Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial.

Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384). Methods and results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively). Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.

Long-Term Incremental Prognostic Value of Cardiovascular Magnetic Resonance After ST-Segment Elevation Myocardial Infarction: A Study of the Collaborative Registry on CMR in STEMI.

OBJECTIVES: This study sought to investigate whether early post-infarction cardiac magnetic resonance (CMR) parameters provide additional long-term prognostic value beyond traditional outcome predictors in ST-segment elevation myocardial infarction (STEMI) patients. BACKGROUND: Long-term prognostic significance of CMR in STEMI patients has not been assessed yet. METHODS: This was a longitudinal study from a multicenter registry that prospectively included STEMI patients undergoing CMR after infarction. Between May 2003 and August 2015, 810 revascularized STEMI patients were included. CMR was performed at a median of 4 days after STEMI. Infarct size, microvascular obstruction (MVO), and left ventricular (LV) volumes and function were measured. Primary endpoint was a composite of all death and decompensated heart failure (HF). RESULTS: During median follow-up of 5.5 years (range 1.0 to 13.1 years), primary endpoint occurred in 99 patients (39 deaths and 60 HF hospitalization). MVO was a strong predictor of the composite endpoint after correction for important clinical, CMR, and angiographic parameters, including age, LV systolic function, and infarct size. The independent prognostic value of MVO was confirmed in all multivariate models irrespective of whether it was included as a dichotomous (presence of MVO, hazard ratio [HR]: 1.985 to 1.995), continuous (MVO extent as % LV, HR: 1.095 to 1.097), or optimal cutoff value (MVO extent ≥2.6% of LV; HR: 3.185 to 3.199; p < 0.05 for all). MVO extent ≥2.6% of LV was a strong independent predictor of all death (HR: 2.055; 95% confidence interval: 1.076 to 3.925; p = 0.029) and HF hospitalization (HR: 5.999; 95% confidence interval: 3.251 to 11.069; p < 0.001). Finally, MVO extent ≥2.6% of LV provided incremental prognostic value over traditional outcome predictors (net reclassification improvement index: 0.16 to 0.30; p < 0.05 for all models). CONCLUSIONS: Early post-infarction CMR-based MVO is a strong independent prognosticator in revascularized STEMI patients. Remarkably, MVO extent ≥2.6% of LV improved long-term risk stratification over traditional outcome predictors.

The degree of restored myocardial perfusion in acute myocardial infarction influences immediate and long-term results of primary coronary angioplasty.

BACKGROUND: Tissue perfusion during acute myocardial infarction (AMI) may be assessed by means of the angiographic method -- TIMI myocardial perfusion (TMP). We hypothesised that TMP grade (TMPG) after primary coronary angioplasty (PCI) implicates immediate and long-term clinical outcomes. METHODS: We studied 588 consecutive patients (mean age 58.7+/-10.8 years) with ST-segment elevation AMI treated with PCI. Infarct-related TMPG was evaluated before and after PCI. Myocardial injury was expressed as an area under the curve (AUC) of CK-MB release in the first 48 hours of reperfusion. Left ventricular ejection fraction (LVEF) was assessed by 2-dimensional echocardiography one day after PCI. Clinical end-points during a 12-month follow-up included death, recurrent MI and repeated revascularisation or hospitalisation. At the end of the follow-up, NYHA functional class was evaluated in all patients. RESULTS: Before PCI, TMPG -3, -2 and -0/1 values were observed in 52 (8.8%), 77 (13.1%) and 459 (78.1%) patients, respectively. After PCI, TMPG-3, -2 and -0/1 were achieved in 196 (33.3%), 174 (29.6%) and 218 (37.1%) patients, respectively. Patients with TMPG-3, -2, and -0/1 had AUC of 10341+/-1194, 12330+/-1272 and 16718+/-1860 (U/l x h) (p<0.01) and LVEF of 53.6+/-8.6%, 45.5+/-9.5% and 41.7+/-10.4% (p<0.001), respectively. In-hospital mortality rate in patients with TMPG-3, -2 and -0/1 was 0%, 4% and 11.9%, respectively (p<0.001), and after 12-months - 2%, 6.3% and 16.5%, respectively (p<0.001). The event-free survival rate after 1-year was 83.2%, 74.1% and 65.1% respectively (p<0.001). The percentage of patients in NYHA class > or =2 was 10.2%, 16.1% and 20.6% (p=0.003), respectively. CONCLUSIONS: The TIMI myocardial perfusion grade after primary coronary angioplasty in acute myocardial infarction effects left ventricular injury and function as well as early and long-term clinical outcome.

Platelet activation and microvascular injury in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Dual antiplatelet therapy reduces the risk of thrombotic complications after primary percutaneous coronary intervention (PCI). AIM: To assess whether inhibition of platelet function attenuates microvascular damage in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 83 STEMI patients treated with primary PCI. Platelet aggregation was measured on admission (ADM) and 4 days later (D4) by light transmission aggregometry after stimulation with 0.5 mM of arachidonic acid and after stimulation with 5 and 20 µM of adenosine diphosphate (ADP) on treatment with dual antiplatelet therapy with aspirin and clopidogrel. Platelet-neutrophil aggregate (PNA) and platelet-monocyte aggregate (PMA) were analysed by flow cytometry. Contrast-enhanced magnetic resonance imaging was performed 2-4 days after STEMI to detect the area of perfusion defect at rest and to determine the size of microvascular obstruction. Microvascular obstruction was expressed as a percentage of infarct area. RESULTS: Perfusion defect at rest was found in 56 (67.5%) patients whereas microvascular obstruction in 63 (75.9%) patients. Patients with perfusion defect at rest had on admission a significantly higher level of both PMA (7.0 vs. 4.5%, p = 0.004) and PNA (4.1 vs. 2.2%, p = 0.016), however there were no significant differences at D4. Platelet aggregation after stimulation with 5 µM of ADP on ADM was correlated (r = 0.37, p = 0.004) with microvascular obstruction area. Moreover, the higher the concentration of PMA(ADM) (r = 0.31, p = 0.016), PNA(ADM) (r = 0.34, p = 0.006) and PM(AD4) (r = 0.35, p = 0.005) the larger the size of microvascular obstruction. Infarct size (ß = 0.43, 95% CI 0.19 to 0.67, p 〈 0.0001), TIMI < 3 after PCI (ß = -0.27, 95% CI -1.90 to -0.11, p = 0.015) and PMA(D4) (ß = 0.21, 95% CI 0.13 to 1.86, p = 0.032) independently influenced the size of microvascular obstruction (R2 = 0.60, p 〈 0.0001). CONCLUSIONS: Excessive platelet activation during reperfusion in STEMI patients despite dual antiplatelet therapy is associated with greater microvascular impairment.

Evolution of myocardial perfusion during primary angioplasty in spontaneously reperfused infarct-related artery: impact on long-term clinical outcomes and left ventricular function recovery.

BACKGROUND: TIMI myocardial perfusion grade (TMPG) reflects the integrity of microvasculature in ST-elevation myocardial infarction (STEMI). We sought to investigate whether TMPG evolution during primary angioplasty (pPCI) in spontaneously reperfused STEMI patients might predict long-term outcomes. METHODS: 392 patients with TIMI-3 flow before pPCI were analyzed. According to pre- and post-pPCI TMPG four reperfusion patterns were created: A. TMPG deterioration from grade 2/3 to 0/1 after pPCI (n = 55, 14.0%), B. TMPG-0/1 before and after pPCI (n = 111, 28.3%), C. TMPG improvement from grade 0/1 to 2/3 (n = 52, 13.3%), D. TMPG-2/3 before and after pPCI (n = 174, 44.4%). 30-day and 1-year mortality and heart failure requiring hospitalization (HF-hosp) were recorded. Left ventricular ejection fraction (LVEF) was measured at first day (1D) and after 6 months (6M). RESULTS: 1D-LVEF was similar in A-D groups. After 6M, LVEF improved in pattern D (7.5 ± 5.4%, p<0.01) and C (3.7 ± 3.4%, p < 0.05), deteriorated in pattern A (5.2 ± 3.9%, p<0.01) and did not change in pattern B. 6M-LVEF increased (p < 0.001) and frequency of 1-year HF-hosp decreased (p < 0.001) in stepwise fashion among A-D patterns. A 30-day mortality rate for A-D patterns was 9.1%, 2.7%, 1.9% and 0%, respectively (p < 0.001). 1-year mortality was 16.3%, 7.2%, 5.8% and 0.6%, respectively (p < 0.001). By multivariate analysis (c-index = 0.79), TMPG evolution was independent predictor of 1-year mortality (HR = 2.5, 95%CI 1.3-4.0, p = 0.006). CONCLUSIONS: Maintaining TMPG-2/3 or improving TMPG-0/1 through pPCI in STEMI implies LV function recovery and good long-term survival. In contrast, substantial deterioration of TMPG is associated with lack of LV function recovery, and the highest mortality rate.

N-terminal pro-brain natriuretic peptide level in relation to epicardial and myocardial reperfusion in ST-segment elevation myocardial infarction treated with facilitated angioplasty.

UNLABELLED: The aims of this study were firstly to evaluate the relations between N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after ST-segment elevation myocardial infarction (STEMI) and reperfusion injury, and secondly to assess the prognostic value of NT-proBNP. METHODS AND RESULTS: We evaluated 202 consecutive patients with STEMI treated with facilitated angioplasty (PCI). TIMI flow, TIMI myocardial perfusion grade (TMPG) and ST-segment elevation resolution (iST) were assessed before O and 30 minutes (O30) after PCI. Enzymatic injury was expressed as an area under the curve of CK-MB release (AUC, [Uxh]). 48 hours after PCI, the concentration of NT-proBNP ([pg/ml]) and echocardiography-determined left ventricle ejection fraction (LVEF, [%]) were assessed. Death and heart failure (HF) requiring hospitalisation were recorded during a 1-year follow-up and defined as a composite endpoint. NT-proBNP concentration 48 hours after PCI was correlated with iST-O (p<0,001; r=0,48), iST-O30 (p<0,001; r=0,57), AUC (p<0,001; r=0,54) and LVEF (p<0,001; r=-0,5). Increasing quartiles of NT-proBNP were related to mortality (p=0,0012) as well as to composite endpoint (p=0,0012) at 1 year. 4th-quartile of NT-proBNP was independently associated with a composite endpoint at a 1-year follow-up. CONCLUSIONS: NT-proBNP level after STEMI was moderately correlated with the degree of microvascular reperfusion and myocardial injury and function. NT-proBNP was independently associated with the frequency of death and HF requiring hospitalisation.