Postinfarct cardiac remodeling and the substrate for sudden cardiac death: role of oxidative stress and myocardial fibrosis

Keywords::

• antifibrotic
• antioxidant
• arrhythmia
• myocardial fibrosis
• oxidative stress
• postinfarct remodeling
• sudden cardiac death
• ventricular arrhythmia

The biological changes that occur after myocardial infarction (MI) produce gross structural abnormalities in the heart, such as scar tissue, hypertrophy and chamber dilatation, which may be followed by functional deterioration and the clinical symptoms of heart failure or ventricular arrhythmia. Heart failure is a well-known risk factor for ventricular arrhythmia that is associated with significantly higher cardiovascular mortality. It may be too late to cure a dysfunctional heart. Therefore, understanding the molecular mechanisms and signaling pathways involved in post-MI remodeling can provide useful insights for the very important period of time that follows infarction (the ‘golden therapeutic window’). Infarcted hearts show several important pathological changes that are arrhythmogenic, such as nerve sprouting [1], action potential duration (APD) alternans [2] and a decreased cardiac sodium current [3]. Among the underlying pathophysiologic changes, oxidative stress and myocardial fibrosis are particularly important for several reasons. First, there is strong experimental and clinical evidence for their arrhythmogenicity. Second, there are potential therapeutic options to prevent them. Also, oxidative stress promotes cardiac fibrosis. Finally, oxidative stress and cardiac fibrosis potentiate the arrhythmogenic effect of each other. This article highlights the role of oxidative stress and myocardial fibrosis in providing the substrate for sudden cardiac death in infarcted hearts.

Inflammation & oxidative stress after MI

Tissue damage and vascular injury caused by MI results in the recruitment of inflammatory cells (neutrophils and macrophages) to the infarcted region. Macrophages have a particularly important role in degrading macromolecules and scavenging dead cardiac cells [4].

Increased inflammation results in oxidative stress, which is characterized by the excess production of reactive oxygen species (ROS). NADPH oxidase, xanthine oxidase, uncoupled nitric oxide synthase and electron leakage from mitochondria are major sources of ROS in cardiac tissue [5]. Neutrophils and macrophages, which are primary inflammatory cells, overexpress NADPH oxidase in an inflammatory state [6]. This is considered a major link between inflammation and oxidative stress after MI. In addition, there is evidence of a reduction in antioxidant capacity and in the expression of the superoxide dismutase gene and protein, all of which contribute to increased oxidative stress in the infarcted myocardium [7]. In rat hearts it has been shown that levels of superoxide dismutase, catalase, glutathione peroxidase and vitamin E decrease after MI [8]. Although inflammation promotes oxidative stress, ROS can also increase inflammation by stimulating TNF-α production in cardiac tissue via the P38 mitogen-activated protein kinase pathway [9] and by activating NF-κB, which is a critical mediator of inflammation that increases the gene expression of various adhesion molecules, chemoattractant proteins and proinflammatory cytokines [10]. Experimental and clinical studies have shown that the level of ROS is elevated after MI [11–13]. In addition, there is a burst in ROS production during the reperfusion of an ischemic area of the heart and this ROS generation is dependent on the GTP-binding small molecule Rac-1 [14]. Nevertheless, increases in ROS production and the inflammatory cytokine levels after MI are not limited to the reperfusion phase or the early phases of MI; those increases continue during the late phases of cardiac remodeling and in heart failure. For example, explanted human hearts with heart failure exhibit the dimerization and nitrosylation of tropomyosin, as well as an increase in the carbonylation of actin and tropomyosin, all of which are ROS-mediated protein modifications [15,16]. Increases in the level of ROS after MI are not limited to the infarcted region; it has been detected in sites remote from the infarct [17].

There are several plausible ways in which ROS can cause arrhythmias. The addition of H₂O₂ prolongs APD and induces early afterdepolarization (EAD) and delayed afterdepolarization (DAD) mechanisms in myocytes [18]. Also, perfusion of H₂O₂ into fibrotic rat and rabbit hearts in the Langendorff setting induces EAD and subsequent ventricular arrhythmia [19]. One of the mechanisms of H₂O₂-induced APD prolongation and EAD formation is by the development of an enhanced late sodium current [20]. Suppression of ventricular arrhythmia by ranolazine, a late sodium current blocker, supports the above mechanism [21]. ROS such as H₂O₂ also directly stimulate the L-type Ca²⁺ current, which results in abnormal intracellular calcium cycling in myocytes and facilitates EAD [22]. In addition, hydroxyl radicals increase the open probability of cardiac ryanodine receptors, which control the Ca²⁺ release from the sarcoplasmic reticulum to the cytoplasm [23]. Many of the mechanisms of ROS-induced arrhythmia are through the facilitation of EAD and DAD formation. Importantly, ROS enhance fibroblast proliferation and type-I collagen gene expression [24]. In addition, ROS increase the level of TGF-β, which is the major cytokine that promotes cardiac fibrosis [25,26].

Although conventional general scavengers of ROS have not been clinically effective in treating cardiovascular disorders [27], targeting sources of excess ROS production, such as using NADPH oxidase inhibitors [28] and mitochondria-targeted antioxidants [29], may prove to be more effective and they should be more vigorously tested for the prevention of arrhythmia.

Scar tissue & myocardial fibrosis

One of the most important aspects of cardiac remodeling after MI is scar tissue formation. After MI, the area of dead necrotic myocytes is eventually replaced, primarily with myofibroblasts and collagen fibers. Although that compensatory mechanism is an essential component of the healing and repair that occurs after MI, it can also present an anatomic obstacle to wave propagation, which may result in wave break and re-entry. In an infarcted area, scattered live myocytes conduct the action potential wave. The propagation of that wave in scar tissue does not occur homogenously, and the variations in conduction velocity that occur in various parts of scar tissue are the basis for unidirectional block and re-entry [30].

Interstitial fibrosis, which is also increased in noninfarcted areas of the heart after MI [31], reduces conduction velocity, which in turn facilitates re-entry. Fibrosis also reduces myocyte coupling, which can facilitate the propagation of EAD and DAD by reducing the sink-to-source effect [19]. This effect is very important in the setting of oxidative stress. Oxidative stress may facilitate EAD and DAD formation; however, in a heart with well-coupled myocytes, the great electronic sink effect can prevent the emergence and propagation of EADs and DADs arising from a few cells. Therefore, in a heart with well-coupled myocytes, a greater number of myocytes with simultaneous EAD/DAD are required to overcome the electrotonic sink effect and cause an EAD/DAD to propagate and form a premature beat. Increased collagen deposition reduces the coupling between myocytes and facilitates the propagation of EAD/DAD through a reduction of the sink-to-source effect. That important mechanism was unraveled in a series of experiments on aged rat hearts in a Langendorff setting [19]. In that study, perfusion of H₂O₂ induced EAD/DAD in isolated myocytes, but did not cause any focal activity in adult rat hearts with no fibrosis and with well-coupled myocytes. Nevertheless, in aged rat hearts, H₂O₂ perfusion resulted in ventricular arrhythmia via EAD/DAD mechanisms that arose primarily from areas of the heart with critical amount of fibrosis. Thus, cardiac oxidative stress and fibrosis promote the arrhythmogenicity of each other in a way in which oxidative stress increases cardiac fibrosis, while fibrosis facilitates the propagation of oxidative stress-mediated focal activities. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have been shown to partially prevent, and even reverse, collagen deposition and myocardial fibrosis to some degree [32–34]; however, antifibrotic drugs that more completely prevent excess cardiac fibrosis must be identified. TGF-β is the major cytokine that promotes fibroblast proliferation and fibrosis in the heart [35]. Pirfenidone, which exerts its antifibrotic activity primarily by preventing the activation of TGF-β, has been tested as an antifibrotic agent for the reduction of dermal scarring and pulmonary fibrosis, and for the treatment of various nephropathies and a range of diseases in which increased fibrosis is the underlying pathophysiological condition [36–38]. Anti-TGF-β drugs such as pirfenidone may prove to be effective in reducing myocardial fibrosis and preventing ventricular tachycardia/ventricular fibrillation. In addition, the detection of serum markers of fibrosis (e.g., serum TGF-β and matrix metalloproteinases) and the accurate estimate of myocardial fibrosis revealed via cardiac MRI have a great potential for use in risk stratification methods for sudden cardiac death [35,39].

Conclusion

Although oxidative stress and myocardial fibrosis are essential adaptive cardiac changes in response to MI, they become key pathological processes in the chronic postinfarct remodeling of the heart that provides substrate for arrhythmia, and each process promotes the other. Oxidative stress increases cardiac fibrosis, and fibrosis facilitates propagation of oxidative stress-mediated EADs and DADs. Thus, antifibrotic drugs and antioxidants that target major cardiac sources of excess ROS may significantly prevent postinfarct cardiac remodeling and sudden arrhythmic death.

Financial & competing interests disclosure

AA Sovari is funded by the American Heart Association Midwest Affiliate Postdoctoral Fellowship Award (grant no. AHAA10POST4450037) and has the pending patent: Mitochondria antioxidants for prevention of sudden death by raising connexin 43 levels (application no. 61/503,096). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.