Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.

Interleukin-1ß (IL-1ß), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.

NT-proBNP level before primary PCI and risk of poor myocardial reperfusion: Insight from the On-TIME II trial.

BACKGROUND: N-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP), a marker for neurohumoral activation, has been associated with adverse outcome in patients with myocardial infarction. NT-proBNP levels may reflect extensive ischemia and microvascular damage, therefore we investigated the potential association between baseline NT-proBNP level and ST-resolution (STR), a marker of myocardial reperfusion, after primary percutaneous coronary intervention (pPCI). METHODS: we performed a post-hoc analysis of the On-TIME II trial (which randomized ST-elevation myocardial infarction (STEMI) patients to pre-hospital tirofiban administration vs placebo). Patients with measured NT-proBNP before angiography were included. Multivariate logistic-regression analyses was performed to investigate the association between baseline NTproBNP level and STR one hour after pPCI. RESULTS: Out of 984 STEMI patients, 918 (93.3%) had NT-proBNP values at baseline. Patients with STR <70% had higher NT-proBNP values compared to patients with complete STR (>70%) [Mean ±SD 375.2 ±1021.7 vs 1007.4 ±2842.3, Median (IQR) 111.7 (58.4-280.0) vs 168.0 (62.3-601.3), P <.001]. At multivariate logistic regression analysis, independent predictors associated with higher risk of poor myocardial reperfusion (STR <70%) were: NT-proBNP (OR 1.17, 95%CI 1.04-1.31, P = .009), diabetes mellitus (OR 1.87, 95%CI 1.14-3.07, P = .013), anterior infarct location (OR 2.74, 95% CI 2.00-3.77, P <.001), time to intervention (OR 1.06, 95%CI 1.01-1.11, P = .021), randomisation to placebo (OR 1.45, 95%CI 1.05-1.99, P = .022). CONCLUSIONS: In STEMI patients, higher baseline NT-proBNP level was independently associate with higher risk of poor myocardial reperfusion, supporting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients.

Left ventricular functional recovery of infarcted and remote myocardium after ST-segment elevation myocardial infarction (METOCARD-CNIC randomized clinical trial substudy).

BACKGROUND: We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). METHODS: A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. RESULTS: In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (- 8.6 ± 9.0% to - 14.5 ± 8.0%; P < 0.001), while no changes in the remote zone strain were observed (- 19.5 ± 5.9% to - 19.2 ± 3.9%; P = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week (P = 0.038) and at 6 months (P = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without (P < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH (P < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI (P = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed. CONCLUSIONS: Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01311700. Registered 8 March 2011 - Retrospectively registered.

Comparison of clinical outcomes between sufficient versus insufficient diagonal branch flow in anterior acute myocardial infarction.

In primary percutaneous coronary intervention (PCI), revascularization to the main branch is considered to be more important than that to the side branch. The purpose of the present study was to compare in-hospital clinical outcomes between sufficient and insufficient diagonal flow in patients with anterior ST-elevation acute myocardial infarction. A total of 229 left anterior descending artery (LAD)-AMI with final Thrombolysis in Myocardial Infarction (TIMI)-3 LAD flow were included, and divided into the sufficient diagonal flow group (TIMI-3 diagonal flow: n = 170) and the insufficient diagonal flow group (TIMI ≤ 2 diagonal flow: n = 59). The primary endpoint was the incidence of mechanical complication. The secondary endpoints were incidences of in-hospital death, heart failure at discharge, and left ventricular thrombus. There were no significant differences in the primary endpoint (the sufficient diagonal flow group: 1.2%, the insufficient diagonal flow group: 0%, P = 0.403). In-hospital death was more frequently observed in the insufficient diagonal flow group (8.5%) than the sufficient diagonal flow group (2.9%) without reaching statistical significance (P = 0.073). The incidence of heart failure at discharge, and thrombus in left ventricular were not different between the two groups. In conclusion, in-hospital outcomes were not significantly different between the sufficient and insufficient diagonal flow groups. We may not stick to the diagonal flow in LAD-STEMI, as long as the LAD flow is maintained by PCI.

The predictive value of global longitudinal strain on late infarct size in patients with anterior ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention.

Late infarct size (IS) after ST segment elevation myocardial infarction (STEMI) is a determinant of subsequent mortality. Late Gadolinium enhancement in cardiac magnetic resonance imaging (LGE-CMRI) is the gold standard for IS measurement, however, it is not readily accessible in many areas. We aimed to evaluate the value of early baseline 2D-echocardiographic global longitudinal strain (GLS) for the prediction of late IS after STEMI. From October 2017 to July 2018, we studied 100 patients with their 1st anterior STEMI treated with primary percutaneous coronary intervention. Baseline GLS calculation was performed within 48 h of admission. In addition, the average value of the nine segments supplied by the LAD was assessed separately (anterior GLS). Infarct size was assessed 3 months later using LGE-CMRI, and large infarcts were defined as ≥ 20% LV myocardium covered by scar. Based on CMRI, we defined two groups; 57 patients with large infarcts (group I) and 43 patients with small infarcts (group II). Both groups were matched in all baseline demographics and risk factors. There was a good and significant correlation between GLS and late IS (r = - 0.840, P < 0.001). This correlation was even higher for anterior GLS (r = - 0.867, P < 0.001). ROC analysis showed a cut-off point of GLS (- 13%) that identified large late IS with a sensitivity and specificity of 66.7% and 88.4% respectively (AUC = 0.85). For anterior GLS, the cut-off point was - 9.6% (Sensitivity 94%, specificity 86%, AUC = 0.9). We concluded that baseline GLS significantly predicts late IS after anterior STEMI.

Cardiac αVß3 integrin expression following acute myocardial infarction in humans.

OBJECTIVE: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvß3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvß3 integrin expression determines myocardial recovery following MI. METHODS: 18F-Fluciclatide (a novel αvß3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. RESULTS: 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. CONCLUSION: 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. TRIAL REGISTRATION NUMBER: NCT01813045; Post-results.

INNOVATION Study (Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST-Segment-Elevation Myocardial Infarction).

BACKGROUND: The aim of this study was to assess whether deferred stenting (DS) reduces infarct size and microvascular obstruction (MVO) compared with immediate stenting (IS) in primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction. METHODS AND RESULTS: From February 2013 to August 2015, 114 patients (mean age: 69 years) were randomized into the following 2 groups: DS with an intention to stent 3 to 7 days later or IS after primary reperfusion in 2 centers. The primary and secondary end points were infarct size and the incidence of MVO, respectively, assessed by cardiac magnetic resonance imaging at 30 days after primary reperfusion. The median time to the second procedure in the DS was 72.8 hours. Six patients in the DS group were crossed over to the IS group because of progression of dissection or safety concerns after randomization. In the intention-to-treat analysis, DS did not significantly reduce infarct size (15.0% versus 19.4%; P=0.112) and the incidence of MVO (42.6% versus 57.4%; P=0.196), compared with IS. However, in anterior wall myocardial infarction, infarct size (16.1% versus 22.7%; P=0.017) and the incidence of MVO (43.8% versus 70.3%; P=0.047) were significantly reduced in the DS group. There was no urgent revascularization event during deferral period. CONCLUSIONS: A routine DS did not significantly reduce infarct size and MVO compared with IS, although it was safe. The beneficial effect of DS in patients with anterior myocardial infarction should be confirmed by larger randomized studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02324348.

Infarct size and left ventricular remodelling after preventive percutaneous coronary intervention.

OBJECTIVE: We hypothesised that, compared with culprit-only primary percutaneous coronary intervention (PCI), additional preventive PCI in selected patients with ST-elevation myocardial infarction with multivessel disease would not be associated with iatrogenic myocardial infarction, and would be associated with reductions in left ventricular (LV) volumes in the longer term. METHODS: In the preventive angioplasty in myocardial infarction trial (PRAMI; ISRCTN73028481), cardiac magnetic resonance (CMR) was prespecified in two centres and performed (median, IQR) 3 (1, 5) and 209 (189, 957) days after primary PCI. RESULTS: From 219 enrolled patients in two sites, 84% underwent CMR. 42 (50%) were randomised to culprit-artery-only PCI and 42 (50%) were randomised to preventive PCI. Follow-up CMR scans were available in 72 (86%) patients. There were two (4.8%) cases of procedure-related myocardial infarction in the preventive PCI group. The culprit-artery-only group had a higher proportion of anterior myocardial infarctions (MIs) (55% vs 24%). Infarct sizes (% LV mass) at baseline and follow-up were similar. At follow-up, there was no difference in LV ejection fraction (%, median (IQR), (culprit-artery-only PCI vs preventive PCI) 51.7 (42.9, 60.2) vs 54.4 (49.3, 62.8), p=0.23), LV end-diastolic volume (mL/m2, 69.3 (59.4, 79.9) vs 66.1 (54.7, 73.7), p=0.48) and LV end-systolic volume (mL/m2, 31.8 (24.4, 43.0) vs 30.7 (23.0, 36.3), p=0.20). Non-culprit angiographic lesions had low-risk Syntax scores and 47% had non-complex characteristics. CONCLUSIONS: Compared with culprit-only PCI, non-infarct-artery MI in the preventive PCI strategy was uncommon and LV volumes and ejection fraction were similar.

Acute Myocardial Infarction due to Left Atrial Myxoma.

Myxoma is a common benign cardiac tumor that may rarely cause an acute myocardial infarction. A 77-year-old woman was admitted to our hospital with chest pain. Electrocardiography showed an ST elevation in leads V3-6. Transthoracic echocardiography revealed an ovoid mass with fragmentation in the left atrium and hypokinesia of the left ventricular apex. Coronary angiography indicated the presence of a coronary embolism that was suspected to be from the left atrial mass. The mass was removed by emergency surgical resection to avoid a further systemic embolism and was diagnosed pathologically as a myxoma. The patient was discharged after 13 days with no complications.

[Recurrent acute myocardial infarction as a thromboembolic complication of atrial fibrillation]. / Recidív akut myocardialis infarctus pitvarfibrilláció miatt.

Coronary thromboembolism with subsequent myocardial infarction is a rare complication of atrial fibrillation. The authors present the history of a 55-year-old male with a history of acute myocardial infarction caused by thromboembolism in the distal part of left anterior descending coronary artery and paroxysmal atrial fibrillation, who presented one year later with new chest pain, ST-segment elevation and atrial fibrillation. Coronarography confirmed the presence of thrombus in the circumflex coronary artery. Transesophageal echocardiogram showed left atrial appendage thrombus. To the knowledge of the authors this is the first report of recurrent myocardial infarction caused by atrial fibrillation.

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial†.

AIMS: Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1-7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. METHODS AND RESULTS: A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: -0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0-0.20; P = 0.048). Major adverse events were rare in both treatment groups. CONCLUSION: The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage.

Relationship between QRS score and microvascular obstruction after acute anterior myocardial infarction.

BACKGROUND: The QRS score on electrocardiogram (ECG) in patients with myocardial infarction (MI) reportedly reflects the severity of myocardial damage. The presence of microvascular obstruction (MO) assessed by cardiac magnetic resonance (CMR) imaging is associated with irreversible myocardial damage. MO assessed by CMR is known to be a predictor for adverse clinical outcome after ST-elevation MI. The aim of the present study was to examine the relationship between QRS score and MO in acute anterior MI patients. METHODS: Sixty-two patients with first acute anterior MI who successfully underwent primary percutaneous coronary intervention (PCI) were enrolled. The QRS score after PCI on admission ECG was calculated by a Selvester-Wagner QRS scoring system. CMR imaging was performed at 11.4±3.9 days after MI. MO was defined as delayed enhancement with contrast-devoid core. Patients were divided into two groups as follows: 37 patients who showed MO (MO group) and 25 patients who did not show it (non-MO group). RESULTS: The QRS score was significantly greater in the MO group than in the non-MO group. The QRS score significantly correlated with MO volume (r=0.418, p=0.010). Multivariate analysis showed that the QRS score (odds ratio 1.362, 95% CI: 1.038-1.951, p=0.024) and the peak creatine kinase levels (odds ratio 1.001, 95% CI: 1.000-1.002, p<0.001) were independent predictors for MO. CONCLUSIONS: Our results indicate that the QRS score derived from simple and widely available ECG may be a useful parameter for assuring the presence of MO.

Usefulness of the Left Anterior Descending Coronary Artery Wrapping Around the Left Ventricular Apex to Predict Adverse Clinical Outcomes in Patients With Anterior Wall ST-Segment Elevation Myocardial Infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial).

The association between anatomic features of the left anterior descending artery (LAD) and outcomes in patients with anterior ST-segment elevation myocardial infarction (STEMI) has not been fully investigated. We sought to clarify the impact of an LAD coronary artery wrapping around the left ventricular (LV) apex on clinical outcomes in patients with anterior STEMI. Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction enrolled patients with STEMI presenting <12 hours after symptom onset who underwent primary percutaneous coronary intervention. Patients with a culprit lesion in the LAD were categorized as (1) LAD wrapping around the LV apex (wrap-around LAD, n = 871) versus (2) LAD not wrapping around the LV apex (non-wrap-around LAD, n = 224). Killip class ≥II, dysrhythmia, and LV mural thrombi were more frequently observed in the wrap-around LAD group; LV ejection fraction was worse in the wrap-around LAD group (54.5% vs 58.7%, p = 0.006). At 3 years of follow-up, major adverse cardiac events (death, stroke, or stent thrombosis, 12.7% vs 5.4%, p = 0.002), death (6.6% vs 3.2%, p = 0.052), stroke (1.9% vs 0.5%, p = 0.12), stent thrombosis (5.6% vs 2.3%, p = 0.047), and severe heart failure (4.5% vs 1.4%, p = 0.03) were more common in patients with a wrap-around LAD versus those with a non-wrap-around LAD. Multivariate analysis indicated that a wrap-around LAD independently and significantly predicted major adverse cardiac events (hazard ratio 2.18, p = 0.02) and severe heart failure (odds ratio 3.31, p = 0.049) in patients with an anterior STEMI. In conclusion, a wrap-around LAD predicted adverse clinical outcomes at 3 years in patients with anterior STEMI who underwent primary percutaneous coronary intervention.

Cardiac Stem Cell Hybrids Enhance Myocardial Repair.

RATIONALE: Dual cell transplantation of cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction improves myocardial repair and performance in large animal models relative to delivery of either cell population. OBJECTIVE: To demonstrate that CardioChimeras (CCs) formed by fusion between CPCs and MSCs have enhanced reparative potential in a mouse model of myocardial infarction relative to individual stem cells or combined cell delivery. METHODS AND RESULTS: Two distinct and clonally derived CCs, CC1 and CC2, were used for this study. CCs improved left ventricular anterior wall thickness at 4 weeks post injury, but only CC1 treatment preserved anterior wall thickness at 18 weeks. Ejection fraction was enhanced at 6 weeks in CCs, and functional improvements were maintained in CCs and CPC+MSC groups at 18 weeks. Infarct size was decreased in CCs, whereas CPC+MSC and CPC parent groups remained unchanged at 12 weeks. CCs exhibited increased persistence, engraftment, and expression of early commitment markers within the border zone relative to combinatorial and individual cell population-injected groups. CCs increased capillary density and preserved cardiomyocyte size in the infarcted regions suggesting CCs role in protective paracrine secretion. CONCLUSIONS: CCs merge the application of distinct cells into a single entity for cellular therapeutic intervention in the progression of heart failure. CCs are a novel cell therapy that improves on combinatorial cell approaches to support myocardial regeneration.