Large Myocardial Infarction Research Articles

Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study.

The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI). This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7g for bivalirudin vs. 27.1±20.7g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8g vs. 7.7±6.3g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility. This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.

Variability in coronary artery anatomy affects consistency of cardiac damage after myocardial infarction in mice.

Low reliability and reproducibility in heart failure models are well established. The purpose of the present study is to explore factors that affect model consistency of myocardial infarction (MI) in mice. MI was induced by left coronary artery (LCA) ligation. The coronary artery was casted with resin and visualized with fluorescent imaging ex vivo. LCA characteristics and MI size were analyzed individually in each animal, and MI size was correlated with left ventricular (LV) function by echocardiography. Coronary anatomy varies widely in mice, posing challenges for surgical ligation and resulting in inconsistent MI size postligation. The length of coronary arterial trunk, level of bifurcation, number of branches, and territory supplied by these branches are unique in each animal. When the main LCA trunk is ligated, this results in a large MI, but when a single branch is ligated, MI size is variable due to differing levels of LCA ligation and area supplied by the branches. During the ligation procedure, nearly 40% of LCAs are not grossly visible to the surgeon. In these situations, the surgeon blindly sutures a wider and deeper area of tissue in an attempt to catch the LCA. Paradoxically, these situations have greater odds of resulting in smaller MIs. In conclusion, variation in MI size and LV function after LCA ligation in mice is difficult to avoid. Anatomic diversity of the LCA in mice leads to inconsistency in MI size and functional parameters, and this is independent of potential technical modifications made by the operator.NEW & NOTEWORTHY In the present study, we demonstrate that left coronary artery diversity in mice is one of the primary causes of variable myocardial infarction size and cardiac functional parameters in the left coronary artery ligation model. Recognition of anatomic diversity is essential to improve reliability and reproducibility in heart failure research.

Abstract 130: The Diversity of Coronary Artery and Myocardial Infarction in Mice

Low reliability and reproducibility in heart failure research has been a major concern. The purpose of the present study is to explore factors that affect model consistency of myocardial infarction (MI) in mice. Methods: MI was induced by left coronary artery (LCA) ligation. Echocardiography was used to measure cardiac function after MI. The coronary artery was casted with resin and visualized with fluorescent imaging in ex vivo. LCA characteristics and MI size were analyzed individually in each animal. MI size was correlated with LV function by echocardiography. Results: Coronary anatomy varies widely amongst animals, posing challenges for surgical ligation and resulting in inconsistent MI size data post-ligation. The length of coronary arterial trunk, level of bifurcation, number of branches, and territory supplied by these branches were unique in every animal. When the main LCA trunk was ligated, this resulted in a large MI, but when a single branch was ligated, MI size varied significantly due to differing levels of LCA ligation and differing amounts of territory supplied by the branches. During the ligation procedure, nearly 40% of LCAs were not grossly visible to the surgeon. In these situations, the surgeon commonly blindly sutures a wider and deeper area of tissue in an attempt to ensure that the LCA is caught and ligated. Paradoxically, these situations have greater odds of resulting in smaller MIs. Conclusion: The current study offers evidence of anatomical LCA diversity and the problems this poses for creating a consistent heart failure model by LCA ligation in mice. Carefully recognizing the inevitable individual variation of coronary anatomy in mice is essential to restoring reliability of the LCA ligation model of heart failure.

Clinical Significance of Postinfarct Fever in ST-Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study.

BackgroundLittle is known about causality and pathological mechanism underlying association of postinfarct fever with myocardial injury in patients with ST‐segment elevation myocardial infarction.Methods and ResultsIn 276 patients undergoing primary percutaneous coronary intervention for ST‐segment elevation myocardial infarction, cardiac magnetic resonance imaging was performed a median of 3.4 days after the index procedure. Forty‐five patients had postinfarct fever (peak body temperature within 4 days after primary percutaneous coronary intervention ≥37.7°C; Fever group) whereas 231 did not (no‐Fever group). Primary outcome was myocardial infarct size as assessed by cardiac magnetic resonance imaging. Secondary outcomes were extent of area at risk, myocardial salvage index, and microvascular obstruction area. In cardiac magnetic resonance imaging analysis, myocardial infarct size (25.6% [19.7–32.4] in the Fever group versus 17.2% [11.8–25.4] in the no‐Fever group; P<0.01), extent of area at risk (43.7% [31.9–54.9] versus 35.3% [24.0–43.7]; P<0.01), and microvascular obstruction area (4.4% [0.0–13.2] versus 1.2% [0.0–5.1]; P=0.02) were greater in the Fever group than in the no‐Fever group. Myocardial salvage index tended to be lower in the Fever group compared to the no‐Fever group (37.7 [28.5–56.1] versus 47.0 [34.1–56.8]; P=0.13). In multivariate analysis, postinfarct fever was associated with larger myocardial infarct (odds ratio, 3.48; 95% CI, 1.71–7.07; P<0.01) and lower MSI (odds ratio, 2.10; 95% CI, 1.01–4.08; P=0.03).ConclusionsPostinfarct fever could predict advanced myocardial injury and less salvaged myocardium in ST‐segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

Chronic Heart Rate Reduction by Ivabradine Does Not Modify the Elastic Fiber Content in Post‐Myocardial Infarction Scar of Middle‐Aged Rats

A large myocardial infarction (MI) triggers progressive cardiac remodeling which results in left ventricular (LV) chamber dilatation and, as a consequence, in greater wall tension, particularly in the area of scar formation. Chronically elevated mechanical stress applied to fibroblasts and myofibroblasts within the scar has been known to stimulate the production of extracellular matrix proteins, predominantly collagen and elastin, that improves the tensile strength of the thinning LV wall. Considering that during a prolonged diastole the end‐diastolic volume and, hence, the force and duration of mechanical signals transduced into the scar become even more augmented it is feasible to assume that any heart rate‐lowering agent would promote further deposition of extracellular proteins by activated fibrogenic cells. Nevertheless, we have previously shown that chronic heart rate reduction (HRR) by ivabradine (IVA), a selective inhibitor of a pacemaker If current, did not alter the content of fibrillar collagen in post‐MI scar of middle‐aged rats. However, whether IVA‐induced HRR affects the content of elastic fibers in the scar remains undetermined. To test this hypothesis a large transmural MI (greater than 50% of the LV free wall) was induced in 12‐month‐old male Sprague‐Dawley rats by ligation of the left coronary artery. Post‐MI rats were then assigned in IVA‐treated (MI+IVA) and corresponding placebo (MI) groups. In MI+IVA groups, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/d for 8 and 12 weeks. At the end of each treatment period, the hearts were collected and processed into paraffin‐embedded sections for histological evaluations. Eight‐micron‐thick sections of the left ventricle were stained with picrosirius red and Verhoeff's elastic tissue stains. The entire scar of each heart stained for collagen and elastic fibers were digitally captured on a computer using an Olympus BX53 microscope and the fractional volumes of collagen and elastic fibers were determined by using Image‐Pro Analyzer v.7.0 software. We found that the mean scar size and thickness were comparable among all groups of rats. Furthermore, the spatial distribution of the elastic fibers within the scars demonstrated almost identical pattern with an evident accumulation along the subendocardial and subepicardial regions, in the remnants of coronary vessels, and in isolated areas near the edge or throughout the middle portion of the scar. In addition, IVA‐treated and untreated rats showed a similar tendency in reduction of elastic component of the scars that was directly correlated with scar maturation. The quantitative analysis has revealed that the content of elastic fibers remained relatively analogous in scars of MI and MI+IVA rats 8 weeks (1.88±0.36% vs. 1.21±0.31%, respectively) and 12 weeks (0.99±0.45% vs. 0.89±0.18%, respectively) after MI. Moreover, there was no significant difference in ratio between elastic and collagenous components of the scar in corresponding IVA‐treated and untreated groups of rats. Our data are the first to demonstrate that chronic IVA‐induced HRR does not modify the elastic fiber content in post‐MI scar.

Improved Survival of Patients with ST-Segment Elevation Myocardial Infarction 3–6 Hours After Symptom Onset Is Associated with Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention (PCI) at a Large Regional ST-Segment Elevation Myocardial Infarction (STEMI) Program vs. In-Hospital Thrombolysis in a Community Hospital

BackgroundThis study sought to compare the 30-day and 1-year survival of patients diagnosed with ST-segment elevation myocardial infarction (STEMI), whose symptom onset to in-hospital first medical contact (IHFMC) was 3–6 h, who received either in-hospital thrombolysis (IHT) in the nearest county hospital or direct transfer to a larger hospital in Henan province, China for primary percutaneous coronary intervention (PPCI).Material/MethodsPatients were allocated into 2 groups: one group received IHT in the local county hospital, whereas the other group were transferred to the PCI centers to receive PPCI. Patient demographic data, baseline characteristics, and time between different stages of patient contact to the initiation of treatment for IHT or PPCI were recorded for analysis.ResultsNo significant difference was identified between the 2 groups with the baseline characteristics and demographic data. The all-cause mortality was not significantly different between the IHT and PPCI group at 30 days (13.0% vs. 9.9%, p=0.386). However, a significant difference in mortality between the IHT and PPCI group was observed at 1 year (23.4% vs. 14.1%, p=0.035). Inter-hospital transfer time for PPCI tended to be the independent predictor for survival (OR: 4.4 CI 95%: 1.9–14.5, p 0.001). Overall, the patients undergoing PPCI in inter-hospital transfer had a higher survival rates for 1 year compared with patients receiving IHT.ConclusionsDespite the delay associated with inter-hospital transfer for PPCI, patients with STEMI 3–6 h after symptom onset have improved survival with PPCI over patients treated locally with IHT.

Clearance of cardiac troponin T with and without kidney function

ObjectiveThe extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known. Methods and resultsWe examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8–19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort. ConclusionsAt high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.

Increased Density of SERCA Pumps at the Periphery of Cardiac Purkinje Cells after Myocardial Infarction

BACKGROUND. The trigger of ventricular tachyarrhythmias after myocardial infarction (MI) has been attributed to increased incidence of electrogenic Ca2+ waves in cardiac Purkinje cells (Pcells). A change in Ca2+ release channel (CRC) gating properties and overload of intracellular Ca2+ store are 2 potential causes of this increase. We analysed through a model of intracellular Ca2+ dynamics the spontaneous Ca2+ transients of Pcells after MI. Regional protein expression was assessed for potential remodelling associated with ischemia.METHODS. Pcells were dispersed enzymatically from dog, pig, sheep, and human Purkinje fibers dissected from normal hearts and from hearts with MI. Spontaneous local Ca2+ transients were studied by high resolution confocal fluorescence microscopy techniques. Specific antibodies were used to map proteins involved in Ca2+ release/uptake functions (ERCs, SERCAs).RESULTS. In Pcells of MI heart, the density and firing rate of Ca2+-release sites were increased by 20% [Normal: 3.0 ± 0.3 sites /25µm (14 scans; 12 cells) vs MI: 3.6 ± 0.2 sites /25µm (9 cells); P<0.05] and 120% [Normal:0.77 ± 0.10 sparks/s (42 sites, 12 cells) vs MI: 1.74 ± 0.23 sparks /s (40 sites, 9 cells); P<0.05), respectively. A model fit of Ca2+-waves in MI Pcells revealed 50% increase in amplitude, 25% faster decay, and 35% elevation of Ca2+-uptake rate. No change was observed in CRC expression. However SERCAs redistribution to the cell periphery was detected in all animal MI models and in human heart with large MI. Peripheral protein expression and gene expression of SERCA2 showed 4.5 and 2.3 times increases post MI, respectively. Interestingly, no change was observed in regulatory protein phospholamban.CONCLUSION. An unknown factor associated with myocardial ischemia mediates a dramatic increase in SERCA expression at the Pcell periphery, i.e. wherein the CRCs IP3R and RyR3 are specifically located. We propose a mechanistic model of intracellular Ca2+ cycling demonstrating that augmentation of peripheral SERCA activity is sufficient to promote pro-arrhythmic spontaneous Ca2+ release in Pcells of post-MI human heart.

New or presumed new left bundle branch block in patients with suspected ST-elevation myocardial infarction.

Using a comprehensive large prospective regional ST-elevation myocardial infarction (STEMI) system database, we evaluated the prevalence, clinical and angiographic characteristics, and outcomes in patients with ischemic symptoms and new or presumed new left bundle branch block (LBBB). We then tested a new hierarchical diagnosis and triage algorithm to identify more accurately new LBBB patients with an acute culprit lesion. From March 2003 to June 2013, 3903 consecutive STEMI patients were treated using the Minneapolis Heart Institute regional STEMI protocol including 131 patients (3.3%) with new LBBB. These patients had fewer culprit arteries (54.2% vs. 86.4%; P<0.001), were older, more commonly women, with a lower ejection fraction, and more frequently presented with cardiac arrest or heart failure than those without new LBBB. At 1 year follow-up, all-cause mortality accounting for baseline differences was higher in patients with new LBBB (hazard ratio 1.73, 95% confidence interval 1.17-2.58; P=0.007). The new algorithm yielded high sensitivity (97%) and negative predictive value (94%) for identification of a culprit lesion. Using the definition of new LBBB with either hemodynamically unstable features or Sgarbossa concordance criteria on electrocardiogram (ECG), 45% of new LBBB patients would have been treated as 'STEMI equivalent'. Patients with acute ischemic symptoms and new LBBB represent a high-risk population with unique clinical challenges. If validated in an independent dataset, the new algorithm may improve the diagnostic accuracy regarding reperfusion therapy for new LBBB patients.

The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting with ST-Elevation Myocardial Infarction.

BackgroundIdentification of the infarct-related artery (IRA) in patients with STEMI using coronary angiography (CA) is often based on the ECG and can be challenging in patients with severe multi-vessel disease. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on cardiac magnetic resonance imaging (CMR).MethodsWe evaluated 113 patients from the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, who underwent CMR within 4±2 days of revascularization. Blinded reviewers interpreted CA to determine the IRA and CMR to determine the location of infarction on a 17-segment model. In patients with multiple infarcts on CMR, acuity was determined with T2-weighted imaging and/or evidence of microvascular obstruction.ResultsA total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and CA. In 4/5 cases, there were multiple infarcts noted on CMR. Thirteen patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts.ConclusionsIn this select population of patients, the identification of the IRA by CA was incorrect in 4% of patients presenting with STEMI. Four patients with a mismatch had an acute infarction in more than one coronary artery territory on CMR. The role of CMR in patients presenting with STEMI with multi-vessel disease on CA deserves further investigation.

Abstract 12654: PBI-4050 Therapy Selectively Improves Pulmonary Hypertension, Lung Remodeling and Right Ventricular Function in Heart Failure With Reduced Ejection Fraction

Introduction: There is currently no approved treatment for the most prevalent form of PH that is associated with left heart disease (Group II PH). Heart failure with reduced ejection fraction (HFrEF) causes lung remodeling characterized by myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome contributing to PH and RV dysfunction. Hypothesis: We evaluated PBI-4050, a novel first-in-class agent with anti-fibrotic and anti-proliferative actions, for the treatment of PH in a model of HFrEF. Methods: HFrEF was induced by myocardial infarction (MI) after coronary artery ligation in rats. Two weeks after surgery, sham-operated and MI groups were treated with PBI-4050 (200 mg/kg/day by gavage) or with saline for 3 weeks. Animals were analyzed according to pathological infarct size into large MI (≥35% LV) and small to medium MI (&lt; 35%). Hemodynamic evaluation was performed with microtip cathethers and lung function testing evaluated with a Flexivent respirator. Cardiac ultrasound was performed at 2 weeks and at 5 weeks. Scar size and lung fibrosis were quantified by histology. Results: Pathological infarct size correlated with echocardiographic wall motion score index (r 2 =0.73, p&lt;0.001). Large MI (≥35% LV) resulted in PH and RVH with a restrictive lung syndrome. For a similar infarct size, PBI-4050 did not affect LV function but markedly reduced PH and RVH. The compensatory increase in RV contractility was normalized by PBI-4050. PBI-4050 reduced lung remodeling evidenced by a reduction in lung weight and improved respiratory compliance. Finally, lung fibrosis was reduced by PBI-4050 with histological evidence of reduced alveolar wall cellular proliferation. Conclusions: PBI-4050 effectively reduces PH and RVH in HFrEF by reducing lung fibrosis and remodeling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function without affecting LV function. PBI-4050 is a promising therapy for group II PH.

Antithrombotic therapy before, during and after emergency angioplasty for ST elevation myocardial infarction.

The first three hours after symptom onset hold the maximum potential for myocardial reperfusion and salvage in ST-elevation myocardial infarction (STEMI) patients. During this period timely primary percutaneous coronary intervention (PPCI) or, when PPCI is not promptly feasible, pre-hospital administration of fibrinolyis or a glycoprotein IIb/IIIa-inhibitor (GPI) have been shown to restore coronary patency and reperfusion and even result in myocardial infarction (MI) abortion. On the other hand, oral antiplatelet therapy may not yet guarantee sufficient platelet inhibition. Patients presenting after this golden time have less, if any, benefit from an aggressive antithrombotic treatment prior to PPCI. Antithrombotic treatment during primary angioplasty should be tailored on the basis of the coronary thrombotic burden, vascular approach and the patient's risk of bleeding complications. A GPI-based approach may be favourable in patients presenting early with large MI and high thrombus burden, whereas a bivalirudin-based approach without GPI may be preferred in patients with higher bleeding risk. There are no data to support the use of GPI in bailout conditions. The powerful oral P2Y12 inhibitors, prasugrel and ticagrelor, have been clearly shown to prevent stent thrombosis and recurrent ischaemic events after emergency percutaneous coronary intervention in STEMI patients. Open issues remaining are the treatment of patients with high bleeding risk, such as the elderly and those requiring anticoagulation, as well as the duration of dual antiplatelet therapy after STEMI.

Shock Index as a Predictor of Myocardial Injury in ST-segment Elevation Myocardial Infarction

BackgroundLittle is known about the association between shock index and myocardial injury in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). MethodsWe analyzed cardiac magnetic resonance imaging from 306 consecutive patients treated with primary PCI for STEMI. The patients were divided into the following 2 groups: initial shock index >0.7 (n = 88) and ≤0.7 (n = 218). Shock index was calculated as the ratio of heart rate to systolic blood pressure based on the first recorded vital signs upon arrival. The primary end point was myocardial infarct size. ResultsThe shock index >0.7 group, exhibited a lower baseline left ventricular ejection fraction (P = 0.01), higher N-terminal prohormone of brain natriuretic peptide level (P = 0.01), higher Killip class (P < 0.01) and higher prevalence of diabetes (P = 0.02) than the shock index ≤0.7 group. There were no significant differences in the angiographic or procedural characteristics between the 2 groups. In cardiac magnetic resonance imaging analysis, the shock index >0.7 group had a larger infarct size than did the shock index ≤0.7 group (22.9 ± 11.2% versus 19.2 ± 11.5%, P < 0.01). According to multivariate analysis, shock index >0.7 was associated with large myocardial infarctions (odds ratio = 3.02; 95% CI: 1.62-5.65; P < 0.01). ConclusionsInitial shock index is a potentially reliable predictor of myocardial injury in patients with STEMI undergoing primary PCI.

Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress.

Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. We generated inducible cardiac-specific PDH E1α knockout (CreER(T2)-PDH(flox/flox)) mice that demonstrated a high mortality rate. It was hypothesized that PDH modulating cardiac glucose metabolism is crucial for heart functions under normal physiological and/or stress conditions. The myocardial infarction was conducted by a ligation of the left anterior descending coronary arteries. Cardiac PDH E1α deficiency caused large myocardial infarcts size and macrophage infiltration in the hearts (P < .01 vs wild-type [WT]). Wheat germ agglutinin and Masson trichrome staining revealed significantly increased hypertrophy and fibrosis in PDH E1α-deficient hearts (P < .05 vs WT). Measurements of heart substrate metabolism in an ex vivo working heart perfusion system demonstrated a significant impairment of glucose oxidation in PDH E1α-deficient hearts during ischemia/reperfusion (P < .05 vs WT). Dichloroacetate, a PDH activator, increased glucose oxidation in WT hearts during ischemia/reperfusion and reduced myocardial infarct size in WT, but not in PDH E1α-deficient hearts. Immunoblotting results demonstrated that cardiac PDH E1α deficiency leads to an impaired ischemic AMP-activated protein kinase activation through Sestrin2-liver kinase B1 interaction which is responsible for an increased susceptibility of PDH E1α-deficient heart to ischemic insults. Thus, cardiac PDH E1α deficiency impairs ischemic AMP-activated protein kinase signaling and sensitizes hearts to the toxicological actions of ischemic stress.

Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction

BackgroundBioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models. ObjectivesThis study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months. MethodsIn an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months. ResultsIn total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m2 vs. saline 11.7 ± 26.9 ml/m2; p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37). ConclusionsIntracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563)

Effect of Smoking on Infarct Size and Major Adverse Cardiac Events in Patients With Large Anterior ST-Elevation Myocardial Infarction (from the INFUSE-AMI Trial)

We sought to investigate the effect of smoking on infarct size (IS) and major adverse cardiac events (MACE) in patients with large anterior ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Participants from the Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction study were categorized according to smoking status (current or previous smoking vs no history of smoking). The primary imaging outcome was cardiac magnetic resonance imaging-assessed IS of left ventricular mass (%) at 30days. The primary clinical outcome was the rate of MACE at 30days and 1year, defined as the composite of death, reinfarction, new-onset heart failure, or rehospitalization. Of 447 patients enrolled in Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction, 271 (60.6%) were current or past smokers. Compared with nonsmokers, smokers were almost 10years younger and had a lower prevalence of clinical co-morbidities. Smokers had better procedural success and angiographic reperfusion compared with nonsmokers. At 30days, there were no differences between smokers and nonsmokers in median IS (16.8% vs 17.4%, p= 0.67) or metrics of left ventricular function. By multivariable linear regression analysis, smoking was not significantly associated with IS at 30days (beta coefficient: 0.83, p= 0.42). At 1year, smokers had lower crude rates of MACE (7.6% vs 15%, p= 0.01). After multivariable adjustment, there were no significant differences in 1-year MACE between smokers and nonsmokers (adjusted hazard ratio 0.73, 95% CI 0.40 to 1.33, p= 0.30). In conclusion, smoking history had no significant effect on IS at 30days. Although current or previous smokers had lower rates of 1-year MACE than those with no history of smoking, adjustment for baseline characteristics rendered this association nonsignificant. These findings support the hypothesis that the smoker's paradox is largely attributable to differences in demographic and clinical baseline risk, rather than differences in IS after primary percutaneous coronary intervention.

Abstract 82: Reduction of SHP2’s Phosphatase Activity Improves Cardiac Adaptation to Pressure and Volume Overload

Since the inability of the heart to adapt to pathological stress results in heart failure, supporting cardiac stress adaptation may improve clinical outcome. We hypothesized that the protein tyrosine phosphatase SHP2 controls adaptation by modulating several signaling pathways involved. To test whether SHP2 plays an active role in stress adaptation, we generated transgenic (TG) mice with cardiomyocyte-specific overexpression of Q510E-SHP2, which is a dominant-negative mutant (dnSHP2). Under unstressed conditions, TG mice do not exhibit a cardiac phenotype. TG and nonTG (NTG) mice were subjected to pressure overload by transverse aortic constriction (TAC) or to volume overload by inducing large myocardial infarction (MI) via coronary artery ligation. Expression of dnSHP2 significantly improved stress adaptation after TAC (n=17 TG, n=13 NTG). Twelve weeks after banding, TG mice exhibited well preserved contractile function with significantly higher fractional shortening (FS) [TG 33.2±1.7 vs. NTG 22.2±1.5 %, p&lt;0.001] and ejection fraction (EF) [TG 67.7±2.7 vs. NTG 50.3±3.0 %, p&lt;0.001]. dnSHP2 TGs also had smaller left ventricular (LV) chamber dimensions [LV inner diameter at end-diastole (LVIDd) TG 4.4±0.2 vs. NTG 5.1±0.2 mm, p=0.02]. There were no significant differences in ventricular wall thickness or heart weights, indicating that the degree of hypertrophy in response to TAC was not affected by dnSHP2 expression. In response to volume overload induced by large MI (n=22 TG, n=24 NTG), TG hearts displayed only a trend towards improved contractile function [FS TG 21.3±1.5 vs. NTG 18.9±1.1%, EF TG 48.4±2.7 vs. NTG 44.2±2.1%]. However, chamber dimensions were better preserved in TGs [LVIDd TG 5.1±0.1 vs. NTG 5.7±0.2 mm, p=0.03]. In summary, dnSHP2 expression ameliorated LV chamber dilation and increased contractile function under pressure overload. In TGs subjected to volume overload, reduced LV dimensions were observed but with only a trend towards improved contractile function. Taken together, it is evident that reducing SHP2’s phosphatase activity indeed improves cardiac stress adapation, making SHP2 a potential novel therapeutic target.

Abstract 55: The Natural Course of Myocardial Infarction in Large Animal Models; a Systematic Review and Meta-analysis

Background: Large animal models of myocardial infarction (MI) are essential for the development of novel therapeutic strategies. However, it is unclear which experimental factors are independent determinants of disease progression outcomes and the fidelity with which these models resemble MI in humans. The aim of this study was to investigate systematically what independently influences the outcome after MI in large animal models and determine which methodological factors influence primary endpoints and disease progression. Methods: We used control animal data from two meta-analyses of large animal models of MI. We performed univariable and multivariable meta-regression to analyze if potential relevant variables were influencing outcomes; infarct size as a ratio of the area at risk (IS/AAR), as a ratio of the left ventricle (IS/LV) and ejection fraction (EF). Pre-defined independent variables were species, sex, weight, ischemia model (open vs closed), occlusion type (temporary vs permanent), occluded vessel, follow-up duration, use of co-medication, use of immunosuppression and study quality. Outcomes and variables were complemented per dataset if needed. Results: Our analyses yielded 246 relevant studies, reporting 1500, 1221 and 775 control animals for IS/AAR, IS/LV and EF respectively. Multivariable meta-regression showed IS/AAR was influenced by species (p&lt;0.001), sex (p=0.03), co-medication (p=0.01), occlusion type (p&lt;0.001), occluded vessel (p=0.002) and follow-up (p=0.001). For IS/LV occlusion type (p=0.03), occluded vessel (p=0.03) and study quality (p=0.03) showed significant effects. EF measurements revealed that species (p=0.04), sex (p=0.04) and occluded vessel (p=0.05) were independent predictors. Using these variables, we can partially predict these outcomes for certain study setups. Conclusion: Many methodological variations exist in the design of large animal MI studies. This should be taken into account when selecting a model to study therapy efficacy. We provide evidence that disease manifestation and progression greatly depend on certain biological characteristics, e.g. location of MI and sex of the patient. It is therefore possible that therapies have a different effect in specific patient populations.

The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction.

Myocardial infarction (MI) triggers an intense inflammatory response that is associated with infarct expansion and is detrimental for cardiac function. Interleukin (IL)-1β and IL-18 are key players in this response and are controlled by the NLRP3-inflammasome. In the current study, we therefore hypothesized that selective inhibition of the NLRP3-inflammasome reduces infarct size and preserves cardiac function in a porcine MI model. Thirty female landrace pigs were subjected to 75 min transluminal balloon occlusion and treated with the NLRP3-inflammasome inhibitor MCC950 (6 or 3 mg/kg) or placebo for 7 days in a randomized, blinded fashion. After 7 days, 3D-echocardiography was performed to assess cardiac function and Evans blue/TTC double staining was executed to assess the area at risk (AAR) and infarct size (IS). The IS/AAR was lower in the 6 mg/kg group (64.6 ± 8.8%, P = 0.004) and 3 mg/kg group (69.7 ± 7.2%, P = 0.038) compared with the control group (77.5 ± 6.3%). MCC950 treatment markedly preserved left ventricular ejection fraction in treated animals (6 mg/kg 47 ± 8%, P = 0.001; 3 mg/kg 45 ± 7%, P = 0.031; control 37 ± 6%). Myocardial neutrophil influx was attenuated in treated compared with non-treated animals (6 mg/kg 132 ± 72 neutrophils/mm2, P = 0.035; 3 mg/kg 207 ± 210 neutrophils/mm2, P = 0.5; control 266 ± 158 neutrophils/mm2). Myocardial IL-1β levels were dose-dependently reduced in treated animals. NLRP3-inflammasome inhibition reduces infarct size and preserves cardiac function in a randomized, blinded translational large animal MI model. Hence, NLRP3-inflammasome inhibition may have therapeutic potential in acute MI patients.

Effects of late exercise on cardiac remodeling and myocardial calcium handling proteins in rats with moderate and large size myocardial infarction

BackgroundPhysical exercise attenuates myocardial infarction (MI)-induced cardiac remodeling. However, it is unsettled whether late exercise modulates post-infarction cardiac remodeling differentially according to infarct size. We investigated the effects of exercise started at late stage heart failure on cardiac remodeling in rats with moderate and large sized MI. MethodsThree months after MI, rats were assigned into sedentary and exercise groups. Exercise rats underwent treadmill for three months. After assessing infarct size by histological analysis, rats were subdivided into four groups: moderate MI sedentary (Mod MI-Sed; n=7), Mod MI exercised (Mod MI-Ex; n=7), Large MI-Sed (n=11), and Large MI-Ex (n=10). ResultsBefore exercise, MI-induced cardiac changes were demonstrated by comparing results to a Sham group; alterations were more intense in rats with large than moderate MI size. Systolic function, evaluated by echocardiogram using the variation in LV fractional area change between after and before exercise, was improved in exercise than sedentary groups. Calsequestrin expression increased in exercised compared to sedentary groups. L-type calcium channel was higher in Mod MI-Ex than Mod MI-Sed. SERCA2a, phospholamban, and Na+/Ca2+ exchanger expression did not differ between groups. ConclusionLate exercise improves systolic function and modulates intracellular calcium signaling proteins in rats with moderate and large MI.