Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial

Objective

Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI.

Methods

371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01217307","term_id":"NCT01217307"}}NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging.

Results

Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001).

Conclusion

LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.     

Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

Aims

Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI.

Methods and Results

Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15.

Conclusion

Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.     

Xenotransplantation of Human Cardiomyocyte Progenitor Cells Does Not Improve Cardiac Function in a Porcine Model of Chronic Ischemic Heart Failure. Results from a Randomized,Blinded, Placebo Controlled Trial

Background

Recently cardiomyocyte progenitor cells (CMPCs) were successfully isolated from fetal and adult human hearts. Direct intramyocardial injection of human CMPCs (hCMPCs) in experimental mouse models of acute myocardial infarction significantly improved cardiac function compared to controls.

Aim

Here, our aim was to investigate whether xenotransplantation via intracoronary infusion of fetal hCMPCs in a pig model of chronic myocardial infarction is safe and efficacious, in view of translation purposes.

Methods & Results

We performed a randomized, blinded, placebo controlled trial. Four weeks after ischemia/reperfusion injury by 90 minutes of percutaneous left anterior descending artery occlusion, pigs (n = 16, 68.5 ± 5.4 kg) received intracoronary infusion of 10 million fetal hCMPCs or placebo. All animals were immunosuppressed by cyclosporin (CsA). Four weeks after infusion, endpoint analysis by MRI displayed no difference in left ventricular ejection fraction, left ventricular end diastolic and left ventricular end systolic volumes between both groups. Serial pressure volume (PV-)loop and echocardiography showed no differences in functional parameters between groups at any timepoint. Infarct size at follow-up, measured by late gadolinium enhancement MRI showed no difference between groups. Intracoronary pressure and flow measurements showed no signs of coronary obstruction 30 minutes after cell infusion. No premature death occurred in cell treated animals.

Conclusion

Xenotransplantation via intracoronary infusion of hCMPCs is feasible and safe, but not associated with improved left ventricular performance and infarct size compared to placebo in a porcine model of chronic myocardial infarction.     

Impact of Heart Rate on Myocardial Salvage in Timely Reperfused Patients with ST-Segment Elevation Myocardial Infarction: New Insights from Cardiovascular Magnetic Resonance

Background

Previous studies evaluating the progression of the necrotic wave in relation to heart rate were carried out only in animal models of ST-elevated myocardial infarction (STEMI). Aim of the study was to investigate changes of myocardial salvage in relation to different heart rates at hospital admission in timely reperfused patients with STEMI by using cardiovascular magnetic resonance (CMR).

Methods

One hundred-eighty-seven patients with STEMI successfully and timely treated with primary coronary angioplasty underwent CMR five days after hospital admission. According to the heart rate at presentation, patients were subcategorized into 5 quintiles: <55 bpm (group I, n = 44), 55–64 bpm (group II, n = 35), 65–74 bpm (group III, n = 35), 75–84 bpm (group IV, n = 37), ≥85 bpm (group V, n = 36). Area at risk, infarct size, microvascular obstruction (MVO) and myocardium salvaged index (MSI) were assessed by CMR using standard sequences.

Results

Lower heart rates at presentation were associated with a bigger amount of myocardial salvage after reperfusion. MSI progressively decreased as the heart rates increased (0.54 group I, 0.46 group II, 0.38 group III, 0.34 group IV, 0.32 group V, p<0.001). Stepwise multivariable analysis showed heart rate, peak troponin and the presence of MVO were independent predictor of myocardial salvage. No changes related to heart rate were observed in relation to area at risk and infarct size.

Conclusions

High heart rates registered before performing coronary angioplasty in timely reperfused patients with STEMI are associated with a reduction in salvaged myocardium. In particular, salvaged myocardium significantly reduced when heart rate at presentation is ≥85 bpm.     

Experimental Myocardial Infarction Induces Altered Regulatory T Cell Hemostasis,and Adoptive Transfer Attenuates Subsequent Remodeling

Background

Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling.

Methods and Results

The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling.

Conclusion

Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling.     

Longitudinal Strain Is a Marker of Microvascular Obstruction and Infarct Size in Patients with Acute ST-Segment Elevation Myocardial Infarction

Objectives

We assessed the value of speckle tracking imaging performed early after a first ST-segment elevation myocardial infarction (STEMI) in order to predict infarct size and functional recovery at 3-month follow-up.

Methods

44 patients with STEMI who underwent revascularization within 12 h of symptom onset were prospectively enrolled. Echocardiography was performed 3.9±1.2 days after myocardial reperfusion, assessing circumferential (CGS), radial (RGS), and longitudinal global (GLS) strains. Late gadolinium-enhanced cardiac magnetic imaging (CMR), for assessing cardiac function, infarct size, and microvascular obstruction (MVO), was conducted 5.6±2.5 days and 99.4±4.6 days after myocardial reperfusion.

Results

GLS was evaluable in 97% of the patients, while CGS and RGS could be assessed in 85%. Infarct size significantly correlated with GLS (R = 0.601, p<0.001), RGS (R = −0.405, p = 0.010), CGS (R = 0.526, p = 0.001), ejection fraction (R = −0.699, p<0.001), wall motion score index (WMSI) (R = 0.539, p = 0.001), and left atrial volume (R = 0.510, p<0.001). Baseline ejection fraction and GLS were independent predictors of 3-month infarct size. MVO mass significantly correlated with GLS (R = 0.376, p = 0.010), WMSI (R = 0.387, p = 0.011), and ejection fraction (R = −0.389, p = 0.011). In multivariate analysis, GLS was the only independent predictor of MVO mass (p = 0.015). Longitudinal strain >−6.0% within the infarcted area exhibited 96% specificity and 61% sensitivity for predicting the persistence of akinesia (≥3 segments) at 3-month follow-up.

Conclusions

Speckle-tracking strain imaging performed early after a STEMI is easy-to-use as a marker for persistent akinetic territories at 3 months. In addition, GLS correlated significantly with MVO and final infarct size, both parameters being relevant post-MI prognostic factors, usually obtained via CMR.     

Donepezil, anti-Alzheimer's disease drug, prevents cardiac rupture during acute phase of myocardial infarction in mice

Background

We have previously demonstrated that the chronic intervention in the cholinergic system by donepezil, an acetylcholinesterase inhibitor, plays a beneficial role in suppressing long-term cardiac remodeling after myocardial infarction (MI). In comparison with such a chronic effect, however, the acute effect of donepezil during an acute phase of MI remains unclear. Noticing recent findings of a cholinergic mechanism for anti-inflammatory actions, we tested the hypothesis that donepezil attenuates an acute inflammatory tissue injury following MI.

Methods and Results

In isolated and activated macrophages, donepezil significantly reduced intra- and extracellular matrix metalloproteinase-9 (MMP-9). In mice with MI, despite the comparable values of heart rate and blood pressure, the donepezil-treated group showed a significantly lower incidence of cardiac rupture than the untreated group during the acute phase of MI. Immunohistochemistry revealed that MMP-9 was localized at the infarct area where a large number of inflammatory cells including macrophages infiltrated, and the expression and the enzymatic activity of MMP-9 at the left ventricular infarct area was significantly reduced in the donepezil-treated group.

Conclusion

The present study suggests that donepezil inhibits the MMP-9-related acute inflammatory tissue injury in the infarcted myocardium, thereby reduces the risk of left ventricular free wall rupture during the acute phase of MI.     

Toll-Like Receptor 9-Activation during Onset of Myocardial Ischemia Does Not Influence Infarct Extension

Aim

Myocardial infarction (MI) remains a major cause of death and disability worldwide, despite available reperfusion therapies. Inflammatory signaling is considered nodal in defining final infarct size. Activation of the innate immune receptor toll-like receptors (TLR) 9 prior to ischemia and reperfusion (I/R) reduces infarct size, but the consequence of TLR9 activation timed to the onset of ischemia is not known.

Methods and Results

The TLR9-agonist; CpG B was injected i.p. in C57BL/6 mice immediately after induction of ischemia (30 minutes). Final infarct size, as well as area-at-risk, was measured after 24 hours of reperfusion. CpG B injection resulted in a significant increase in circulating granulocytes and monocytes both in sham and I/R mice. Paradoxically, clear evidence of reduced cardiac infiltration of both monocytes and granulocytes could be demonstrated in I/R mice treated with CpG B (immunocytochemistry, myeloperoxidase activity and mRNA expression patterns). In addition, systemic TLR9 activation elicited significant alterations of cardiac inflammatory genes. Despite these biochemical and cellular changes, there was no difference in infarct size between vehicle and CpG B treated I/R mice.

Conclusion

Systemic TLR9-stimulation upon onset of ischemia and subsequent reperfusion does not alter final infarct size despite causing clear alterations of both systemic and cardiac inflammatory parameters. Our results question the clinical usefulness of TLR9 activation during cardiac I/R.     

Comparison of NOGA Endocardial Mapping and Cardiac Magnetic Resonance Imaging for Determining Infarct Size and Infarct Transmurality for Intramyocardial Injection Therapy Using Experimental Data

Objectives

We compared the accuracy of NOGA endocardial mapping for delineating transmural and non-transmural infarction to the results of cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement (LE) for guiding intramyocardial reparative substance delivery using data from experimental myocardial infarction studies.

Methods

Sixty domestic pigs underwent diagnostic NOGA endocardial mapping and cMRI-LE 60 days after induction of closed-chest reperfused myocardial infarction. The infarct size was determined by LE of cMRI and by delineation of the infarct core on the unipolar voltage polar map. The sizes of the transmural and non-transmural infarctions were calculated from the cMRI transmurality map using signal intensity (SI) cut-offs of>75% and>25% and from NOGA bipolar maps using bipolar voltage cut-off values of <0.8 mV and <1.9 mV. Linear regression analysis and Bland-Altman plots were used to determine correlations and systematic differences between the two images. The overlapping ratios of the transmural and non-transmural infarcted areas were calculated.

Results

Infarct size as determined by 2D NOGA unipolar voltage polar mapping correlated with the 3D cMRI-LE findings (r = 0.504, p<0.001) with a mean difference of 2.82% in the left ventricular (LV) surface between the two images. Polar maps of transmural cMRI and bipolar maps of NOGA showed significant association for determining of the extent of transmural infarction (r = 0.727, p<0.001, overlap ratio of 81.6±11.1%) and non-transmural infarction (r = 0.555, p<0.001, overlap ratio of 70.6±18.5%). NOGA overestimated the transmural scar size (6.81% of the LV surface) but slightly underestimated the size of the non-transmural infarction (−3.04% of the LV surface).

Conclusions

By combining unipolar and bipolar voltage maps, NOGA endocardial mapping is useful for accurate delineation of the targeted zone for intramyocardial therapy and is comparable to cMRI-LE. This may be useful in patients with contraindications for cMRI who require targeted intramyocardial regenerative therapy.     

No Myocardial Vulnerability to Mental Stress in Takotsubo Stress Cardiomyopathy

Objectives

Due to the frequent use of coronary angiography the awareness of Takotsubo stress cardiomyopathy (TSC) has increased although the exact pathophysiology of TSC is still largely unknown. Our objective was to investigate the effects of mental stress on myocardial function, heart rate variability (HRV) and salivary cortisol (SC) in TSC patients.

Design

This study is a case-control study and a sub-study of the Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study.

Setting

Mental stress test was performed more than 6 months after the acute event in TSC patients and age- and sex-matched controls. Standard echocardiography and tissue Doppler imaging (TDI) - derived time-phases of cardiac cycle were recorded to calculate myocardial performance index (MPI) to assess ventricular function before and during mental stress. Holter-ECG recording was made to estimate HRV before, during and after mental stress. SC was measured at baseline, before and 20 minutes after mental stress.

Subjects

Twenty-two TSC patients and 22 sex-and age-matched controls were recruited from the SMINC-study and investigated with a mental stress test. All TSC patients had a previous normal cardiovascular magnetic resonance investigation.

Results

There were no significant differences at rest or during mental stress for left and right ventricular MPI or other standard diastolic variables between TSC patients and controls. HRV did not differ between TSC patients and controls. There was a trend towards less increase in SC after mental stress in TSC patients compared to controls.

Conclusion

Mental stress did not induce a significant difference in myocardial function or HRV response between TSC and controls. Moreover, no significant difference could be seen in SC response at baseline, during or after mental stress. This study indicates that myocardial vulnerability to mental stress does not persist in TSC patients.     

Improvement of cardiac function in mouse myocardial infarction after transplantation of epigenetically-modified bone marrow progenitor cells

Objective

To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice.

Methods and Results

We tested the therapeutic efficacy of bone marrow progenitor cells treated with the clinically-used chromatin modifying agents Trichostatin A (TSA, histone deacetylase inhibitor) and 5Aza-2-deoxycytidine (Aza, DNA methylation inhibitor) in a mouse model of acute myocardial infarction (AMI). Treatment of BPCs with Aza and TSA induced expression of pluripotent genes Oct4, Nanog, Sox2, and thereafter culturing these cells in defined cardiac myocyte-conditioned medium resulted in their differentiation into cardiomyocyte progenitors and subsequently into cardiac myocytes. Their transition was deduced by expression of repertoire of markers: Nkx2.5, GATA4, cardiotroponin T, cardiotroponin I, α-sarcomeric actinin, Mef2c and MHC-α. We observed that the modified BPCs had greater AceH3K9 expression and reduced histone deacetylase1 (HDAC1) and lysine-specific demethylase1 (LSD1) expression compared to untreated BPCs, characteristic of epigenetic changes. Intra-myocardial injection of modified BPCs after AMI in mice significantly improved left ventricular function. These changes were ascribed to differentiation of the injected cells into cardiomyocytes and endothelial cells.

Conclusion

Treatment of BPCs with Aza and TSA converts BPCs into multipotent cells, which can then be differentiated into myocyte progenitors. Transplantation of these modified progenitor cells into infarcted mouse hearts improved left ventricular function secondary to differentiation of cells in the niche into myocytes and endothelial cells.     

Phosphomimetic Modulation of eNOS Improves Myocardial Reperfusion and Mimics Cardiac Postconditioning in Mice

Objective

Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection.

Methods and Results

We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation.

Conclusions and Significance

Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.     

Altered Gene Expression Pattern in Peripheral Blood Mononuclear Cells in Patients with Acute Myocardial Infarction

Background

Despite a substantial progress in diagnosis and therapy, acute myocardial infarction (MI) is a major cause of mortality in the general population. A novel insight into the pathophysiology of myocardial infarction obtained by studying gene expression should help to discover novel biomarkers of MI and to suggest novel strategies of therapy. The aim of our study was to establish gene expression patterns in leukocytes from acute myocardial infarction patients.

Methods and Results

Twenty-eight patients with ST-segment elevation myocardial infarction (STEMI) were included. The blood was collected on the 1^st day of myocardial infarction, after 4–6 days, and after 6 months. Control group comprised 14 patients with stable coronary artery disease, without history of myocardial infarction. Gene expression analysis was performed with Affymetrix Human Gene 1.0 ST microarrays and GCS3000 TG system. Lists of genes showing altered expression levels (fold change >1.5, p<0.05) were submitted to Ingenuity Pathway Analysis. Gene lists from each group were examined for canonical pathways and molecular and cellular functions. Comparing acute phase of MI with the same patients after 6 months (stable phase) and with control group we found 24 genes with changed expression. In canonical analysis three pathways were highlighted: signaling of PPAR (peroxisome proliferator-activated receptor), IL-10 and IL-6 (interleukin 10 and 6).

Conclusions

In the acute phase of STEMI, dozens of genes from several pathways linked with lipid/glucose metabolism, platelet function and atherosclerotic plaque stability show altered expression. Up-regulation of SOCS3 and FAM20 genes in the first days of myocardial infarction is observed in the vast majority of patients.     

Combinatorial G-CSF/AMD3100 Treatment in Cardiac Repair after Myocardial Infarction

Aims

Several studies suggest that circulating bone marrow derived stem cells promote the regeneration of ischemic tissues. For hematopoietic stem cell transplantation combinatorial granulocyte-colony stimulating factor (G-CSF)/Plerixafor (AMD3100) administration was shown to enhance mobilization of bone marrow derived stem cells compared to G-CSF monotherapy. Here we tested the hypothesis whether combinatorial G-CSF/AMD3100 therapy has beneficial effects in cardiac recovery in a mouse model of myocardial infarction.

Methods

We analyzed the effect of single G-CSF (250 µg/kg/day) and combinatorial G-CSF/AMD3100 (100 µg/kg/day) treatment on cardiac morphology, vascularization, and hemodynamics 28 days after permanent ligation of the left anterior descending artery (LAD). G-CSF treatment started directly after induction of myocardial infarction (MI) for 3 consecutive days followed by a single AMD3100 application on day three after MI in the G-CSF/AMD3100 group. Cell mobilization was assessed by flow cytometry of blood samples drawn from tail vein on day 0, 7, and 14.

Results

Peripheral blood analysis 7 days after MI showed enhanced mobilization of white blood cells (WBC) and endothelial progenitor cells (EPC) upon G-CSF and combinatorial G-CSF/AMD3100 treatment. However, single or combinatorial treatment showed no improvement in survival, left ventricular function, and infarction size compared to the saline treated control group 28 days after MI. Furthermore, no differences in histology and vascularization of infarcted hearts could be observed.

Conclusion

Although the implemented treatment regimen caused no adverse effects, our data show that combinatorial G-CSF/AMD therapy does not promote myocardial regeneration after permanent LAD occlusion.     

Right ventricular dysfunction following acute myocardial infarction in the absence of pulmonary hypertension in the mouse

Background

Cardiac remodelling after AMI is characterized by molecular and cellular mechanisms involving both the ischemic and non-ischemic myocardium. The extent of right ventricular (RV) dilatation and dysfunction and its relation to pulmonary hypertension (PH) following AMI are unknown. The aim of the current study was to evaluate changes in dimensions and function of the RV following acute myocardial infarction (AMI) involving the left ventricle (LV).

Methods

We assessed changes in RV dimensions and function 1 week following experimental AMI involving the LV free wall in 10 mice and assessed for LV and RV dimensions and function and for the presence and degree of PH.

Results

RV fractional area change and tricuspidal annular plane systolic excursion significantly declined by 33% (P = 0.021) and 28% (P = 0.001) respectively. Right ventricular systolic pressure measured invasively in the mouse was within the normal values and unchanged following AMI.

Conclusion

AMI involving the LV and sparing the RV induces a significant acute decline in RV systolic function in the absence of pulmonary hypertension in the mouse indicating that RV dysfunction developed independent of changes in RV afterload.     

A Novel Method in the Stratification of Post-Myocardial-Infarction Patients Based on Pathophysiology

Objectives

We proposed that the severity of ST-segment elevation myocardial infarction (STEMI) could be classified based on pathophysiological changes.

Methods

First-STEMI patients were classified within hospitalization. Grade 0: no detectable myocardial necrosis; Grade 1: myocardial necrosis without functional and morphological abnormalities; Grade 2: myocardial necrosis with reduced LVEF; Grade 3: reduced LVEF on the basis of cardiac remodeling; Grade 4: mitral regurgitation additional to the Grade-3 criteria.

Results

Of 180 patients, 1.7, 43.9, 26.1, 23.9 and 4.4% patients were classified as Grade 0 to 4, respectively. The classification is an independent predicator of 90-day MACEs (any death, resuscitated cardiac arrest, acute heart failure and stroke): the rate was 0, 5.1, 8.5, 48.8 and 75% from Grade 0 to 4 (p<0.001), respectively. The Grade-2 patients were more likely to have recovered left ventricular ejection fraction than the Grade-3/4 patients did after 90 days (48.9% vs. 19.1%, p<0.001). Avoiding complicated quantification, the classification served as a good reflection of infarction size as measured by cardiac magnetic resonance imaging (0±0, 15.68±8.48, 23.68±9.32, 36.12±11.35 and 40.66±14.33% of the left ventricular mass by Grade 0 to 4, P<0.001), and with a comparable prognostic value (AUC 0.819 vs. 0.813 for infarction size, p = 0.876 by C-statistics) for MACEs.

Conclusions

The new classification represents an easy and objective method to scale the cardiac detriments for STEMI patients.     

Acute Myocardial Infarction in Sub-Saharan Africa: The Need for Data

Background

Trends in the prevalence of acute myocardial infarction in sub-Saharan Africa have not been well described, despite growing recognition of the increasing burden of cardiovascular disease in low- and middle-income countries. The aim of this systematic review was to describe the prevalence of acute myocardial infarction in sub-Saharan Africa.

Methods

We searched PubMed, EMBASE, Global Health Archive, CINAHL, and Web of Science, and conducted reference and citation analyses. Inclusion criteria were: observational studies, studies that reported incidence or prevalence of acute myocardial infarction, studies conducted in sub-Saharan Africa, and studies that defined acute myocardial infarction by EKG changes or elevation of cardiac biomarkers. Studies conducted prior to 1992 were excluded. Two independent reviewers analyzed titles and abstracts, full-texts, and references and citations. These reviewers also performed quality assessment and data extraction. Quality assessment was conducted with a validated scale for observational studies.

Findings

Of 2292 records retrieved, seven studies met all inclusion criteria. These studies included a total of 92,378 participants from highly heterogeneous study populations in five different countries. Methodological quality assessment demonstrated scores ranging from 3 to 7 points (on an 8-point scale). Prevalence of acute myocardial infarction ranged from 0.1 to 10.4% among the included studies.

Interpretation

There is insufficient population-based data describing the prevalence of acute myocardial infarction in sub-Saharan Africa. Well-designed registries and surveillance studies that capture the broad and diverse population with acute myocardial infarction in sub-Saharan Africa using common diagnostic criteria are critical in order to guide prevention and treatment strategies.

Registration

Registered in International Prospective Register of Systematic Reviews (PROSPERO) Database #CRD42012003161.     

Association between Exposure to Environmental Tobacco Smoke and Biomarkers of Oxidative Stress Among Patients Hospitalised with Acute Myocardial Infarction

Objective

To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction.

Design

An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction.

Setting

Nine acute hospitals in Scotland.

Participants

Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine ≥3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine ≤0.1 ng/mL).

Intervention

None.

Main outcome measures

Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders.

Results

After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI −8.94, 13.21, p = 0.703).

Conclusions

Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction.     

Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse

Background

Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI.

Methods

IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery.

Results

When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (−25%), less cardiomyocyte apoptosis (−50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], −20%) and dysfunction (LV ejection fraction [LVEF] decrease, −50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values <0.05).

Conclusions

An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm.     

Altered Resting-State fMRI Signals in Acute Stroke Patients with Ischemic Penumbra

Background

Identifying the ischemic penumbra in acute stroke subjects is important for the clinical decision making process. The aim of this study was to use resting-state functional magnetic resonance singal (fMRI) to investigate the change in the amplitude of low-frequency fluctuations (ALFF) of these subjects in three different subsections of acute stroke regions: the infarct core tissue, the penumbra tissue, and the normal brain tissue. Another aim of this study was to test the feasilbility of consistently detecting the penumbra region of the brain through ALFF analysis.

Methods

Sixteen subjects with first-ever acute ischemic stroke were scanned within 27 hours of the onset of stroke using magnetic resonance imaging. The core of infarct regions and penumbra regions were determined by diffusion and perfusion-weighted imaging respectively. The ALFF were measured from resting-state blood oxygen level dependent (BOLD) fMRI scans. The averaged relative ALFF value of each regions were correlated with the time after the onset of stroke.

Results

Relative ALFF values were significantly different in the infarct core tissue, penumbra tissue and normal brain tissue. The locations of lesions in the ALFF maps did not match perfectly with diffusion and perfusion-weighted imagings; however, these maps provide a contrast that can be used to differentiate between penumbra brain tissue and normal brain tissue. Significant correlations between time after stroke onset and the relative ALFF values were present in the penumbra tissue but not in the infarct core and normal brain tissue.

Conclusion

Preliminary results from this study suggest that the ALFF reflects the underlying neurovascular activity and has a great potential to estimate the brain tissue viability after ischemia. Results also show that the ALFF may contribute to acute stroke imaging for thrombolytic or neuroprotective therapies.