Dziewięcka, Ewa

Holcman, Katarzyna

Podolec, Piotr

Rubiś, Paweł

Wiśniowska-Śmiałek, Sylwia

Wypasek, Ewa

Polish Archives of Internal Medicine

English

Jagiellonian Univeristy Repository

RESEARCH LETTER Potential fibrosis ‑attenuating effect of ARNIs in HFrEF 1017sex ‑matched control group consisting of 28 HFrEF patients treated with ACEIs. Both groups were fol‑lowed up for 12 months and all patients had blood samples collected for biomarker tests at baseline as well as at 3 and 12 months. We analyzed the fol‑lowing serum markers of collagen synthesis: pro‑collagen type I carboxyterminal propeptide and procollagen type III aminoterminal propeptide (PICP and PIIINP; Cloud Clone Corp. Houston, Texas, United States), and fibrosis controlling factors: transforming growth factor β1 (TGF ‑β1; Diaclone SAS, Besancon Cedex, France) and con‑nective tissue growth factor (CTGF; Cloud Clone Corp., Houston, Texas, United States). The study was approved by an appropriate ethics commit‑tee, and patients provided written informed con‑sent to participate in the study.Statistical analysis Statistical analyses were per‑formed using the Statistica PL software (Dell Inc., Round Rock, Texas, United States). The signifi‑cance level was set at 0.05. Normality of variable distribution was assessed with the Shapiro–Wilk test. In both study groups, continuous data were compared using the t test or the Mann–Whitney test, as appropriate, whereas categorical val‑ues, with the χ2 test. Blood levels of fibrosis biomarkers were compared at specific and pre‑defined time points, ie, at baseline and at 3 and 12 ‑month follow ‑up. Both groups (ie, ARNI‑ and Introduction Myocardial fibrosis (MF) plays a cru‑cial role in cardiac remodeling during the course of heart failure with reduced ejection fraction (HFrEF).1 The dynamics of MF may be indirectly assessed by measuring the levels of circulating se‑rum markers of fibrosis.2 The clinical use of mul‑tilevel neurohormonal blockers (eg, β ‑adrenergic blockers) and antagonists of the renin–angio‑tensin–aldosterone system (eg, angiotensin‑‑converting enzyme inhibitors [ACEIs], angio‑tensin receptor blockers [ARBs], and mineralocor‑ticoid receptor antagonists) show numerous ben‑eficial effects in HFrEF as well as attenuates MF.3 A recently introduced class of agents—angioten‑sin receptor–neprilysin inhibitors (ARNIs)—has proven to be superior in patients with HFrEF of various etiologies in comparison to ACEIs and ARBs; however, the role of ARNI treatment in MF remains poorly understood.4-6In this study, we investigated the kinetics of serum fibrosis markers in ARNI ‑treated patients with HFrEF and compared the results with a con‑trol group of HFrEF patients treated with ACEIs.Methods It was a nonrandomized, prospective, observational, longitudinal open ‑label study with a control group. From January 2017 to November 2018, we included 28 patients with HFrEF who started ARNI therapy. Patients treat‑ed with ARNIs were compared with an age‑ and RESEARCH LETTERComparison of the 12 ‑month kinetics of the serum markers of fibrosis between treatment with angiotensin receptor–neprilysin inhibitors and angiotensin ‑converting enzyme inhibitors in patients with heart failure with reduced ejection fractionSylwia Wiśniowska ‑Śmiałek1, Ewa Dziewięcka1, Katarzyna Holcman1, Piotr Podolec1, Ewa Wypasek2,3, Paweł Rubiś11  Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland2  Department of Molecular Biology, John Paul II Hospital, Kraków, Poland3  Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Kraków, PolandCorrespondence to: Sylwia Wiśniowska ‑Śmiałek, MD, BMedSc, Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, ul. Prądnicka 80, 31‑202 Kraków, Poland, phone: +48 12 614 22 87, email: swisniowskasmialek@gmail.comReceived: July 17, 2020.Revision accepted: September 11, 2020.Published online: September 15, 2020.Pol Arch Intern Med. 2020; 130 (11): 1017‑1020doi:10.20452/pamw.15599Copyright by the Author(s), 2020POLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)1018The  baseline median (IQR) values of se‑rum markers of collagen synthesis were simi‑lar for patients treated with ARNIs and ACEIs: PICP—0.09 (0.07–0.32) ng/ml in the ARNI group and 0.15 (0.1–0.25) ng/ml in the ACEI group (P = 0.41); and PIIINP—2537.7 (1873.8–9413.4) pg/ml in the ARNI group and 3043.7 (2923.9–5454.9) pg/ml in the ACEI group (P = 0.58). How‑ever, over the follow ‑up period, PICP levels were significantly lower in patients treated with ARNIs (at 3 months: 0.09 [0.08–0.21] ng/ml in the ARNI group and 0.23 [0.18–0.28] ng/ml in the ACEI group; at 12 months: 0.1 [0.08–0.22] ng/ml in the ARNI group and 0.34 [0.29–0.36] ng/ml in the ACEI group; all P <0.01) (FIguRE 1A). The lev‑els of PIIINP were similar at 3 months in patients treated with ARNIs and ACEIs (2949.6 [1 359.7–10 437.9] pg/ml vs 4084.2 [3182.9–4642.1] pg/ml; P = 0.89); however, at 12 months, PIIINP lev‑els were significantly higher in patients receiv‑ing ARNIs compared with those treated with ACEIs (3471.2 [1 962.9–12 546.1] pg/ml vs 1299.2 [809.8–2875.9] pg/ml; P <0.021) (FIguRE 1B).The median (IQR) levels of TGF‑β1 were sig‑nificantly lower in the ARNI group compared with the ACEI group at each time point dur‑ing the follow ‑up period, including at baseline (783.8 [693.5–907] pg/ml in the ARNI group vs 227 [1809–2787] pg/ml in the ACEI group [P <0.001]); at 3 months (769.1 [697–831.8] pg/ml in the ARNI group vs 2226 [1816‑3145] pg/ml in the ACEI group [P <0.001]); and at 12 months (776.5 [722‑934] pg/ml in the ARNI group vs 1031 [763‑2055] pg/ml in the ACEI group [P <0.002]) (FIguRE 1C). The median (IQR) levels of CTGF were similar at baseline (2.9 [2.38–10.7] ng/ml in the ARNI group and 3.4 [2.8–6.2] ng/ml in the ACEI group [P = 0.8]) and at 3 months (2.75 [2.3–6.9] ng/ml in the ARNI group and 3 [2.3–6.1] ng/ml in the ACEI group [P = 0.92]). Interest‑ingly, at 12 months, CTGF was found to be signif‑icantly higher in the ARNI group (median [IQR], 4.3 [2.7–11.3] ng/ml) in comparison to the ACEI group (2.6 [2.2–3.2] ng/ml) (P <0.002) (FIguRE 1D).Discussion So far, only 3 studies have addressed the issue of ARNI treatment with regard to MF in patients with HF: 2 studies on HFrEF (both be‑ing subanalyses of the landmark PARADIGM ‑HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Mor‑bidity in Heart Failure) trial, although with pop‑ulations of slightly different sizes),and a single study on HF with preserved EF (HFpEF).6-8 Simi‑lar to our study, these studies investigated MF by means of a variety of circulating markers of fibro‑sis. In the first subanalysis of the PARADIGM ‑HF trial, Zile et al7 observed that, after 8 months of ARNI therapy, the levels of circulating fibrosis‑‑bound biomarkers, including soluble suppres‑sion of tumorigenicity 2 (sST2), matrix metal‑loproteinases (MMP ‑2 and MMP ‑9), tissue in‑hibitor of matrix metalloproteinase, galectin ‑3 (Gal ‑3), N ‑terminal propeptide of collagen I, and ACEI ‑treated patients) were matched by propen‑sity score matching according to age and sex. Val‑ues were expressed as median (interquartile range [IQR]) or mean (SD) values, whereas nominal vari‑ables, as numbers and percentages.Results Both study groups were matched with the following crucial variables: age (mean [SD]: ARNI group, 52.9 [15.3] years vs ACEI group, 49.3 [11.6] years; P = 0.23) and male sex (ARNI group, 21 [75%] vs ACEI group, 24 [87%]; P = 0.51). In addition, other clinically relevant parameters were also similarly distributed between the groups: New York Heart Association class (class I: ARNI group, 1 [3.6%] vs ACEI group, 3 [10.7%]; class II: ARNI group, 15 [53.6%] vs ACEI group, 11 [39.3%]; class III: ARNI group, 12 [42.9%] vs ACEI group, 12 [42.9%]; class IV: ARNI group, 0 vs ACEI group, 2 [7.1%]; P = 0.4), ejection frac‑tion (mean [SD]: ARNI group, 24.7% [7.6%] vs ACEI group, 21.8% (8.3%); P = 0.16), and N ‑termi‑nal fragment of the prohormone brain natriuret‑ic peptide levels (mean [SD]: ARNI group, 2156.6 (1478) pg/ml vs ACEI group, 2493 (1872) pg/ml; P = 0.6). The detailed baseline characteristics of the ARNI and ACEI groups, respectively, were as follows: mean (SD) body mass index—25.3 (10.8) kg/m2 and 27.1 (5.2) kg/m2 (P = 0.65); hy‑pertension—11 (40.7%) and 14 (50%) (P = 0.49); diabetes—11 (40.7%) and 4 (14.3%) (P = 0.03); dyslipidemia—15 (55.6%) and 10 (35.7%) (P = 0.14); smoking—8  (29.6%) and 15 (53.6%) (P = 0.07); atrial fibrillation—9 (32.1%) and 6 (21.4%) (P = 0.36); QRS width—137.3 (40.4) ms and 109.6 (36.8) ms (P = 0.15); mean (SD) left ven‑tricular end ‑diastolic diameter—67.1 (9.1) mm and 71.5 (15.9) mm (P = 0.19); mean (SD) left ventricular end ‑diastolic volume—251.7 (106.7) ml and 279.8 (151.7) ml (P = 0.44); the median (IQR) ratio of early mitral inflow velocity (E wave) to early myocardial diastolic velocity (E/E’)—11.5 (10.7–18.5) and 20 (12.3–26.4) (P = 0.01); pulmo‑nary artery systolic pressure—32.5 (15.9) mm Hg and 30.4 (14.2) mm Hg (P = 0.63); mean (SD) he‑moglobin level—13.8 (1.8) g/dl and 14.4 (1.6) g/dl (P = 0.17); median (IQR) creatinine level—95.5 (78.2–124.7) μmol/l and 87.5 (69.5–104) μmol/l (P = 0.69); median (IQR) high ‑sensitivity C ‑reac‑tive protein level—2.6 (0.32–5.3) mg/l and 3.7 (1.1–6.5) mg/l (P = 0.37). The following drugs were used for HF therapy: β ‑blockers—in 28 pa‑tients (100%) in the ARNI group and in 28 pa‑tients (100%) in the ACEI group (P = 1); miner‑alocorticoid receptor antagonists—25 (89.3%) in the ARNI group and 24 (85.7%) in the ACEI group (P = 0.69); loop diuretics—17 (60.7%) in the ARNI group and 19 (69.7%) in the ACEI group (P = 0.58); digoxin—6 (22.2%) in the ARNI group and 5 (17.9%) in the ACEI group (P = 0.69); im‑plantable cardioverter ‑defibrillator—11 (39.3%) in the ARNI group and 10 (35.7%) in the ACEI group (P = 0.85); and cardiac resynchroniza‑tion therapy— 5 (17.9%) in the ARNI group and 4 (14.3%) in the ACEI group (P = 0.85).RESEARCH LETTER Potential fibrosis ‑attenuating effect of ARNIs in HFrEF 1019environment of randomized controlled trials. The obvious limitation of our study, which should be acknowledged, is that it was based on a much smaller study population than used in any ran‑domized controlled trial. In addition, the in‑creased risk of false ‑positive results when com‑paring laboratory data at different time points should also be considered. Nonetheless, our study focused on previously unstudied biomarkers of fibrosis (in this context), such as PICP (a poten‑tial marker of collagen type I synthesis) as well as TGF ‑β1 and CTGF. Collagen type I and III is the major component of myocardial fibrous tis‑sue, and its ratio is distorted during MF in HFrEF (ie, there is an excess of collagen type I at the expense of collagen type III). Collagen type I, PIIINP, decreased to a greater degree in the ARNI group compared with the enalapril group. In a similar analysis, authors from the same group confirmed more pronounced reductions of sST2 levels in ARNI ‑treated patients and an associa‑tion between baseline sST2 levels and outcomes.7 The effect of ARNIs on 4 fibrosis biomarkers: sST2, Gal ‑3, MMP ‑2, and PIIINP in patients with HFpEF was studied by the PARAMOUNT inves‑tigators; however, in contrast to the findings ob‑tained in HFrEF patients, ARNI treatment did not influence the blood levels of the measured biomarkers.8Thus, this is the first report on the poten‑tial effects of ARNI therapy on MF in patients with HFrEF outside of the highly controlled FIguRE 1 The 12 ‑month kinetics of the serum markers of fibrosis in patients treated with angiotensin receptor–neprilysin inhibitors (ARNIs) and angiotensin ‑converting enzyme inhibitors (ACEIs): A –procollagen type I carboxy terminal propeptide (PICP); B – procollagen type III aminoterminal propeptide (PIIINP); C – transforming growth factor β1 (TGF ‑β1); D – connective tissue growth factor (CTGF). Data are presented as median (dots) and interquartile range (whiskers).0400080002000600014 00012 00010 0005001500200010003500PICP, ng/mlTGF-β1, pg/mlPIIINP, pg/mlCTGF, ng/ml300025000.050.10.150.20.30.4 ARNIACEIARNIACEIARNIACEIARNIACEI0.250.3528461210Baseline 3 12Time, moBaseline 3 12Time, moBaseline 3 12Time, moBaseline 3 12Time, moADCBPOLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)1020REFEREnCES1 Kong P, Christia P, Frangogiannis N. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014; 71: 549‑574. 2 Rubis P, Wiśniowska ‑Śmiałek S, Wypasek E, et al. 12 ‑month patterns of serum markers of collagen synthesis, transforming growth factor and con‑nective tissue growth factor are similar in new ‑onset and chronic dilated cardiomyopathy in patients both with and without cardiac fibrosis. Cyto‑kine. 2017; 96: 217‑227. 3 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the di‑agnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016; 37: 2129‑2200. 4 Thorvaldsen T, Lund LH. Improving outcomes in heart failure requires im‑proving implementation of heart failure therapy. Pol Arch Intern Med. 2019; 129: 73‑74. 5 McMurray JJ, Packer M, Desai AS, et al. Angiotensin ‑neprilysin inhibi‑tion versus enalapril in heart failure. N Engl J Med. 2014; 371: 993‑1004. 6 Rubiś P, Wiśniowska ‑Śmiałek S, Holcman K, et al. Angiotensin receptor neprilysin inhibitor treatment is safe and potentially efficacious in end ‑stage hypertrophic cardiomyopathy. Pol Arch Intern Med. 2017; 127: 216‑218. 7 Zile MR, O’Meara E, Claggett B, et al. Effects of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Coll Cardiol. 2019; 73: 795‑806. 8 O’Meara E, Prescott MF, Claggett B, et al. Independent prognostic value of serum soluble ST2 measurements in patients with heart failure and a re‑duced ejection fraction in the PARADIGM ‑HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circ Heart Fail. 2018; 11: e004446. 9 Zile MR, Jhund PS, Baicu CF, et al. Plasma biomarkers reflecting pro‑fibrotic processes in heart failure with a preserved ejection fraction: data from the prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction study. Circ Heart Fail. 2016; 9: e002551. 10 González A, Schelbert EB, Díez J, et al. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol. 2018; 71: 1696‑1706. 11 Kałużna ‑Oleksy M, Kolasa J, Migaj J, et al. Initial clinical experience with the first drug (sacubitril/valsartan) in a new class – angiotensin recep‑tor neprilysin inhibitors in patients with heart failure with reduced left ven‑tricular ejection fraction in Poland. Kardiol Pol. 2018; 76: 381‑387. being stronger and less elastic, leads to a stiff‑er and less compliant left ventricle, whereas col‑lagen type III is more elastic and compliant.9,10 Therefore, the gradual increase of PICP levels (over the follow ‑up period) in patients treated with ACEIs indicated the ongoing overproduc‑tion of collagen type I, whereas ARNI ‑treated patients had a sustained attenuation of collagen type I production. On the other hand, the pro‑duction of collagen type III seems to gradually rise in ARNI ‑treated patients over a long peri‑od of time, whereas it remains at the same lev‑el in the ACEI treatment group. In brief, 2 dia‑metrically opposed patterns emerge in terms of collagen type I and III synthesis: one pattern is seen in ARNI ‑treated patients, characterized by low collagen type I synthesis and increased syn‑thesis of collagen type III; conversely, in ACEI‑‑treated patients, an increase in collagen type I synthesis and a decrease in collagen type III pro‑duction are observed.Regarding fibrosis controlling factors, it is more challenging to elucidate this issue, as TGF‑β1 val‑ues were initially significantly higher in the ACEI group and this effect persisted during the follow‑‑up, ie, TGF ‑β1 levels were higher at 3 and 12 months. Finally, CTGF levels seemed to rise in the ARNI group over a long period of time, since we noted that CTGF values differed between the study groups only at 12 months. However, the true significance of these TGF‑β1 and CTGF patterns in patients receiving ARNIs and ACEIs is far from clear and, as such, it is difficult to in‑terpret these findings at this stage. The initial experience with ARNI therapy in HFrEF is very encouraging and further research is needed to elucidate the mechanisms of its action, such as fibrosis ‑attenuating effects.11Conclusions In summary, we investigated the po‑tential role of ARNIs in MF in a real ‑world setting and observed that treatment with ARNIs may po‑tentially improve the distorted ratio of collagen type I and III synthesis. This, in turn, may trans‑late into favorable changes in the morphology and function of the left ventricle in HFrEF.ARTICLE InFoRMATIonACknowLEDgMEnTS This study was funded by the Department of Sci‑entific Research and Structural Funds of Jagiellonian University Medical Col‑lege (grant no.; N41/DBS/000307; to PR).ConFLICT oF InTEREST PR received consultant honoraria from Novar‑tis. Other authors declare no conflict of interest.opEn ACCESS This is an Open Access article distributed under the terms of the Creative Commons Attribution ‑NonCommercial ‑ShareAlike 4.0 Inter‑national License (CC BY ‑NC ‑SA 4.0), allowing third parties to copy and re‑distribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited, distrib‑uted under the same license, and used for noncommercial purposes only. For commercial use, please contact the journal office at pamw@mp.pl.How To CITE Wiśniowska ‑Śmiałek S, Dziewięcka E, Holcman K, et al. Com‑parison of the 12 ‑month kinetics of the serum markers of fibrosis between treat‑ment with angiotensin receptor–neprilysin inhibitors and angiotensin ‑converting enzyme inhibitors in patients with heart failure with reduced ejection fraction. Pol Arch Intern Med. 2020; 130: 1017‑1020. doi:10.20452/pamw.15599

Comparison of the 12-month kinetics of the serum markers of fibrosis between treatment with angiotensin receptor-neprilysin inhibitors and angiotensin-converting enzyme inhibitors in patients with heart failure with reduced ejection fraction

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Comparison of the 12-month kinetics of the serum markers of fibrosis between treatment with angiotensin receptor-neprilysin inhibitors and angiotensin-converting enzyme inhibitors in patients with heart failure with reduced ejection fraction

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