Heart and Metabolism

Anti-inflammatory treatment in postinfarction left ventricular remodeling

Luigi Marzio Biasucci, Christian Colizzi, Dominick Joseph Angiolillo
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
Correspondence: Luigi Marzio Biasucci, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Roma, Italy. e-mail: biasucci@pelagus.it

Left ventricular remodeling after myocardial infarction is the sum total of various processes involving myocytes and the interstitial fibrous structures which provide the matrix in which the myocytes function, causing an increase in ventricular mass and cavity dimensions. These changes in size and shape of the ventricle, defined as remodeling, are a continuous phenomenon. Progressive changes in myocardial structure lead to deterioration in myocardial function and, if not treated, may lead to clinical heart failure.
Multiple mechanisms, including inflammatory reactions, are involved in remodeling. Initially these mechanisms may be adaptive but become maladaptive if left untreated. A better understanding of these mechanisms may lead to novel preventive pharmacotherapeutic approaches. In the past, therapy was focused on the use of drugs (e.g., diuretics) to obtain symptomatic improvement in patients in whom heart failure had already occurred. Various clinical trials subsequently provided insight into the potential of certain agents to prevent or delay the onset or worsening of heart failure. These agents include ACE inhibitors and, in addition to the former b-blockade, the vasodilator b-blocking agent carvedilol.[1–5]
Although these therapeutic strategies have consistently improved survival and quality of life after myocardial infarction, no specific therapy toward remodeling is yet available; however, much interest has been focused on the role of inflammation and on the potential use of anti-inflammatory agents to prevent remodeling after myocardial infarction.

New anti-inflammatory therapeutic approaches
Although no data are available on the effects of anti-inflammatory agents in left ventricular remodeling, recent evidence suggests that anti-inflammatory therapy, targeted at specific cytokines or other proinflammatory molecules, may be helpful (Table I).

Table I. Potential anti-inflammatory therapeutic approaches in postinfarction left ventricular remodeling.

Anti-tumor necrosis factor-b (TNFa) activity
Recently, etanercept was used in patients with heart failure. Etanercept, a soluble recombinant anti-tumor necrosis factor-a (TNFa) receptor (sTNF-R-Fc fusion protein) was used in a randomized, double-blind, placebo-controlled, multidose trial in 47 patients with heart failure (NYHA class III–IV). The results demonstrated a dose-dependent improvement in left ventricular ejection fraction and left ventricular remodeling (reduction in left ventricular enddiastolic and endsystolic volume), with a trend toward an improvement in patient functional status.[6] Because of the pivotal role of TNFa in the inflammatory reaction following myocardial infarction,[7] its use might lead to an even more pronounced improvement of the remodeling process also in the early postinfarction phases. More information on the clinical utility of this molecule will be available as soon as three ongoing multicenter trials have been completed (RENAISSANCE, RECOVER, and RENEWAL).
A similar effect is likely to be obtained by interleukin (IL)-1 receptor antagonist, a molecule with anti-TNFa and anti-IL-1 activity which is also under investigation in patients with rheumatoid arthritis.[8] This molecule has similar characteristics to etanercept and therefore is likely to have similar, or improved, clinical efficacy also on left ventricular remodeling.

Anti-inflammatory cytokines
Anti-inflammatory cytokines have been shown to be effective in preventing atherosclerosis in animal models, but to our knowledge no data are available on congestive heart failure and postinfarction remodeling. However, Gullestad et al[9] demonstrated that intravenous immunoglobulin improved left ventricular ejection fraction in patients with congestive heart failure through a net anti-inflammatory effect, which was determined by a rise in plasma levels of anti-inflammatory cytokines.
Another molecule with modulatory activity on inflammation, transforming growth factor (TGF)-b, a family of multifunctional proteins that regulate cell growth, differentiation, migration, and extracellular matrix production, plays an important role in tissue remodeling.[10] Schenowitz et al[11] demonstrated that systemic administration of basic fibroblast growth factor following myocardial infarction in rats prevents left ventricular dilatation and induces hypertrophy of the noninfarcted myocardium.

Matrix metalloproteinase (MMP) activity inhibitors
Recently the possibility to counteract matrix metalloproteinase (MMP) activity by the use of doxycycline, a commercially available tetracycline modified antibiotic, has opened the way for the use of this molecule in left ventricular remodeling following myocardial infarction.[12] MMP is involved in many remodeling processes in the organism[13–15] and its level is raised after myocardial infarction: in a rat model of ischemia reperfusion injury MMP2 was raised in the coronary effluent and correlated negatively with left ventricular function. In this model the use of doxycycline and anti-MMP2 antibody improved left ventricular function after ischemia reperfusion.[16]

Anti-C-reactive protein (CRP) activity
There is growing evidence that C-reactive protein (CRP), the prototypic acute-phase reactant produced in the liver under IL-1 and IL-6 stimulation,[17] is an important and independent predictor of cardiac events following myocardial infarction.[18–22] Colocalization of CRP and complement in the infarcted myocytes has been demonstrated. Recently, Griselli et al[23] demonstrated that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by 40%: human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. These authors showed that in vivo complement depletion completely abrogated this effect and markedly reduced infarct size. These observations suggest that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease. Anti-CRP antibodies are under investigation and may result in a new therapeutic option in the treatment of postinfarction remodeling.
Evidence that statins may reduce CRP levels in patients with ischemic heart disease[24,25] suggests that early treatment with high doses of statins may help in reducing infarct size and improve remodeling.

Adenosine
Adenosine therapy has been proposed as a new treatment for the prevention and attenuation of chronic heart failure due to its various possible cardioprotective activities. Adenosine induces collateral circulation by inducing growth factors and triggering ischemic preconditioning; reduces the release of norepinephrine and endothelin production, and attenuates the activation of the renin-angiotensin system, all of which contribute to cardiac hypertrophy and remodeling; reduces the severity of ischemia and reperfusion injury; and counteracts neurohumoral factors, including cytokine systems, known to be related to ventricular remodeling and progression towards heart failure.[26]
It is also intriguing to note that drugs we currently use for the treatment of postinfarction left ventricular failure have anti-inflammatory effects, as is the case of ACE inhibitors and
b-blocking agents.[27,28]

Conclusion
The identification of stimuli that initiate and maintain the processes of cardiac hypertrophy and remodeling, and eventually heart failure, remains a major pursuit in cardiac molecular biology and remodeling. The growing evidence that inflammation plays a role in these mechanisms suggests that new drugs with a specific anti-inflammatory activity targeted to the molecules involved in remodeling will play an important role in the future pharmacological armamentarium of cardiologists.

REFERENCES

1: Eur Heart J 1998 Feb;19 Suppl B:B47-53

Related Articles, Books, LinkOut

Prevention of worsening heart failure: future focus.

Remme WJ.

STICARES, Cardiovascular Research Foundation, Rotterdam, The Netherlands.

For decades heart failure therapy has focused on symptomatic treatment, whereas preventive aspects have received less attention. However, 10 years of large controlled trials has provided insight into the potential of certain agents to prevent or delay the onset or worsening of heart failure. Such agents include ACE inhibitors and, in addition to the former beta-blockade, the vasodilator beta-blocking agent carvedilol, which possesses additional properties such as antioxidant effects. In contrast, drugs which typically are used to improve heart failure symptoms, such as diuretics, do not necessarily lead to prevention of (worsening) heart failure. Multiple mechanisms underlie worsening of left ventricular dysfunction and heart failure and have been, or may well be, instrumental in the development of novel preventive therapies of this syndrome. Principal mechanisms include: cardiac and vascular remodelling; neurohormonal and cytokine activation; hibernation and stunning; ischaemia-induced free radical formation; apoptosis; abnormalities in the cardiac membrane receptor, downstream signalling pathways, in intracellular calcium homeostasis, and sensitivity. As these mechanisms interact, leading to progression of heart failure, they provide opportunities for novel pharmacotherapeutic approaches. It is to be expected that many drugs currently in development will be added to the list of accepted heart failure therapy. As polypharmacy is likely to result and is to some extent unavoidable, the future challenge will be to detect the usefulness of alternative treatments to currently accepted therapy to prevent worsening of heart failure, enabling a more individualized and hence effective approach in each patient.

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Review
Review, Tutorial

PMID: 9519352 [PubMed - indexed for MEDLINE]

2: Eur Heart J 1993 Jul;14 Suppl C:24-9