Post-infarct remodelling: contribution of wound healing and inflammation

Abstract

In human and experimental myocardial infarction (MI), cessation of blood supply leads to rapid necrosis of cardiac myocytes in the ischaemic heart. Immediately after injury, various intra- and intercellular pathways contribute to healing the myocardial wound in order to achieve tissue integrity and function. MI and the consequent loss of myocardium are the major aetiology for heart failure. Despite aggressive primary therapy, prognosis remains poor in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to improve healing of the cardiac wound to maintain structure and function of the heart. Healing in the heart occurs in overlapping phases. Herein, we review the inflammatory phase as a trigger of tissue formation.

Figure 1

TLR4 in rat, murine, and human myocardium. Primary isolates of adult rat ventricular myocytes 24 h after isolation, stained with a polyclonal antibody targeted to a TLR4-specific epitope adjacent to the cytoplasmic TIR domain of hTLR4 (upper panel). Normal murine cardiac muscle (magnification 200×; second panel) exhibited diffuse, homogeneous myocyte staining. However, cardiac myocytes adjacent to an area of ischaemic injury induced by coronary artery ligation exhibited intense sarcolemmal TLR4 staining. Finally, cardiomyocytes from humans with dilated cardiomyopathy (lower panel) displayed intensely stained focal expression of TLR4 (figure reprinted with permission of Frantz et al.).

Figure 2

NF-κB activation in the heart after ischaemic injury. In transgenic mice that express a luciferase reporter whose transcription is dependent on NF-κB, light generated at the site of NF-κB activation within the transgenic mouse is sufficiently intense to be detected externally by a light-sensitive camera upon injection of luciferin. Myocardial infarction induced NF-κB-dependent in vivo luminescence in the heart of transgenic mice when compared with sham-operated mice. Maximal NF-κB activity was observed 3 days after myocardial infarction by serial molecular imaging (figure reprinted with permission of Tillmanns et al.).

Figure 3

MR blockade after myocardial infarction reduced thinning and dilatation of the infarcted wall. (A) Typical sections from infarcted hearts, perfusion-fixed 7 days after myocardial infarction, scar thickness, and infarct expansion index in placebo (PLA) and eplerenone-treated rats (EPLE). Mean±SEM (n = 10 to 14). †P < 0.05, ‡P < 0.01 vs. PLA. (B) Representative LV pressure–volume loops measured in vivo with conductance catheter in sham-operated rats (sham) and in placebo- (PLA) and eplerenone-treated (EPLE) rats 7 days after MI (figure reprinted with permission of Fraccarollo et al.).

Figure 4

Detrimental left ventricular dilatation following myocardial infarction and inhibition of TGF. Illustrated are representative examples of two-dimensional echocardiography of mice treated with an anti-TGF-β antibody started either 1 week before (anti-TGF pre-MI) or 5 days after (anti-TGF post-MI) induction of myocardial infarction. Treatment with an anti-TGF-β antibody aggravated left ventricular dilatation (figure reprinted with permission of Frantz et al.).