Higher Myocardial Salvage Index Research Articles

Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size

Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect. The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI. In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24hours and 3 to 7days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI). All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7days (all P<0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P=0.001 [dsDNA] and 0.02, P=0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (10.9 [95%CI: 4.0-15.0] [dsDNA] and 8.9 [95%CI: 2.0-15.9] [H3Cit], both P=0.01). NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab onMSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction:The ASSAIL-MI Trial [ASSAIL-MI]; NCT03004703).

Novel cardiac extracellular matrix biomarkers in STEMI: Associations with ischemic injury and long-term mortality.

We aimed to determine whether serum levels of proteins related to changes in cardiac extracellular matrix (ECM) were associated with ischemic injury assessed by cardiac magnetic resonance (CMR) and mortality in patients with ST-elevation myocardial infarction (STEMI). The concentrations of six ECM-related proteins (periostin, osteopontin, syndecan-1, syndecan-4, bone morphogenetic protein 7, and growth differentiation factor (GDF)-15) were measured in serum samples from patients on Day 1 and Month 4 after STEMI (n = 239). Ischemic injury was assessed by myocardial salvage index, microvascular obstruction, infarct size, and left ventricular function measured by CMR conducted during the initial admission (median 2 days after admission) and after 4 months. All-cause mortality was recorded after a median follow-up time of 70 months. Levels of periostin increased from Day 1 to Month 4 after hospitalization, while the levels of GDF-15, osteopontin, syndecan-1, and syndecan-4 declined. At both time points, high levels of syndecan-1 were associated with microvascular obstruction, large infarct size, and reduced left ventricular ejection fraction, whereas high levels of syndecan-4 at Month 4 were associated with a higher myocardial salvage index and less dilatation of the left ventricle. Higher mortality rates were associated with periostin levels at both time points, low syndecan-4 levels at Month 4, or high GDF-15 levels at Month 4. In patients with STEMI, we found an association between serum levels of ECM biomarkers and ischemic injury and mortality. The results provide new insight into the role ECM components play in ischemic injury following STEMI and suggests a potential for these biomarkers in prognostication after STEMI.

Colchicine added to standard therapy further reduces fibrosis in pigs with myocardial infarction.

The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling.

Changes in novel cardiac extracellular matrix biomarkers in STEMI: associations with adverse outcomes

Abstract Background Ischemia-reperfusion (IR)-injury contributes to adverse outcomes following myocardial infarction undergoing reperfusion. Exaggerated remodelling of the extracellular matrix (ECM) is likely to be involved in IR-injury, potentially releasing ECM components to the systemic circulation. To improve prognostication and future therapeutic options in patients with myocardial infarction, more knowledge is warranted about ECM components associated with IR-injury. Purpose To investigate whether ECM components quantified in serum samples associate with myocardial injury and function, and clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Methods We selected biomarkers previously suggested to be involved in ECM changes in the heart, i.e. growth differentiation factor 15 (GDF-15), periostin, osteopontin, syndecan-1, syndecan-4, and bone morphogenetic protein 7. The concentrations of the biomarkers were measured in serum samples from patients with STEMI (n=239) enrolled in the POSTEMI trial, at day 1 and month 4 after hospital admission. Infarct size, microvascular obstruction (MVO), left ventricular remodelling, and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging. Major adverse cardiovascular events (MACE) and all-cause mortality were recorded after 12 months and with a median of 70 months, respectively. Results Serum levels of GDF-15, osteopontin, syndecan-1 and syndecan-4 declined, whereas periostin increased, from day 1 to month 4. Higher levels of syndecan-1 were associated with the presence of MVO (n=116) (day 1 OR 1.39 (1.06–1.82); month 4 OR 1.53 (1.08–2.17)), while higher GDF-15 and syndecan-1 were associated with the development of large infarct size (&amp;gt;75th percentile, n=57) and reduced cardiac function defined as LVEF &amp;lt;50% (n=64) at month 4. Higher levels of GDF-15 at month 4 and periostin at both time points were associated with increased risk of both MACE (n=16) (GDF-15: HR 1.42 (1.04–1.94); periostin day 1: HR 1.88 (1.09–3.25); periostin month 4: HR 1.64 (1.03–2.62)) and all-cause mortality (n=20) (GDF-15: HR 1.59 (1.28–1.97); periostin day 1: HR 1.85 (1.16–2.95); periostin month 4: HR 2.02 (1.35–3.02)) (Figure 1). On the contrary, elevated levels of syndecan-4 at month 4 were associated with lower risk of adverse outcomes, including all-cause mortality (HR 0.48 (0.28–0.84)) (Figure 1) and less IR-injury as assessed by a higher myocardial salvage index. Conclusion Elevated serum levels of GDF-15, periostin, and syndecan-1 were associated with a higher risk of adverse outcomes or detrimental remodelling in patients with STEMI. Increased levels of syndecan-4 measured 4 months after STEMI were associated with a reduced risk of all-cause mortality. Our results suggest the potential use of these biomarkers as prognostic tools and may suggest a role for these ECM components in IR injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health AuthorityNorwegian Health Association

Iron deficiency in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Iron deficiency (ID) is a known co-morbidity and a potential therapeutic target in heart failure. Whether ID is frequent also in ST-segment elevation acute myocardial infarction (STEMI) patients and is associated with worse in-hospital outcomes has never been evaluated. We defined ID as a serum ferritin < 100 μg/L or transferrin saturation < 20% at hospital admission. We assessed the association between ID and the primary endpoint (a composite of in-hospital mortality and Killip class ≥ 3). We explored the potential association between ID, circulating cell-free mitochondrial DNA (mtDNA), and cardiac magnetic resonance (CMR) parameters. Four-hundred-twenty STEMI patients undergoing primary percutaneous coronary intervention (pPCI) were included. Of them, 237 (56%) had ID. They had significantly higher admission high-sensitivity troponin and mtDNA levels as compared to non-ID patients (145 ± 35 vs. 231 ± 66 ng/L, P < 0.001; 917 [404-1748] vs. 1368 [908-4260] copies/μL; P < 0.003, respectively). A lower incidence of the primary endpoint (10% vs. 18%, P = 0.01) was observed in ID patients (adjusted OR 0.50 [95% CI 0.27-0.93]; P = 0.02). At CMR (n = 192), ID patients had a similar infarct size (21 ± 18 vs. 21 ± 19 g; P = 0.95), but a higher myocardial salvage index (0.56 ± 0.30 vs. 0.43 ± 0.27; P = 0.002), and a smaller microvascular obstruction extent (3.6 ± 2.2 vs. 6.9 ± 3.9 g; P < 0.001). Iron deficiency is frequent in STEMI patients, it is coupled with mitochondrial injury, and, paradoxically, with a better in-hospital outcome. This unexpected clinical result seems to be associated with a smaller myocardial reperfusion injury. The mechanisms underlying our findings and their potential clinical implications warrant further investigation.

Comparison of Outcome of Patients With ST-Segment Elevation Myocardial Infarction and Complete Versus Incomplete ST-Resolution Before Primary Percutaneous Coronary Intervention

Some patients presenting with ST-segment elevation myocardial infarction (STEMI) have complete ST resolution in the electrocardiogram, which may be clinical useful in the triage of patients with STEMI. However, the importance of complete ST resolution in these patients remains uncertain. Thus, the purpose was to describe the prognosis of patients with complete ST resolution before primary percutaneous coronary intervention (PCI). Continuous ST monitoring from arrival until 90minutes after PCI was performed in 933 patients with STEMI. Complete ST resolution was defined as no residual significant ST elevations before intervention. The patients were followed clinically for 5.5years (range 0 to 6.8years). Infarct size and myocardial salvage were assessed in a subgroup of patients (n=221) by cardiovascular magnetic resonance. Complete ST resolution was observed in 24% of the patients, who had a higher incidence of Thrombolysis In Myocardial Infarction grade 2/3 flow before intervention (64% vs 24%), smaller infarct size (6% vs 11%), and higher myocardial salvage index (0.82 vs 0.69; all p <0.001) compared with patients with continuous ST elevations. Complete ST resolution was associated with a significantly lower rate of the composite end point of all-cause death and admission for heart failure (14% vs 22%; p= 0.006) although it only tended to be an independent predictor in a multivariate analysis (hazard ratio 0.69, 95% CI 0.49 to 1.06; p= 0.09). In conclusion, compared to patients without incomplete ST resolution, patients with STEMI and complete ST resolution before primary PCI have a higher incidence of normalized epicardial flow before PCI, a larger myocardial salvage and smaller infarct size after the procedure and presumably improved long-term outcome compared with incomplete ST resolution.

Abstract 15198: Infarct Size in Patients on Chronic Statin Therapy Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction

Introduction: Statin pre-treatment has been reported to have a cardio-protective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on ST-elevation myocardial infarction (STEMI) patients undergoing primary PCI are still controversial. Hypothesis: We prospectively evaluated the effect of chronic statin therapy on infarct size (IS), myocardial salvage index (MSI), and micro-vascular obstruction in consecutive STEMI patients undergoing primary PCI. Methods: Two-hundred-thirty STEMI patients (mean age 61±11 years, 183 men) who underwent primary PCI were evaluated with cardiac magnetic resonance (CMR) imaging during hospitalization (median 4 days after primary PCI). In all patients, we measured peak troponin I level, while IS, MSI, and micro-vascular obstruction were determined by CMR. Results: Fifty (22%) patients were on chronic statin therapy and showed a significantly lower troponin I peak value when compared to patients without prior statins (54±47 vs. 88±106 ng/ml; P=0.02). At CMR evaluation, IS related to the index event was significantly smaller (12.5±11.5 vs. 18.5±18.5 grams,P=0.05), and MSI was higher (0.68±0.25 vs. 0.52±0.30; P=0.01) in patients with prior statin therapy. Micro-vascular obstruction was also less frequent (10% vs. 20%; P=0.14) in this group. At multivariable analysis, prior statin therapy remained significantly associated with IS and MSI (P=0.05 and P=0.02, respectively). No significant association was observed between index IS and LDL-cholesterol levels at hospital admission in the entire population (P=0.91). Moreover, no relationship between IS or MSI and statin dose (r=-0.10, P=0.56 and r=0.10, P=0.55, respectively), and length of statin treatment (r=-0.06, P=0.71 and r=0.29; P=0.10, respectively) was found. Conclusions: The results of the present study demonstrated that prior statin therapy is associated with significant smaller IS and higher MSI in patients presenting with STEMI and treated with primary PCI. Whether these preliminary findings will translate into a potential therapeutic strategy warrants further research.

Myocardial Infarct Size in Patients on Long-Term Statin Therapy Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction

Statin pretreatment has been reported to have a cardioprotective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI are still controversial. We prospectively evaluated the effect of long-term statin therapy on infarct size (IS), myocardial salvage index (MSI), and microvascular obstruction (MVO) in consecutive patients with STEMI who underwent primary PCI. Two-hundred thirty patients with STEMI (mean age 61 ± 11 years, 183 men) who underwent primary PCI were evaluated with cardiac magnetic resonance (CMR) imaging during hospitalization (median 4 days after primary PCI). In all patients, we measured peak troponin I level, whereas IS, MSI, and MVO were determined by CMR. Fifty patients (22%) were on long-term statin therapy and showed a significantly lower troponin I peak value compared to patients without previous statins (54 ± 47 vs 88 ± 106 ng/ml; p = 0.02). At CMR evaluation, IS related to the index event was significantly smaller (12.5 ± 11.5 vs 18.5 ± 18.5 g, p = 0.05), and MSI was higher (0.68 ± 0.25 vs 0.52 ± 0.30; p <0.01) in patients with previous statin therapy. MVO was also less frequent (10% vs 20%; p = 0.14) in this group. At multivariate analysis, previous statin therapy remained significantly associated with IS and MSI (p = 0.05 and 0.02, respectively). In conclusion, this study suggests that long-term statin therapy before primary PCI in patients with STEMI is associated with smaller IS and higher MSI. Future studies are warranted to confirm these findings and to investigate potential clinical implications.

Impact of gender differences on myocardial salvage and post-ischaemic left ventricular remodelling after primary coronary angioplasty: new insights from cardiovascular magnetic resonance

There is conflicting evidence on the impact of gender on reperfusion after primary coronary angioplasty (PPCI), and on left ventricular (LV) remodelling (LVR). In a cohort of patients with reperfused ST elevation myocardial infarction (STEMI), gender-related differences on myocardial reperfusion, and sex-related differences on LVR were assessed by using a comprehensive cardiac magnetic resonance (CMR) approach. In four tertiary referral centres, 283 (238 males and 45 females) consecutive STEMI patients, treated with PPCI within 12 h from symptoms onset underwent CMR 3 ± 2 days after STEMI and at 4-month follow-up. By CMR, the area at risk, infarct size (IS), microvascular obstruction (MVO), and myocardial salvage index (MSI) were assessed. Women were older than men (P = 0.014), more hypertensive (P < 0.001) and more frequently presented with pre-infarct angina (P = 0.018). An MSI extent was significantly higher (P = 0.013), IS was significantly smaller at both time points (acute P < 0.001, follow-up P < 0.001), and the MVO extent was significantly smaller (P < 0.001) in women. At multivariate analysis, Killip class and female sex were independently associated with a higher MSI (P = 0.02, P = 0.05, respectively). A similar incidence of LVR in both sexes was observed at follow-up (P = 0.808). The better reperfusion pattern observed in women by CMR in our population of reperfused STEMI suggests sex-based differences exist. No gender differences were observed with respect to incidence of LV remodelling at the follow-up mainly occurring in the subset of patients with a larger IS.

THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST EXENATIDE IS SAFE AND MAY BE CARDIOPROTECTIVE IN ACUTE MYOCARDIAL INFARCTION: THE EXAMI PHASE L TRIAL

.Reperfusion limits myocardial necrosis, however induces reperfusion injury leading to additional necrosis and apoptosis. Glucagon Like Peptide-1 (GLP-1), an incretin hormone, has anti-apoptotic properties and proved to be cardioprotective in experimental studies. This pilot study assessed the safety and feasibility of the GLP-1 receptor agonist exenatide in patients with acute MI undergoing primary PCI. Methods: Seventy-one non-diabetic patients with acute MI undergoing primary PCI were randomized to placebo or exenatide 5μg bolus administered in 30 minutes prior to PCI, followed by continuous infusion of 20μg/ 24 hours for 72 hours. Blood samples were obtained including enzymatic infarct size and glucose levels. Magnetic resonance imaging and echocardiography were conducted 3-5 days and 4 months post MI for measurements including infarct size, cardiac function and myocardial salvage index (MSI), a predictor for mortality and major adverse cardiac events. Results: Forty out of 71 randomized patients completed the full protocol. Exclusion was mainly due to angiographic criteria. Patient characteristics were well balanced between the groups. An equal amount of hypo- and hyperglycemic episodes (glucose 10 mmol/L) were observed in both groups. No deaths, CABG or re-infarction occurred during the 4-month follow-up. Although more patients in the exenatide group experienced nausea (58% v 20%, p = 0.015), no decrease or cessation of exenatide was required. Infarct size, cardiac function and MSI at 4 months did not differ signiicantly. However, a trend towards a higher MSI was seen in patients with TIMI 0 and 1 low receiving exenatide (0.65 ± 0.14 (n = 12) v 0.53 ± 0.17 (n = 11), p = 0.09). Conclusions: We demonstrated that administering exenatide in patients with acute MI undergoing primary PCI is feasible and safe. Although not powered for this analysis, Exami phase l seems to show a trend towards a higher MSI in the exenatide group. A large randomized placebo controlled study is required to assess the eficacy of exenatide on myocardial salvage.