Main clinical article

Role of RAAS inhibition in

preventing left ventricular
remodeling in patients post
myocardial infarction
Doralisa Morrone and Mario Marzilli
Cardiovascular Medecine Division, Cardiothoracic Department, University of Pisa, Pisa, Italy

Correspondence: Professor Mario Marzilli, Cardiovascular Medicine Division, Cardiothoracic Department,

Via Paradisa 2, 56100 Pisa, Italy.
Tel: +39 050 996571; fax: +39 050 995352; e-mail: [email protected]
Conflicts of interest: Prof. Marzilli has given lectures on Ischemic Heart Disease for Servier International.

Abstract

Left ventricular remodeling after myocardial infarction has been identified as a predictor of adverse
outcome and as a relevant therapeutic target. It has been shown that upregulation of the renin–
angiotensin–aldosterone system (RAAS)
has an important role in the pathogenesis of cardiac
remodeling. In this paper we summarize evidence on the role of the RAAS in the development of
left ventricular remodeling and review major trials based on the addition of an RAAS inhibitor to
standard therapy in the post myocardial infarction setting to prevent remodeling and improve outcome.
Heart Metab. 2010;47:9–13.

Keywords: Aldosterone blockers, angiotensin converting enzyme inhibitors, angiotensin receptor

blockers, left ventricular remodeling, renin–angiotensin–aldosterone system

Introduction adequate cardiac output despite the loss of contractile

elements; however, at the same time, it is a detri-
Mechanical reperfusion therapy and current pharma- mental process because it renders the ventricle more
cological treatment can, to some extent, limit cardiac prone to dysfunction and eventually to heart failure.
dysfunction and adverse ventricular remodeling in Importantly, left ventricular remodeling may also be
patients with acute myocardial infarction; however, associated with an increased risk of ventricular
progressive ventricular dilatation is still observed in a arrhythmias.
substantial proportion of patients [1]. Left ventricular Left ventricular remodeling is most pronounced in
remodeling includes changes in ventricular structure, patients with a large anterior infarction or microvas-
volume, and shape after an acute myocardial infarc- cular dysfunction, or both. Endocrine/autocrine/para-
tion. The process develops in two phases: an early crine neurohormonal signaling is the driver for the
one, with expansion limited to the infarct zone, and a process, the acute phase of myocardial infarction
late one, the so-called late remodeling phase, when being characterized by a short-lived but intense
the entire left ventricle undergoes progressive dilata- neuroendocrine activation, with plasma concen-
tion. Left ventricular remodeling eventually results in trations of angiotensin II peaking at 3 days. Myocyte
chamber dilatation and sphericity [2]. Initially, ven- hypertrophy and excess extracellular deposition of
tricular dilatation may be useful in maintaining an collagen are key histologic components.

Heart Metab. 2010; 47:9–13 9

 Main clinical article
Doralisa Morrone and Mario Marzilli

Activation of the renin–angiotensin–aldosterone mortality. In the Studies Of Left Ventricular Dysfunc-

system (RAAS) participates actively in the process of tion Treatment and Prevention (SOLVD) trial [6],
left ventricular remodeling. Renin is a proteolytic patients with acute myocardial infarction, ejection
enzyme that is released into the circulation primarily fraction <35%, with or without signs and symptoms
by the juxtaglomerular cells. Its release is stimulated of heart failure, were allocated randomly to groups
by renal artery hypotension and is followed by sym- receive to enalapril or placebo within the 24–
pathetic nerve activation and by decreased delivery of 36 hours from their admission to hospital. The study
sodium to the distal renal tubules. When renin is again showed an improved survival in patients receiv-
released into the blood, it acts upon a circulating ing the ACE inhibitor. An echocardiographic substudy
substrate, angiotensinogen, that undergoes a proteo- of the SOLVD trial demonstrated a trend toward
lytic cleavage to form the decapeptide, angiotensin I. reduction in left ventricular end-diastolic volume in
Vascular endothelium, particularly in the lungs, has the enalapril group with respect to those receiving
an enzyme, angiotensin converting enzyme (ACE), placebo [7] (Figure 1). In the Gruppo Italiano per lo
that cleaves off two amino acids to form the active Studio della Sopravvivenza nell’Infarto Miocardico
octapeptide, angiotensin II. (GISSI-3) trial, administration of lisinopril was associ-
Under pathological conditions, the RAAS is acti- ated with an improved outcome in patients treated
vated by several factors – in particular, inflammation after 24–36 hours from an acute myocardial infarc-
and endothelial dysfunction. Its stimulation, with tion. The beneficial effects of the drug on left ventri-
the spillover of aldosterone, is responsible for extra- cular volumes have been documented in an echocar-
cellular matrix proliferation and contributes to the diography substudy [8] of the main trial. A significant
increased deposition of fibrous tissue within the ven- reduction in left ventricular enlargement was already
tricular myocardium [3]. The presence of myocardial present after 6 weeks of lisinopril treatment. Accord-
fibrosis and endothelial dysfunction may affect the ing to the study investigators, early RAAS blockade
coronary microcirculation; in particular, the decrease should be included in a systematic strategy of pre-
in myocardial capillary density can contribute to the vention of post infarction left ventricular remodeling.
progression of left ventricular remodeling towards Most of the above-mentioned trials did not include
heart failure [4]. For this and other reasons, thera- elderly patients. As aging is a factor well known to be
peutic interventions in patients with post infarction involved in the process of left ventricular remodeling,
left ventricular dysfunction should be aimed at pre- a study was designed to investigate the effects of a
venting the activation of the RAAS, with possible relatively new ACE inhibitor, perindopril, in elderly
beneficial effects on left ventricular structure, size, patients diagnosed with acute myocardial infarction.
and function. In this respect, a number of pharmaco- In the Perindopril and Remodeling in Elderly With
logical approaches have demonstrated their efficacy Acute Myocardial Infarction (PREAMI) trial, 1252 post
and have significantly reduced mortality and morbid- myocardial infarction patients aged at least 65 years
ity in patients with a history of acute myocardial with ejection fractions of at least 40% were allocated
infarction. randomly to groups to receive perindopril or placebo.
The study showed that the administration of perindo-
pril was associated with a 0.22 absolute risk reduction
Inhibition of the renin–angiotensin– in the composite endpoint of death, admission to
aldosterone system hospital because of heart failure, or remodeling
(95% confidence intervals [CI], 0.16 to 0.28;
ACE inhibitors were the first drugs to be used to block P < 0.001) [9]. In a recent echocardiographic sub-
the RAAS. Inhibition of ACE results in a decrease in the study of that trial, it became apparent that the admin-
concentration of angiotensin II at the angiotensin istration of a daily dose of 8 mg of perindopril was
receptor sites. Over the past 25 years, several clinical associated with prevention of progressive left ventri-
trials have demonstrated the beneficial effects of ACE cular dilatation [10].
inhibitors in patients with acute myocardial infarc- The selective blockade of the angiotensin II receptor
tion, with favorable prognostic implications. type 1 is another means by which to inhibit the RAAS
The Survival And Ventricular Enlargement (SAVE) that is associated with favorable effects on left ven-
trial was a landmark study by Pfeiffer et al [5]. They tricular structure and function. This is likely to be one
enrolled patients with left ventricular dysfunction of the mechanisms that contribute to the improved
(ejection fraction no greater than 40%) after acute outcome of patients with heart failure secondary to
myocardial infarction, who were treated with capto- postischemic left ventricular dysfunction, as shown
pril, starting between 3 and 16 days after admission to by several clinical trials (eg, Candesartan in Heart
hospital. An attenuation of ventricular enlargement failure – Assessment of Reduction in Mortality and
became apparent after 12 months and was associated Morbidity [CHARM] [11], Optimal Trial in Myo-
with a significant reduction in morbidity and cardial Infarction with Angiotensin II Antagonist

10 Heart Metab. 2010; 47:9–13

 Main clinical article
RAAS inhibition to prevent LV remodeling

Figure 1. Findings in a substudy of the Studies Of Left Ventricular Dysfunction (SOLVD) trial. LVEDP, left ventricular end-
diastolic pressure; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left
ventricular end-systolic pressure; ns, nonsignificant.

Losartan [OPTIMAAL] [12], Valsartan Heart Failure Therapeutic perspectives

Trial [Val-HeFT] [13]). A positive impact on remodel-
ing has also been observed in patients treated with Although ACE inhibitors and ARBs have both been
aldosterone antagonists [14]. Aldosterone exerts sev- shown to be effective in improving mortality and
eral actions that may contribute to adverse left ven- morbidity in acute myocardial infarction complicated
tricular remodeling: worsening tissue injury, myocyte by left ventricular systolic dysfunction, left ventricular
loss, and reparative myocardial fibrosis. Additional remodeling remains a frequent and adverse con-
mechanisms include myocyte apoptosis and direct sequence of myocardial infarction. Left ventricular
stimulation of collagen synthesis, which may derive remodeling contributes to the progression from left
from repetitive stunning and oxidative stress. Two ventricular dysfunction to heart failure, and markedly
large trials evaluated the use of aldosterone receptor affects clinical outcome and quality of life of patients
antagonists: the Eplerenone Post–Acute Myocardial who have suffered myocardial infarction. For this
Infarction Heart Failure Efficacy and Survival Study reason, alternative therapeutic options that may be
(EPHESUS) and the Randomized Aldactone Evalu- implemented in these patients are actively sought
ation Study (RALES). The EPHESUS trial compared (Table I).
placebo with the selective aldosterone blockade, A number of new therapeutic interventions target-
eplerenone, added to a background ACE inhibitor – ing left ventricular remodeling have been proposed.
and, in most cases, b-blocker treatment – in patients Because aldosterone stimulation is recognized to have
with post ischemic left ventricular systolic dysfunc- a negative effect on left ventricular remodeling [16],
tion. Eplerenone significantly reduced mortality (by Chan et al [17] undertook a magnetic resonance
15%), supporting the strategy of adding an aldoster- imaging study to investigate the addition of spirono-
one receptor blocker to an ACE inhibitor or an angio- lactone to candesartan (an angiotensin type II receptor
tensin II type 1 receptor blocking agent (ARB). This blocker) in patients who had suffered acute myo-
makes sense from a pathophysiological standpoint, cardial infarction. They reported a significant
because aldosterone is regulated independently of reduction in left ventricular end-diastolic and end-
angiotensin II. Aldosterone blockade is therefore a systolic volumes and an improvement in left ventri-
complementary, rather than a competing, treatment cular ejection fraction.
for the survivors of acute myocardial infarction [15]. Aliskiren, a direct renin antagonist, improved left
The RALES trial, which was discontinued early ventricular function and prevented cardiac remodel-
because an interim analysis determined that spirono- ing in experimental mice submitted to an acute
lactone was efficacious by substantially reducing the ischemic injury [18].
risk of both mortality and morbidity, confirmed the After myocardial infarction, excessive deposition
efficacy of this strategy. of extracellular collagen matrix (ECCM) has been

Heart Metab. 2010; 47:9–13 11

 Main clinical article
Doralisa Morrone and Mario Marzilli

Table I. Potential therapeutic strategies to prevent left ventricular glycosylation, formation of procollagen triple helixes,
remodeling. secretion into the extracellular space, conversion into
Nitric oxide modulators/enhancers less soluble molecules, assembly into fibrils, and aggre-
Statins gation into fibers. Prolyl-4-hydroxylase catalyzes the
Phosphodiesterase 5A inhibitors hydroxylation of proline on a monomers to yield stable
Antioxidants
protocollagen molecules that are secreted into the
Metalloproteinase inhibitors
Proangiogenic factors ECCM; this enzyme could be a possible therapeutic

target. Both ACE inhibitors and ARBs, in addition to
Antagomirs (micro-RNA controlling growth promoting factors)
Modulators of proinflammatory cytokines aldosterone blockers, decrease ECCM. The aldosterone
antagonist, spironolactone, decreases collagen turn-
over and ARBs also decrease prolyl-4-hydroxylase
associated with evidence of left ventricular diastolic [20–23]. Protecting the ECCM post myocardial infarc-
dysfunction. Modulation of collagen formation and tion could be a promising target for treatment.
degradation and control of extracellular matrix depo- A new pharmacological option may be offered by
sition have been proposed as possible therapeutic agents that inhibit both the ACE and neutral endopep-
approaches. Preservation of a correct balance tidase enzymes: vasopeptidase inhibitors (Figure 2).
between matrix metalloproteinase activity and Lapointe et al [24] demonstrated that the neutral
endogenous tissue inhibitors of matrix metalloprotei- endopeptidase inhibitor, omapatrilat, improved post
nases could be an effective therapeutic strategy with myocardial infarction cardiac function and prevented
which to prevent ventricular remodeling [19]. cardiac remodeling in a rat model.
Collagen formation occurs by eight enzymatic steps: However, not all treatments that were associated
intracellular synthesis of pro-chains, hydroxylation, with a beneficial effect on left ventricular remodeling

Figure 2. Mechanism of action of vasopeptidase inhibitors. Synergistic effects resulting from combined inhibition of angiotensin
converting enzyme (ACE) and neutral endopeptidase (NEP) are due to similar mechanisms — blockade of angiotensin (AT)
synthesis and concomitant potentiation of natriuretic peptides
and bradykinin
(BK), leading to vasodilatation, natriuresis and
improvement in myocardial function. ", increased; ANP, atrial natriuretic peptide; AT I, angiotensin I; AT II, angiotensin II;
AT (1–7), angiotensin II types 1–7 receptors; B2, bradykinin receptor; bET-1, big endothelin-1; cGMP, cyclic guanosine 30 50 -
monophosphate; CNP, C-type natriuretic peptide; ECE-1, endothelin converting enzyme-1; EDMP, endothelial cell-derived
microparticules; eNOS, endothelial nitric oxide synthase; ET-1, ET-3, endothelins 1 and 3; ETA, ETB, endothelins A and B
receptors; L-Arg, L-arginine; NO, nitric oxide; NPA, NPB, natriuretic peptide receptors A and B; P, adenosine receptor; pGC,
particular guanylyl cyclase; sGC, soluble guanylyl cyclase; T, thrombin receptor; Thr, thrombin.

12 Heart Metab. 2010; 47:9–13

 Main clinical article
RAAS inhibition to prevent LV remodeling

have later been associated with an improved clinical 10. Nicolosi GL, Golcea S, Ceconi C, et al. Effects of perindopril
on cardiac remodelling and prognostic value of pre-discharge
outcome, suggesting that disease progression may quantitative echocardiographic parameters in elderly patients
also occur through alternative mechanisms, indepen- after acute myocardial infarction: the PREAMI echo sub-study.
dent of cardiac remodeling [25]. It is possible that sex Eur Heart J. 2009;30:1656–1665.
11. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in heart
differences could have a critical role in this respect, failure – assessment of reduction in mortality and morbidity
based on different concentrations of the sex-related (CHARM): rationale and design. Charm-Programme Investi-
gators. J Card Fail. 1999;5:276–282.
hormones, estrogens and testosterone [26]. 12. Dickstein K, Kjekshus J. Effects of losartan and captopril on
mortality and morbidity in high-risk patients after acute myo-
cardial infarction: the OPTIMAAL randomised trial. Optimal
Trial in Myocardial Infarction with Angiotensin II Antagonist
Summary Losartan. Lancet. 2002;360:752–760.
13. Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN.
Augmented short- and long-term hemodynamic and hormonal
RAAS inhibition in the setting of acute myocardial effects of an angiotensin receptor blocker added to angioten-
infarction represents an established strategy to reduce sin converting enzyme inhibitor therapy in patients with heart
failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group.
cardiovascular mortality and morbidity. The bene- Circulation. 1999;99:2658–2664.
ficial effects of RAAS inhibition with ACE inhibitors, 14. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective
ARBs, and aldosterone antagonists can be attributed, aldosterone blocker, in patients with left ventricular dysfunc-
tion after myocardial infarction. N Engl J Med. 2003;348:
at least in part, to the prevention or attenuation of left 1309–1321.
ventricular remodeling. 15. Weintraub WS, Zhang Z, Mahoney EM, et al. Cost-effective-

ness of eplerenone compared with placebo in patients with
see glossary for definition of these terms.
myocardial infarction complicated by left ventricular dysfunc-
tion and heart failure. Circulation. 2005;111:1106–1113.
16. Cohn JN, Tognoni G. A randomized trial of the angiotensin-
REFERENCES receptor blocker valsartan in chronic heart failure. N Engl J
Med. 2001;345:1667–1675.
17. Chan AK, Sanderson JE, Wang T, et al. Aldosterone receptor
1. Sezer M, Aslanger EK, Cimen AO, et al. Concurrent micro- antagonism induces reverse remodeling when added to an-
vascular and infarct remodeling after successful reperfusion of giotensin receptor blockade in chronic heart failure. J Am Coll
ST-elevation acute myocardial infarction. Circ Cardiovasc Cardiol. 2007;50:591–596.
Interv. June 2010, In press. 18. Westermann D, Riad A, Lettau O, et al. Renin inhibition
2. Hittinger L, Shannon RP, Bishop SP, Gelpi RJ, Vatner SF. improves cardiac function and remodeling after myocardial
Subendomyocardial exhaustion of blood flow reserve and infarction independent of blood pressure. Hypertension.
increased fibrosis in conscious dogs with heart failure. Circ 2008;52:1068–1075.
Res. 1989;65:971–980. 19. Buralli S, Dini FL, Ballo P, et al. Circulating matrix metallo-
3. Weber KT, Brilla CG. Pathological hypertrophy and cardiac proteinase-3 and metalloproteinase-9 and tissue Doppler
interstitium. Fibrosis and renin–angiotensin–aldosterone sys- measures of diastolic dysfunction to risk stratify patients with
tem. Circulation. 1991;83:1849–1865. systolic heart failure. Am J Cardiol. 2010;105:853–856.
4. Sabbah HN, Stein PD, Kono T, et al. A canine model of chronic 20. Jugdutt BI. Remodeling of the myocardium and potential
heart failure produced by multiple sequential coronary micro- targets in the collagen degradation and synthesis pathways.
embolizations. Am J Physiol. 1991;260:H1379–H1384. Curr Drug Targets Cardiovasc Haematol Disord. 2003;3:1–30.
5. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on
mortality and morbidity in patients with left ventricular dys- 21. Jugdutt BI. Ventricular remodeling after infarction and the
function after myocardial infarction. Results of the survival and extracellular collagen matrix: when is enough enough? Cir-
ventricular enlargement trial. The SAVE Investigators. N Engl J culation. 2003;108:1395–1403.
Med. 1992;327:669–677. 22. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of
6. Pouleur H. Results of the treatment trial of the studies of left excessive extracellular matrix turnover may contribute to
ventricular dysfunction (SOLVD). The SOLVD Investigators. survival benefit of spironolactone therapy in patients with
Am J Cardiol. 1992;70:135C–136C. congestive heart failure: insights from the randomized aldac-
7. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long- tone evaluation study (RALES). Rales Investigators. Circula-
term enalapril therapy on cardiac structure and function in tion. 2000;102:2700–2706.
patients with left ventricular dysfunction. Results of the 23. Weber KT. Extracellular matrix remodeling in heart failure: a
SOLVD echocardiography substudy. Circulation. 1995;91: role for de novo angiotensin II generation. Circulation. 1997;
2573–2581. 96:4065–4082.
8. Temporelli PL, Giannuzzi P, Nicolosi GL, et al. Doppler- 24. Lapointe N, Blais C Jr, Adam A, et al. Comparison of the
derived mitral deceleration time as a strong prognostic marker effects of an angiotensin-converting enzyme inhibitor and a
of left ventricular remodeling and survival after acute myo- vasopeptidase inhibitor after myocardial infarction in the rat.
cardial infarction: results of the GISSI-3 echo substudy. J Am J Am Coll Cardiol. 2002;39:1692–1698.
Coll Cardiol. 2004;43:1646–1653. 25. Landmesser U, Wollert KC, Drexler H. Potential novel phar-
9. Ferrari R. Effects of angiotensin-converting enzyme inhibition macological therapies for myocardial remodelling. Cardio-
with perindopril on left ventricular remodeling and clinical vasc Res. 2009;81:519–527.
outcome: results of the randomized Perindopril and Remodel- 26. Piro M, Della Bona R, Abbate A, Biasucci LM, Crea F. Sex-
ing in Elderly with Acute Myocardial Infarction (PREAMI) related differences in myocardial remodeling. J Am Coll Car-
Study. Arch Intern Med. 2006;166:659–666. diol. 2010;55:1057–1065.

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