP-1. Furthermore, spironolactone did not improve diastolic function in the subset of patients with lower CITP:MMP-1 ratio, indicative according to the authors of a higher degree of CCL, and did not reduce serum levels of PICP in the subset of patients with lower CITP:MMP-1 ratio. These results may be pathophysiologically relevant, since the same group of Diez showed an association between myocardial CCL and increased left ventricular filling pressures in patients with HF and specifically in patients with HFpEF.12 The results reported by Ravassa et al.11 were generated post-hoc and, therefore, are at best 'hypothesis-generating'. The fact that not all HFpEF patients may respond equally to an MRA, and that MRAs may be more effective in patients with specific fibrotic bioprofiles obviously warrants prospective replication and further investigation. One may also consider the choice of different or additional synthesis/degradation ratios to measure collagen turnover or cross-linking and explore which is/are the most relevant for phenotyping, prognostication and predicting MRA response in HFpEF. Indeed, the authors did not analyse serum N-terminal propeptide of type III collagen (PIIINP) or the PICP:CITP ratio, also markers of collagen synthesis and collagen turnover, respectively. PIIINP stems from the conversion of procollagen type III into collagen type III and has been correlated with the amount of collagen type III fibres in the myocardium of HF patients.13 The PICP:CITP ratio is a marker of collagen turnover, since it reflects the ratio of collagen synthesis to its degradation.13 The analysis of these markers may provide additional insight into the fibrotic process and its response to MRA, in relation to clinical outcome. PICP is produced during the conversion of procollagen type I to collagen type I in a 1:1 ratio, hence serum PICP concentrations are direct indicators of collagen type I synthesis.13 Serum PICP levels are correlated with total myocardial collagen volume fraction (assessed in myocardial samples with collagen-specific staining) in patients with hypertension and HF.14 However, the effect of MRA on serum concentrations of PICP has been less reproducible and of smaller magnitude as compared to the effect of MRAs on PIIINP. Nonetheless, much of the available data have been obtained in HFrEF and/or post-MI populations, and not from HFpEF to date, which makes the Ravassa et al. data especially novel and provocative. In a subpopulation of the Randomized Aldactone Evaluation Study (RALES), PICP levels were not significantly reduced by spironolactone contrary to PIIINP levels. Moreover, the reduction in mortality achieved with spironolactone was only observed in patients with serum PIIINP above the median concentration, whereas no effect was observed when serum PIIINP was below the median (HR 0.44, 95% CI 0.26–0.75 vs. HR 1.11, 95% CI 0.66–1.88).9 In MI patients with systolic dysfunction and/or HF enrolled in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),10 eplerenone reduced serum PIIINP. In 134 patients with acute anterior ST-elevation MI, intravenous potassium canrenoate (the active metabolite of spironolactone) also reduced serum PIIINP. In the Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Early Treatment with Eplerenone in Patients with Acute Myocardial Infarction (REMINDER), only those patients with PIIINP levels above the median of 3.9 ng/mL exhibited a significant reduction in this biomarker with eplerenone (as compared to placebo).15 Unfortunately, PICP was not available in the EPHESUS10 and REMINDER15 trials. The increasing amount of evidence in HFrEF and/or post-MI suggests that patients with higher collagen content (PIIINP and/or PICP) are those who respond better to MRA therapy. Whether this is also the case for HFpEF cannot be ascertained from the present analysis. The potential use of circulating collagen turnover markers for fibrosis phenotyping in HF is depicted in Figure 1. In our view, despite the limitations of the TOCAT trial mainly related to the reported significant regional differences between the Americas and Russia/Georgia, and in the absence of more compelling data [e.g. such as the prospectively randomized, open-label Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) in which the primary outcome is cardiovascular mortality16], the TOPCAT results may help guide physicians currently faced with clinical decisions for patients with HFpEF with anticipated risks similar to those in patients enrolled from the Americas. Whether an in-depth fibrosis phenotyping using a panel of collagen turnover biomarkers, including CITP:MMP-1 ratio, PICP, cross-linked telopeptide of type I collagen and PIIINP concentrations may help select patients more susceptible to favourably respond to an MRA or more generally to an antifibrotic drug, deserves dedicated trials. Importantly, the ongoing Heart Omics in Ageing (HOMAGE) trial (NCT02556450) is investigating whether spironolactone (compared to 'control') can favourably alter extracellular matrix remodelling, assessed by changes in circulating PIIINP, PICP and echocardiography, in patients at increased risk of developing HF, and enable identifying those patients more likely to respond to MRA therapy. The HOMAGE trial may be one step forward in achieving this goal and strengthen the hypothesis that fibrosis mechanistic phenotyping using circulating biomarkers may help predict the response to antifibrotic drugs. The authors acknowledge Pierre Pothier for the editing of the manuscript. Conflict of interest: P.R. has received board membership fees from CTMA, CVRx, Fesenius Medical Care, Novartis, Relypsa, Vifor Fresenius Medical Renal Pharma and Steathpeptides. F.Z. has received fees for serving on the board of Boston Scientific; consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, and Resmed; and speakers' fees from Pfizer and AstraZeneca. P.R. and F.Z. are CardioRenal co-founders. P.R., J.P.F. and F.Z. are supported by the French National Research Agency (Fight HF programme ANR-15-RHU-0004 and GEENAGE Impact programme Lorraine University d'Excellence).