Editorial

The role of the neutrophil and free radicals in ischemic myocardial injury

Inflammatory serine proteases (ISPs) play an important role in cardiac repair after injury through hydrolysis of dead cells and extracellular matrix (ECM) debris. Evidence also suggests an important role of ISPs in the coordination of the inflammatory response. However, the effect of ISPs on inflammation is obfuscated by the confounding factors associated with cell death and inflammatory cell infiltration induced after cardiac injury. This study investigated whether neutrophil-derived cathepsin G (Cat.G) influences inflammation and remodeling in the absence of prior cardiac injury and cell death.

Intracardiac catheter delivery of Cat.G (1 mg/kg) in rats induced significant left ventricular (LV) dilatation and cardiac contractile dysfunction at day 5, but not at day 2, post-delivery compared to vehicle-treated animals. Cat.G delivery also significantly increased matrix metalloprotease activity and collagen and fibronectin degradation at day 5 compared to vehicle-treated rats and these changes were associated with increased death signaling pathways and myocyte apoptosis. Mechanistic analysis shows that Cat.G-treatment induced potent chemotactic activity in hearts at day 2 and 5 post-delivery, characterized by processing and activation of interleukin (IL)-1β and IL-18, stimulation of inflammatory signaling pathways and accumulation of myeloid cells when compared to vehicle-treated rats. Cat.G-induced processing of IL-1β and IL-18 was independent of the canonical NLRP-3 inflammasome pathway and treatment of isolated cardiomyocytes with inhibitors of NLRP-3 or caspase-1 failed to reduce Cat.G-induced cardiomyocyte death. Notably, rats treated with IL-1 receptor antagonist (IL-1Ra) show reduced inflammation and improved cardiac remodeling and function following Cat.G delivery.

Cat.G exerts potent chemoattractant and pro-inflammatory effects in non-stressed or injured heart in part through processing and activation of IL-1 family cytokines, subsequently leading to adverse cardiac remodeling and function. Thus, targeting ISPs could be a novel therapeutic strategy to reduce cardiac inflammation and improve cardiac remodeling and function after injury or stress.

Both the Global Registry of Acute Coronary Events (GRACE) risk score and neutrophil count could predict clinical outcomes in patients with acute coronary syndromes. However, the ability of them to identify high risk patients leaves room for improvement. The purpose of the present study was to evaluate whether the combination of them could have a better performance in predicting clinical outcomes in patients with ST-elevation myocardial infarction (STEMI).

A total of 1287 consecutive STEMI patients were recruited at two centers in China. Neutrophil count was measured and the GRACE risk score was calculated.

During a median period of 37 months (IQR, 29–47), 135 (10.9%) patients had major adverse cardiovascular events (MACE), including 116 all-cause death. Neutrophil count and the GRACE risk score were higher in patients with MACE. Both neutrophil count and the GRACE score were significant and independent predictors for MACE [HR: 1.260 (1.203–1.319), P < 0.001; HR: 1.007 (1.002–1.011), P < 0.001; respectively). Combination of them increased the area under the ROC (0.698 vs. 0.796, P < 0.001). The addition of neutrophil count to GRACE model enhanced net reclassification improvement (0.637, P = 0.020) and integrated discrimination improvement (0.180, P < 0.001), suggesting effective discrimination and reclassification.

Both neutrophil count and the GRACE risk score are independent predictors for MACE in patients with STEMI. A combination of them could derive a more accurate prediction for clinical outcomes in these patients.

Activation of the complement system has been demonstrated to be an important mechanism in the mediation of myocardial ischemia and reperfusion (MIR) injury. C1 inhibitor (C1INH) has been shown to be beneficial in experimental MIR models. The underlying mechanism of this effect has been assumed to result primarily from inhibition of complement system activation. We recently demonstrated that C1INH plays a direct role in suppression of leukocyte transmigration in the mouse intestinal ischemia and reperfusion model. The purpose of this study was to investigate the mechanism of the beneficial effect of C1INH in mouse MIR model.

C57BL/6, C1INH-deficient (C1INH^−/−), and C3-deficient mice (C3^−/−) were subjected to 30-min (C57BL/6 and C1INH^−/−) or 60-min (C3^−/−) occlusion of the left anterior descending branch of the coronary artery followed by 4-h reperfusion. C1INH or reactive center cleaved inactive C1INH (iC1INH) was injected intravenously 5 min before reperfusion.

Myocardial infarct size relative to the area at risk or relative to left ventricular area was significantly reduced in C1INH-treated wild-type, C1INH^−/−, and C3^−/− mice compared with vehicle-treated mice. MIR induced an increase in myocardial polymorphonuclear neutrophil accumulation and plasma cardiac specific troponin I levels in vehicle-treated MIR mice, while C1INH treatment significantly attenuated these effects. iC1INH had a similar protective effect.

These results suggested that C1INH prevented MIR injury in mice and that this cardioprotective effect may not solely result from complement inhibition, but might be also contributed by inhibiting leukocyte recruitment into ischemic tissue, an effect that is not mediated via protease inhibition.

The aims of this study are to analyze the factors that predispose the occurrence of ventricular arrhythmia (VA) in young patients with a first acute myocardial infarction (AMI) in the emergency department (ED) and to establish predictive implications.

This is a 10-year retrospective cohort study. Patients who were older than 18 years and younger than 45 years with a first attack of AMI were recruited from the ED of 3 university teaching hospitals from January 1, 1998, to December 31, 2007.

Five hundred young patients (472 men and 28 women) who met the inclusion criteria were enrolled. Within these patients, the incidence of life-threatening VA with first attack of AMI was 8% (n = 40). They were categorized into 2 groups: VA attack (n = 40) and non-VA attack (n = 460). In univariable analyses, acute anterolateral ST-segment elevation myocardial infarction (65% vs 47.8%; P = .04), elevate white blood cell (WBC) count (16.4 ± 3.4 vs 11.5 ± 3.1 × 10³/mm³; P < .01), and initial serum glucose level (202.6 ± 90.9 vs 151.9 ± 64.7 mg/dL; P < .01) were significantly increased in the VA group. Multiple logistic regression model identified WBC count and initial serum glucose level as the significant independent variables in the prediction of VA attack for young patients with first attack of AMI. The receiver operating characteristic area for WBC count and serum glucose level in predicting the risk of VA occurring after AMI was 0.869 and 0.756, respectively.

Initial serum glucose level and WBC may be used as valuable predictors for VA attack in young patients with first AMI.

Most of the available evidence on the role of neutrophils on pathological cardiac remodeling has been pertained after acute myocardial infarction. However, whether neutrophils directly contribute to the pathogenesis of cardiac remodeling after events other than acute myocardial infarction remains unknown. Here we show that acute eccentric hypertrophy induced by aorto-caval fistula (ACF) in the rats induced an increase in the inflammatory response characterized by activation of the STAT pathway and increased infiltration of neutrophils in the myocardium. This early inflammation was associated with a decrease in interstitial collagen accumulation and an increase in myocyte apoptosis. Neutrophil infiltration blockade attenuated MMP activation, ECM degradation, and myocyte apoptosis induced by ACF at 24 hours and attenuated the development of eccentric hypertrophy induced by ACF at 2 and 3 weeks, suggesting a causal relationship between neutrophils and the ACF-induced cardiac remodeling. In contrast, sustained neutrophil depletion over 4 weeks resulted in adverse cardiac remodeling with further increase in cardiac dilatation and macrophage infiltration, but with no change in myocyte apoptosis level. These data support a functional role for neutrophils in MMP activation, ECM degradation, and myocyte apoptosis during eccentric cardiac hypertrophy and underscore the adverse effects of chronic anti-neutrophil therapy on cardiac remodeling induced by early volume overload.