ACE inhibitors reduce the risk of myocardial fibrosis post-cardiac injury: a systematic review

Myocardial fibrosis is a common pathological process associated with various cardiovascular diseases, contributing to adverse cardiac remodelling and increased morbidity. Angiotensin-converting enzyme inhibitors (ACEi) have been widely used for myocardial protection in high-risk patients. However, there are no clear recommendations for their use for the prevention of fibrosis after myocardial injury. On the other hand, procollagen type III amino-terminal propeptide (PIIIP) and procollagen type I propeptide (PIP) have been identified as effective biomarkers for predicting fibrotic change in the myocardium. It is important to evaluate the effects of ACEi by PIIIP and PIP levels to provide insights into the potential antifibrotic effects of ACEi.

We assessed the effects of ACEi on the process of fibrosis in the myocardium through serum levels of PIIIP and PIP. Four databases were searched to identify relevant studies investigating the association between the use of ACEi and myocardial fibrosis marked by PIIIP and PIP levels. Animal and non-original research articles were excluded.

Six studies with a total of 706 participants met the inclusion criteria. Three studies assessed the change of PIIIP and PIP levels in patients with hypertension, while the other three were in patients with heart failure, myocardial infarction and congenital heart diseases. The included studies demonstrated a significant reduction in PIIIP and PIP serum levels with ACEi therapy (p<0.05), except in patients with post-myocardial infarction. The mean reduction in serum PIIIP levels in all patients treated by ACEi was 20.8%.

These results suggest that ACEi can effectively inhibit collagen synthesis and deposition in the myocardium, potentially preventing, or even reversing, the progression of myocardial fibrosis. This supports the idea that ACEi have potent antifibrotic effects and can contribute to improved clinical outcomes in cardiac conditions that are not currently indicated, including myocarditis.

Introduction

Myocardial fibrosis plays a pivotal role in cardiac pathological processes and the development of complications. Preclinical studies demonstrate that angiotensin-converting enzyme inhibitors (ACEi) have inhibitory effects on fibrotic pathways and could reduce myocardial fibrosis.¹ Myocardial fibrosis, triggered by various stimuli, increases morbidity and mortality.² Azevedo et al. revealed that higher degrees of myocardial fibrosis were associated with worse long-term survival.³ Accumulation of myocardial fibrosis is associated with stiffening of the myocardium and failure to relax during diastole.⁴ Further, a higher degree of myocardial fibrosis was associated with lower ventricular ejection fraction.²

The pathological process of myocardial fibrosis is characterised by excessive deposition of extracellular matrix (ECM) components, particularly collagen, within the myocardial tissue.⁵ Cardiac fibroblasts are the main cellular players and are responsible for producing collagen.⁶ This upregulation of collagen synthesis occurs in response to various stimuli, mechanical stress, inflammation and neurohormonal signalling. Transforming growth factor-beta (TGF-β) signalling pathways, released during inflammation, were also shown to be key in activating the transcription of genes involved in collagen synthesis.⁷ Alongside TGF-β signalling pathways, it is thought that aldosterone and angiotensin II play a role in myocardial fibrosis by activating cardiac fibroblasts. Their secretion can be triggered by increased myocardial stress due to pressure or volume overload.^8,9 Aldosterone binds to mineralocorticoid receptors in cardiac fibroblasts, leading to their activation, meanwhile, angiotensin II via Smad proteins, a group of transcriptional factors, stimulates TGF-β activity, further activating the transcription of genes involved in collagen synthesis.

Clinical trials showed that increased serum procollagen type III amino N-terminal propeptide (PIIINP), procollagen type III amino-terminal propeptide (PIIIP), procollagen type I carboxy-terminal propeptide (PICP) and procollagen type I propeptide (PIP), reflect ongoing myocardial fibrosis formation.¹⁰ Revnic et al. also demonstrated that increased levels of PICP and PIIINP are associated with the presence of myocardial fibrosis measured by late gadolinium enhancement (LGE).¹¹

It was previously shown that the effects of cardiac fibroblast activation are probably diminished by ACEi by blocking the conversion of angiotensin I to angiotensin II and reducing aldosterone secretion.¹² ACEi were also shown to slow down TGF-β activity,¹³ thereby, reducing the aberrant development of myocardial fibrosis.¹⁴ ACEi also showed cardioprotective effects in patients with atrial fibrillation (AF), and possibly prevented the progression of myocardial fibrosis.¹⁵ Similar effects were observed in patients with hypertension and previous myocardial infarction (MI).^9,16 However, clinical trials showed less clear-cut conclusions on whether the reduction in myocardial fibrosis was due to direct inhibitory effects or, indirectly, through reduced stress.¹⁷ There is currently no clear advice on using ACEi to prevent myocardial fibrosis. Therefore, it is our aim to quantitively evaluate the effect of ACEi on serum procollagen levels to establish the relationship between ACEi and myocardial fibrosis. This will hopefully highlight the clinical value of ACEi in reducing myocardial fibrosis and improving prognosis in patients who are at high risk of developing myocardial fibrosis.

Method

Research question

We aimed to investigate whether ACEi directly reduce myocardial fibrosis in patients post-cardiac injury, using serum PIIIP, PIIINP, PIP, and/or PICP as biomarkers of fibrotic changes.

Search strategy

A systematic literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,¹⁸ targeting studies on ACEi effects on myocardial fibrosis in humans. Databases searched included PubMed, Google Scholar, EMBASE, and the Cochrane Library. The search used terms related to ACEi (e.g. ramipril, lisinopril) and myocardial fibrosis, with MeSH terms for precision. Only human studies published in English were included. All relevant articles were reviewed.

Eligibility criteria and selection

Titles and abstracts were screened independently, and full texts were reviewed when necessary to assess inclusion criteria. PICOS (Population, Intervention, Comparison, Outcomes and Study) was used to define the criteria:¹⁹

• Study type: observational and interventional studies
• Participants: human subjects
• Interventions: ACEi, with or without other treatments
• Outcomes: statistically significant changes in serum PIIIP, PIIINP, PIP, and/or PICP levels
• Non-original research (e.g. reviews, editorials, case reports) and qualitative studies were excluded.

Quality assurance and data extraction

All studies were appraised using the Critical Appraisal Skills Programme (CASP) checklist for systematic reviews.²⁰ Data were independently standardised, including patient characteristics (age, medications, ACEi dose, cardiac condition) and study details (authors, publication year, study type, sample size, ACEi used, duration, and collagen biomarker levels before and after treatment). The focus was on changes in serum PIIIP, PIIINP, PIP, and/or PICP levels following ACEi treatment.

Results

A total of 2,029 articles were identified in the primary search from four databases. Duplicates (n=966) and non-original research (n=835) were excluded using the Rayyan tool, as were (n=33) animal studies. A further 143 articles were excluded: 103 did not use ACEi, and 40 did not measure myocardial fibrosis. After a full-text review, 43 studies were excluded for not using PIIIP, PIIINP, PIP, or PICP, or for not correlating ACEi effects with these markers. Finally, six studies^21–26 met all inclusion criteria and their main characteristics are summarised in table 1.

Study characteristics

All six studies were prospective, except one randomised-controlled trial.²¹ A total of 713 patients were tested for ACEi effects on collagen production. Conditions included: 533 (74.8%) with hypertension, 113 (15.8%) with acute MI, 10 (1.5%) with coarctation of the aorta, and 56 (7.9%) with heart failure with reduced ejection fraction (HFrEF). Comparisons were made between ACEi and placebo or other drugs. Patients with conditions affecting serum collagen markers (e.g. liver disease, pulmonary fibrosis) were excluded.^22–26 Age ranged from 45 to 73 years, except in one study³⁸ with children aged 0.7–10 years. Common medications prescribed included aspirin, clopidogrel, statins, diuretics, beta blockers, and digoxin, with no significant impact on results.

Hypertension

Three studies with 533 hypertensive patients showed significant reductions in serum PIIIP and PIP after ACEi treatment. Díez et al.²³ found that serum concentrations of PIIIP and PIP were higher in hypertensive patients than in normotensives (PIIIP: 10.08 ± 0.48 vs. 8.47 ± 0.77 ng/ml; PIP: 139 ± 6 vs. 108 ± 6 μg/ml; p<0.001), both of which decreased significantly with lisinopril (PIIIP: 4.82 ± 0.56 ng/ml; PIP: 111 ± 5 μg/ml; p<0.01). Rajzer et al.²¹ randomised 118 hypertensive patients to receive quinapril, amlodipine, or losartan, finding significant reductions in PICP with quinapril compared with amlodipine and losartan (203.13 ± 43.4 μg/L to 130.2 ± 32.1 μg/L, p<0.001). Meanwhile, Fogari et al.²⁵ studied 284 hypertensive patients with AF, showing a 38% reduction in PIP with telmisartan and a 34% reduction with ramipril after 12 months (both p<0.01). No changes were seen with amlodipine.

Acute MI with ST-elevation

In 113 ST-elevation MI (STEMI) patients treated with primary angioplasty, the combined therapy of perindopril and losartan attenuated the increase in PIIINP more than either agent alone at three months (5.05 ± 1.33 ng/ml, 6.84 ± 1.55 ng/ml, 7.44 ± 1.62 ng/ml, respectively, p<0.05).²²

Congenital heart disease (CHD)

A total of 163 paediatric patients with CHD were analysed.²⁴ Eleven of them were on ACEi, whose serum PIIIP levels were significantly reduced compared with those who were not on ACEi (1.60 ± 0.84 vs. 10.92 ± 1.66 ng/ml, p<0.05), with multi-variate regression showing a correlation between PIIIP levels and ventricular overload.

HFrEF

This study compared 28 patients with HFrEF receiving ACEi to 28 matched patients on angiotensin receptor/neprilysin inhibitors (ARNIs).²⁶ PIIINP levels were similar at baseline and three months, but at 12 months, ACEi treatment led to a 57% decrease in PIIINP (1,299.2 pg/ml vs. 3,471.2 pg/ml in ARNIs, p<0.021). PICP levels were higher in the ACEi group throughout the study, with a 127% increase at 12 months compared with an 89% decrease in the ARNI group (both p<0.01).

Discussion

The literature reviewed here, albeit small, shows that ACEi suppressed myocardial fibrosis, as indicated by lower levels of PIIIP, PIIINP, PIP, and PICP, except in patients with MI and HFrEF, where results are mixed.^22,26

In patients with MI, PIIINP levels increased, likely due to acute injury. However, ACEi treatment resulted in a smaller increase in PIIINP compared with angiotensin-receptor blockers (ARBs).²² Previous studies showed PIIINP levels rise rapidly after the first hour of thrombolytic therapy,^27,28 peaking from the second day post-MI and lasting for four months. With ACEi therapy, the increase is limited to three months.²² The HEART (Healing and Early Afterload Reduction Therapy) study found similar results.²⁹ In patients with anterior MI, plasma plasminogen activator inhibitor-1 (PAI-1) activity was reduced by 22% in ramipril-treated patients compared with placebo, with greater suppression in ACEi-treated patients. Early ACEi therapy may reduce fibrotic changes and scar formation.

Meanwhile, in patients with HFrEF, PIIINP levels decreased while PICP increased, but diastolic dysfunction was not considered a separate entity.²⁶ Lopez et al. showed that the extent of myocardial interstitial fibrosis is lower in patients with systolic heart failure than in those with diastolic dysfunction.³⁰ It is said that there is a reduction of myocardial interstitial collagen associated with systolic dysfunction, but increased myocardial interstitial collagen associated with diastolic dysfunction. Therefore, further study may be needed to ascertain the antifibrotic effect of ACEi on heart failure conclusively.

The contrasting effects of ACEi and ARNIs on PIIINP and PICP are intriguing, particularly given the clinical benefits of both therapies in HFrEF. These findings underscore distinct mechanisms influencing ECM remodelling. ACEi, by blocking the conversion of angiotensin I to angiotensin II, reduce the profibrotic effects of angiotensin II, likely explaining the reduction in PIIINP levels.⁷ ARNIs, on the other hand, inhibit neprilysin, increasing natriuretic peptides with antifibrotic properties. However, natriuretic peptides stimulate matrix metalloproteinases, enzymes that degrade ECM components, potentially causing transient elevations in PIIINP.³¹ Additionally, neprilysin inhibition affects vasoactive and inflammatory peptides, such as bradykinin and substance P, which could further modulate ECM dynamics.³² Future studies may reconcile these findings with the clinical benefits of ACEi and ARNIs, and their long-term implications for myocardial health.

Another consideration is the difficulty in disentangling the effects of ACE inhibition from the associated reduction in aldosterone. ACEi primarily reduce angiotensin II levels, but their downstream effects, including aldosterone suppression, play a significant role in myocardial fibrosis.³³ Aldosterone is a potent driver of fibrosis via mineralocorticoid-receptor-mediated pathways, upregulating fibroblast activity. Thus, the reduction in aldosterone secondary to ACE inhibition may amplify the antifibrotic effects of ACEi. This raises questions about the relative contribution of angiotensin II inhibition versus direct aldosterone suppression in mitigating myocardial fibrosis. The implications for therapy selection are significant. Mineralocorticoid-receptor antagonists (MRAs) directly block aldosterone and reduce myocardial fibrosis, particularly in those with HFrEF. In settings where aldosterone levels remain elevated despite ACEi or ARB therapy (a phenomenon known as ‘aldosterone escape’), MRAs might offer superior antifibrotic effects compared with ACEi alone.³⁴

The interplay between ACEi, ARBs, and MRAs highlights the need for careful consideration of underlying processes driving myocardial fibrosis. ACEi provide a multi-faceted approach by addressing angiotensin II, TGF-β and indirectly reducing aldosterone, making them more useful in inflammatory conditions.⁷ Further clinical research, especially studies directly comparing these drug classes in relation to myocardial fibrosis biomarkers (such as PIP and PIIIP), would provide insights into minimising myocardial fibrosis.

In inflammatory conditions like myocarditis, pro-inflammatory cytokines are released under TGF-β signalling pathways that activate fibroblast activity.³⁵ The mechanism of myocardial fibrosis in myocarditis is similar to that in hypertension and MI.^35,36 That ACEi reduce procollagen markers suggests direct antifibrotic effects. By inhibiting TGF-β, ACEi can mitigate collagen deposition post-myocarditis, preserving myocardial compliance and function. While ACEi effects on myocarditis have been extensively studied in animal models of heart failure and hypertension, fewer clinical studies have focused on myocarditis. Daniels et al. summarised studies on ACEi in mouse models of virus-induced, parasite-induced myocarditis, and autoimmune cardiomyopathy.³⁷ The results strongly support renin–angiotensin modulation for treating myocarditis. A review by Godsel et al. extended the implications by correlating results from studies of other pathological models and in vitro experiments, highlighting the immunomodulatory potential of ACEi.³⁸ It would appear that aggressive ACEi therapy not only reduces complications associated with myocarditis, but also downregulates the autoimmune component without increasing infectious agents that initiate the myocarditis.

It is important to consider that fibrosis provides a stabilising framework for the thinned, infarcted myocardial wall, reducing the risk of ventricular rupture. However, excessive fibrosis can compromise ventricular compliance, leading to diastolic dysfunction.³⁹ Early ACEi administration can mitigate these effects by lowering angiotensin II levels, reducing excessive myocardial fibrosis, and promoting vascular remodelling – key processes in both infarcted and surrounding myocardium. ACEi reduce arterial stiffness, improve endothelial function, and exert anti-inflammatory effects on the vasculature, helping to prevent microvascular disease and stroke progression.⁴⁰ These vascular benefits may explain the superior outcomes of ACEi in stroke prevention and cardiac remodelling compared with beta blockers, even when blood pressure reduction is similar.⁴¹

MI that can be complicated with wall rupture or aneurysm, represents acute changes, while remodelling involves longer-term adaptations in both infarcted and non-infarcted myocardium, such as hypertrophy, fibrosis, and chamber dilation. ACEi modulate these processes by lowering wall stress in the short term and attenuating profibrotic and hypertrophic signalling pathways for the longer term.⁴⁰ Their limited direct effect on infarct expansion is likely because this process is primarily mechanical and occurs rapidly post-MI. The superior efficacy of ACEi in remodelling may stem from their influence on the neurohormonal milieu and TGF-β signalling pathways that regulate chronic myocardial changes, rather than the acute mechanical strain of the infarct zone.

Marsan et al. demonstrated that ECM deposition, a hallmark of myocardial fibrosis, was visible as LGE on cardiac magnetic resonance imaging (MRI), and elevated levels of PICP and PIIINP were linked to increased ECM deposition and LGE.^11,42 ACEi therapy has been shown to reduce LGE, reflecting a decrease in focal scar volume.¹¹ Advanced cardiac MRI techniques, such as T1 and T2 mapping, also demonstrated a decrease in diffuse myocardial fibrosis with ACEi therapy and normalisation of T1 and T2 values, which correlated with biochemical improvements in lower PICP and PIIINP levels.⁴³ These imaging changes, along with reductions in PICP and PIIINP, indicate a decrease in the synthesis of type I and type III collagen, respectively. Overall, cardiac MRI-derived indices, including left ventricular mass and diastolic filling dynamics, revealed improved myocardial structure and function with ACEi therapy, offering a spatial and quantitative perspective on the biochemical and structural benefits of these agents.⁴⁴

There are some limitations in this review. First, the heterogeneity in ACEi duration can affect the percentage of decrease in collagen biomarkers, making it difficult to compare the extent of ACEi antifibrotic effects. Second, the lack of specification of ACEi in some studies limits direct comparison among different pathologies. Third, the accuracy of PIIIP, PIIINP, PIP, and PICP as biomarkers to detect myocardial fibrosis has yet to be widely accepted.

Despite these limitations, the potential therapeutic benefits of ACEi in mitigating myocardial fibrosis are evident, reducing collagen formation by slowing fibrotic processes in the myocardium and improving cardiac function.¹⁷ It is, therefore, reasonable to expect the therapeutic and prognostic benefits in other conditions, including myocarditis of any aetiology, pericarditis and increased troponin but non-obstructive coronary arteries. Future research may aim to standardise the type, dose and duration of ACEi to achieve the best effect on myocardial fibrosis.

Conclusion

This systematic review highlights that ACEi can mitigate myocardial fibrosis, especially in patients with hypertension, post-MI, coarctation of the aorta and HFrEF. One may conclude that ACEi can effectively reduce serum levels of PIIIP and PIP, key biomarkers of collagen synthesis and myocardial fibrosis. Therefore, ACEi have a favourable impact on collagen metabolism within the myocardium, potentially reducing myocardial fibrosis and improving cardiac function.

The review also suggests the potential application of ACEi in conditions that are not routine therapeutic targets, such as myocarditis, elevated troponin levels but non-obstructive coronary arteries, pericarditis and preclinical heart failure on the background of aortic stenosis or hypertrophic cardiomyopathy. Further research may help understand the specific effects of different ACEi in various cardiac pathologies.

Key messages

• Myocardial fibrosis is a common pathological process associated with various cardiovascular diseases, contributing to adverse cardiac remodelling and increased morbidity
• Procollagen type III amino-terminal propeptide (PIIIP) and procollagen type I propeptide (PIP) have been identified as effective biomarkers for predicting fibrotic change in the myocardium
• Angiotensin-converting enzyme inhibitors (ACEi) have been shown to reduce myocardial fibrosis by affecting collagen metabolism. This involves some complex interactions among different signalling pathways leading to the reduction of collagen synthesis and deposition in the myocardium, potentially preventing or even reversing the progression of myocardial fibrosis

Conflicts of interest

None declared.

Funding

None.

References

1. Grohé C, Kahlert S, Löbbert K et al. Angiotensin converting enzyme inhibition modulates cardiac fibroblast growth. J Hypertens 1998;16:377–84. https://doi.org/10.1097/00004872-199816030-00015

2. Dweck MR, Joshi S, Murigu T et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol 2011;58:1271–9. https://doi.org/10.1016/j.jacc.2011.03.064

3. Azevedo CF, Nigri M, Higuchi ML et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol 2010;56:278–87. https://doi.org/10.1016/j.jacc.2009.12.074

4. Hein S, Arnon E, Kostin S et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 2003;107:984–91. https://doi.org/10.1161/01.CIR.0000051865.66123.B7

5. Weber KT, Sun Y, Tyagi SC, Cleutjens JP. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol 1994;26:279–92. https://doi.org/10.1006/jmcc.1994.1036

6. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 2013;9:459–69. https://doi.org/10.1038/nrneph.2013.110

7. Martos R, Baugh J, Ledwidge M et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 2007;115:888–95. https://doi.org/10.1161/CIRCULATIONAHA.106.638569

8. Weidemann F, Herrmann S, Störk S et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–84. https://doi.org/10.1161/CIRCULATIONAHA.108.847772

9. Cuspidi C, Ciulla M, Zanchetti A. Hypertensive myocardial fibrosis. Nephrol Dial Transplant 2006;21:20–3. https://doi.org/10.1093/ndt/gfi237

10. Ding Y, Wang Y, Zhang W et al. Roles of biomarkers in myocardial fibrosis. Aging Dis 2020;11:1157–74. https://doi.org/10.14336/AD.2020.0604

11. Revnic R, Cojan-Minzat BO, Zlibut A et al. The role of circulating collagen turnover biomarkers and late gadolinium enhancement in patients with non-ischemic dilated cardiomyopathy. Diagnostics (Basel) 2022;12:1435. https://doi.org/10.3390/diagnostics12061435

12. Kuzuo H, Honda M, Tanaka K et al. Direct effects of angiotensin I, angiotensin II, an ACE inhibitor and a serine proteinase inhibitor on cultured heart cells from spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1995;22:82–6. https://doi.org/10.1111/j.1440-1681.1995.tb01960.x

13. Border WA, Noble NA. Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 1998;31(1 Pt 2):181–8. https://doi.org/10.1161/01.HYP.31.1.181

14. Ambari AM, Setianto B, Santoso A et al. Angiotensin converting enzyme inhibitors (ACEIs) decrease the progression of cardiac fibrosis in rheumatic heart disease through the inhibition of IL-33/sST2. Front Cardiovasc Med 2020;7:115. https://doi.org/10.3389/fcvm.2020.00115

15. Boldt A, Scholl A, Garbade J et al. ACE-inhibitor treatment attenuates atrial structural remodeling in patients with lone chronic atrial fibrillation. Basic Res Cardiol 2006;101:261–7. https://doi.org/10.1007/s00395-005-0571-2

16. Hall AS, Winter C, Bogle SM, Mackintosh AF, Murray GD, Ball SG. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–8. https://doi.org/10.1016/0140-6736(93)92693-N

17. Dietz R, Haberbosch W, Osterziel KJ, Förderer T, Busch C. Reparative effects of ACE inhibitors on the heart. Klin Wochenschr 1992;69(suppl 29):16–24.

18. Page MJ, McKenzie JE, Bossuyt PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71

19. Higgins PT, Green S. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. London: The Cochrane Collaboration, 2011. Available from: http://handbook-5-1.cochrane.org

20. Guyatt GH, Sackett DL, Cook DJ. CASP systematic review checklist. Oxford: Critical Appraisal Skills Programme. Available at: https://casp-uk.net/casp-tools-checklists/ [accessed: 21 June 2023].

21. Rajzer M, Klocek M, Kawecka-Jaszcz K. Effect of amlodipine, quinapril, and losartan on pulse wave velocity and plasma collagen markers in patients with mild-to-moderate arterial hypertension. Am J Hypertens 2003;16:439–44. https://doi.org/10.1016/S0895-7061(03)00052-9

22. Li L, Liu RY, Zhao XY, Zhang JY, Jia M, Lu PQ. Effects of combination therapy with perindopril and losartan on left ventricular remodelling in patients with myocardial infarction. Clin Exp Pharmacol Physiol 2009;36:704–10. https://doi.org/10.1111/j.1440-1681.2009.05143.x

23. Díez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 1995;91:1450–6. https://doi.org/10.1161/01.CIR.91.5.1450

24. Sugimoto M, Masutani S, Seki M, Kajino H, Fujieda K, Senzaki H. High serum levels of procollagen type III N-terminal amino peptide in patients with congenital heart disease. Heart 2009;95:2023–8. https://doi.org/10.1136/hrt.2009.170241

25. Fogari R, Mugellini A, Zoppi A et al. Effect of telmisartan and ramipril on atrial fibrillation recurrence and severity in hypertensive patients with metabolic syndrome and recurrent symptomatic paroxysmal and persistent atrial fibrillation. J Cardiovasc Pharmacol Ther 2012;17:34–43. https://doi.org/10.1177/1074248410395018

26. Wiśniowska-Śmiałek S, Dziewięcka E, Holcman K, Podolec P, Wypasek E, Rubiś P. 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. Pol Arch Intern Med 2020;130:1017–20. https://doi.org/10.20452/pamw.15599

27. Jensen LT, Høst NB. Collagen: scaffold for repair or execution. Cardiovasc Res 1997;33:535–9. https://doi.org/10.1016/S0008-6363(96)00247-7

28. Høst NB, Hansen SS, Jensen LT, Husum D, Nielsen JD. Thrombolytic therapy of acute myocardial infarction alters collagen metabolism. Cardiology 1994;85:323–33. https://doi.org/10.1159/000176705

29. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997;96:442–7. https://doi.org/10.1161/01.CIR.96.2.442

30. López B, González A, Querejeta R, Larman M, Díez J. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 2006;48:89–96. https://doi.org/10.1016/j.jacc.2006.01.077

31. Du H, Li X, Zhao W, Jiang N. The difference between sacubitril valsartan and valsartan on vascular endothelial function, APN, MMP-9, and BNP levels in patients with hypertension and chronic heart failure. J Healthc Eng 2022;2022:9494981. https://doi.org/10.1155/2022/9494981

32. Campbell DJ. Neprilysin inhibitors and bradykinin. Front Med 2018;5:257. https://doi.org/10.3389/fmed.2018.00257

33. Lijnen P, Petrov V. Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 2000;32:865–79. https://doi.org/10.1006/jmcc.2000.1129

34. Struthers AD. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J 1995;16(suppl N):103–06. https://doi.org/10.1093/eurheartj/16.suppl_N.103

35. Kurrer MO, Kopf M, Penninger J, Eriksson U. Cytokines that regulate autoimmune myocarditis. Swiss Med Wkly 2002;132:408–13. https://doi.org/10.4414/smw.2002.10054

36. Satou R, Penrose H, Navar LG. Inflammation as a regulator of the renin-angiotensin system and blood pressure. Curr Hypertens Rep 2018;20:100. https://doi.org/10.1007/s11906-018-0900-0

37. Daniels MD, Hyland KV, Engman DM. Treatment of experimental myocarditis via modulation of the renin-angiotensin system. Curr Pharm Des 2007;13:1299–305. https://doi.org/10.2174/138161207780618812

38. Godsel LM, Leon JS, Engman DM. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in experimental myocarditis. Curr Pharm Des 2003;9:723–35. https://doi.org/10.2174/1381612033455440

39. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction – from repair and remodeling to regeneration. Cell Tissue Res 2016;365:563–81. https://doi.org/10.1007/s00441-016-2431-9

40. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 2012;60:1455–69. https://doi.org/10.1016/j.jacc.2011.11.082

41. Magid DJ, Shetterly SM, Margolis KL et al. Comparative effectiveness of angiotensin-converting enzyme inhibitors versus beta-blockers as second-line therapy for hypertension. Circ Cardiovasc Qual Outcomes 2010;3:453–8. https://doi.org/10.1161/CIRCOUTCOMES.110.940874

42. Barasch E, Gottdiener JS, Aurigemma G et al. Association between elevated fibrosis markers and heart failure in the elderly: the cardiovascular health study. Circulation 2009;2:303–10. https://doi.org/10.1161/CIRCHEARTFAILURE.108.828343

43. Frantz S, Hundertmark MJ, Schulz-Menger J, Bengel FM, Bauersachs J. Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies. Eur Heart J 2022;43:2549–61. https://doi.org/10.1093/eurheartj/ehac223

44. Chamsi-Pasha MA, Zhan Y, Debs D, Shah DJ. CMR in the evaluation of diastolic dysfunction and phenotyping of HFpEF: current role and future perspectives. JACC Cardiovasc Imaging 2020;13(1 Pt 2):283–96. https://doi.org/10.1016/j.jcmg.2019.02.031