Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats.

Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.

Effects of exenatide on cardiac function, perfusion, and energetics in type 2 diabetic patients with cardiomyopathy: a randomized controlled trial against insulin glargine.

BACKGROUND: Multiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored. METHODS AND RESULTS: Twenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine. CONCLUSIONS: T2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT00766857.

Kinetics of coagulation in ST-elevation myocardial infarction following successful primary percutaneous coronary intervention.

INTRODUCTION: ST-elevated myocardial infarction (STEMI) is most frequently caused by coronary occlusion due to formation of an intracoronary thrombus in reaction to rupture of atherosclerotic plaques. Little is known about kinetics of coagulation markers after STEMI in patients treated according to current guidelines. We aimed to investigate kinetics of important coagulation markers in percutaneous coronary intervention (PCI)-treated STEMI patients. MATERIALS AND METHODS: 60 consecutive PCI-treated STEMI patients were prospectively included. Blood samples were collected immediately after as well as 1, 4 and 7 days following PCI. Samples collected 90 days after PCI served as baseline values. ADAMTS13 activity, VWF (von Willebrand factor) activity, VWF antigen, VWF propeptide, fibrinogen antigen, D-dimer, alpha2-antiplasmin (α2AP), plasmin-alpha2-antiplasmin complex (PAP), prothrombin fragment F1+2 (F1+2), prothrombin time (PT), activated partial thromboplastin time (aPTT), and anti-factor Xa (anti-Xa) were measured. Cardiac magnetic resonance (CMR) was performed at 4-6 and 90 days after PCI in 49 patients and left ventricular ejection fraction (LVEF), infarct size and microvascular injury (MVI) were determined. RESULTS: Immediately after PCI, ADAMTS13 activity, fibrinogen antigen and α2AP levels were significantly decreased and VWF activity, VWF antigen and VWF propeptide levels were significantly elevated, compared to baseline. Individual coagulation markers and different combinations thereof were not related to LVEF or infarct size at 90 days, or the occurrence of MVI at 4-6 days after PCI. CONCLUSION: Coagulation parameters show a very dynamic profile in the early days after STEMI. However, individual coagulation parameters or combinations thereof do not predict CMR-defined LVEF, infarct size or MVI.

Long term outcome after mononuclear bone marrow or peripheral blood cells infusion after myocardial infarction.

OBJECTIVES: This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65). METHODS: In addition to 3-5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure. RESULTS: Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9 mL/m(2)) compared with (11.2±19.8 mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2±20.9 mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8±15.0 mL/m(2)) as compared with controls (3.0±16.3 mL/m(2), p=0.07), with again no difference between PBMC (3.3±18.8 mL/m(2)) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67). CONCLUSIONS: Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group. TRIAL REGISTRATION NUMBER: The Netherlands Trial Register #NTR166 (http://www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

Cell therapy in reperfused acute myocardial infarction does not improve the recovery of perfusion in the infarcted myocardium: a cardiac MR imaging study.

PURPOSE: To investigate the effects of cell therapy on myocardial perfusion recovery after treatment of acute myocardial infarction (MI) with primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: In this HEBE trial substudy, which was approved by the institutional review board (trial registry number ISRCTN95796863), the authors assessed the effects of intracoronary infusion with bone marrow-derived mononuclear cells (BMMCs) or peripheral blood-derived mononuclear cells (PBMCs) on myocardial perfusion recovery by using cardiac magnetic resonance (MR) imaging after revascularization. In 152 patients with acute MI treated with PCI, cardiac MR imaging was performed after obtaining informed consent-before randomization to BMMC, PBMC, or standard therapy (control group)-and repeated at 4-month follow-up. Cardiac MR imaging consisted of cine, rest first-pass perfusion, and late gadolinium enhancement imaging. Perfusion was evaluated semiquantitatively with signal intensity-time curves by calculating the relative upslope (percentage signal intensity change). The relative upslope was calculated for the MI core, adjacent border zone, and remote myocardium. Perfusion differences among treatment groups or between baseline and follow-up were assessed with the Wilcoxon signed rank or Mann-Whitney U test. RESULTS: At baseline, myocardial perfusion differed between the MI core (median, 6.0%; interquartile range [IQR], 4.1%-8.0%), border zone (median, 8.4%; IQR, 6.4%-10.2%), and remote myocardium (median, 12.2%; IQR, 10.5%-15.9%) (P < .001 for all), with equal distribution among treatment groups. These interregional differences persisted at follow-up (P < .001 for all). No difference in perfusion recovery was found between the three treatment groups for any region. CONCLUSION: After revascularization of ST-elevation MI, cell therapy does not augment the recovery of resting perfusion in either the MI core or border zone.