High dose statin treatment reduces circulating Dickkopf-1 following acute myocardial infarction.

BACKGROUND: Secreted glycoproteins of the Dickkopf (DKK) family modify Wnt signaling and may influence plaque destabilization but their modulation by statins in MI patients is not known. METHODS: We measured plasma DKK-1 and DKK-3 in patients with acute ST-segment elevation MI (STEMI) before percutaneous coronary intervention (PCI) and after 2 and 7 days and 2 months in patients receiving short-term high-dose (40 mg rosuvastatin, given before PCI; n = 25) and moderate dose (20 mg simvastatin, given the day after PCI; n = 34). In vitro modulation of DKK-1 in human umbilical vein endothelial cells (HUVECs) by statins were assessed. RESULTS: (i) Patients receiving high dose rosuvastatin had a marked decline in DKK-1 at day 2 which was maintained throughout the study period. However, a more prevalent use of ß-blockers in the simvastatin group, that could have contributed to higher DKK-1 levels in these patients. (ii) There was a strong correlation between baseline DKK-1 levels and change in DKK-1 from baseline to day 2 in patients receiving high dose rosuvastatin treatment. (iii) DKK-3 increased at day 2 but returned to baseline levels at 2 months in both treatment groups. (iv) Statin treatment dose-dependently decreased DKK-1 mRNA and protein levels in HUVEC. CONCLUSIONS: Our findings suggest that high dose statin treatment with 40 mg rosuvastatin could persistently down-regulate DKK-1 levels, even at 2 months after the initial event in STEMI patients.

En mann i 50-årene med brystsmerter og synkope.

BACKGROUND: A man in his fifties with hypertension and no other previous health problems was admitted to the hospital after frequent episodes of retrosternal squeezing chest pain, and an episode of syncope. A recent computer tomography coronary angiography demonstrated normal coronary arteries with no atherosclerosis. CASE PRESENTATION: During admission, the patient developed several episodes of chest pain lasting five to fifteen minutes followed by non-sustained ventricular tachycardia, and initially no ST elevation in the electrocardiogram (ECG). He had normal findings on ECG and magnetic resonance imaging of the heart. During hospitalisation, ST elevations in the ECG were observed in relation to chest pain. Due to ST elevation, invasive coronary angiography was performed, revealing a suspected culprit lesion in the left anterior descending artery, treated with percutaneous coronary intervention (PCI). Despite PCI, he had persistent episodes of chest pain with ST elevation and non-sustained ventricular tachycardia. Vasospastic angina was suspected. INTERPRETATION: The clinical presentation is classical for vasospastic angina. After treatment with calcium channel blocker together with long-acting nitrate, there were no new episodes of chest pain or non-sustained ventricular tachycardia. Because of non-sustained ventricular tachycardia with haemodynamic instability and syncope, an implantable cardioverter-defibrillator was implanted.

Aerobic high-intensity interval exercise training in patients with angina and no obstructive coronary artery disease: feasibility and physiological effects.

Aims: Patients with chest pain and normal coronary angiogram [angina with normal coronary arteries (ANOCA)] constitute a therapeutic problem with considerable functional limitation and reduced quality of life. The aims of the current pilot study were to (i) explore if a structured aerobic high-intensity interval training (HIT) program for 12 weeks was feasible in patients with ANOCA, and (ii) to assess mechanisms related to symptoms in this population. Methods and results: Sixteen patients with ANOCA underwent a 3-month aerobic HIT program with one-to-one monitored exercise sessions on treadmill in a 4 min × 4 manner, three times a week. Four patients served as controls. Coronary flow velocity reserve (CFVR) transthoracic Doppler, flow-mediated vasodilation (FMD) and VO2max was measured at baseline and after 12 weeks. The average attendance to training sessions was 82.3% ± 10.1 (56-94). CFVR in the training group increased from 2.50 ± 0.48 to 3.04 ± 0.71 (P < 0.001) whereas FMD increased from 4.19 ± 2.42% to 8.28 ± 2.85% (P < 0.001). Improvement in CFVR correlated with the relative improvement in FMD (R = 0.45, P = 0.047). This was associated with an increase in VO2max from 28.75 ± 6.51 mL/kg/min to 31.93 ± 6.46 mL/kg/min (P < 0.001). Conclusion: A 3-month program of monitored HIT was feasible, with high adherence resulting in improved functional capacity in patients with ANOCA. CFVR improved and this improvement was associated with improved FMD. ClinicalTrialsgov Identifier: NCT02905630.

Pentraxin 3 in primary percutaneous coronary intervention for ST elevation myocardial infarction is associated with early irreversible myocardial damage : Kinetic profile, relationship to interleukin 6 and infarct size.

BACKGROUND: The inflammatory marker long pentraxin 3 (PTX3) has been shown to be a strong predictor of 30-day and one-year mortality after acute myocardial infarction. The aim of this study was to evaluate the kinetic profile of PTX3 and its relationship with interleukin 6 (IL-6), high-sensitive C-reactive protein (hs-CRP) and infarct size. METHODS: PTX3, IL-6 and hs-CRP were measured at predefined time points, at baseline (before percutaneous coronary intervention (PCI)), at 12 and 72 hours after PCI in 161 patients with first-time ST elevation myocardial infarction (STEMI). RESULTS: PTX3 and IL-6 levels increased in the early phase, followed by a gradual decrease between 12 and 72 hours. There were statistically significant correlations between PTX3 and IL-6 in general, for all time points and for changes over time (0-72 hours). In a linear mixed model, PTX3 predicted IL-6 (p < 0.001). PTX3 is also correlated with hs-CRP in general, and at each time point post PCI, except at baseline. PTX3, IL-6 and hs-CRP were all significantly correlated with infarct size in general, and at the peak time point for maximum troponin I. In addition, there was a modest correlation between IL-6 levels at baseline and infarct size at 72 hours after PCI (ρ = 0.23, p = 0.006). CONCLUSIONS: PTX3 had a similar kinetic profile to IL-6, with an early increase and decline, and was statistically significantly correlated with markers of infarct size in STEMI patients post primary PCI. Baseline levels of IL-6 only predicted infarct size at 72 hours post PCI.

Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins.

OBJECTIVES: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. METHODS: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1ß, IL-6, IL-10, TNF, and high-sensitive C-reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. RESULTS: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. CONCLUSION: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI.

Clinical use of optical coherence tomography to identify angiographic silent stent thrombosis.

OBJECTIVES: Patients previously treated with coronary stents may suffer an acute coronary syndrome (ACS) without any evidence of thrombus formation on coronary angiography (CAG). This may be due to partial, nonocclusive stent thrombosis with microembolization. In this paper, we illustrate possible mechanisms both with optical coherence tomography (OCT) and histology. DESIGN: We present two cases with ACS from very late stent thrombosis who have been previously treated with first-generation drug-eluting stents (DES). RESULTS: The first patient had ACS 15 months after DES implantation. The angiogram (CAG) was near normal with slight peri-stent contrast staining. OCT revealed abnormalities including thrombus not visible on CAG. These are findings that may explain the ACS. The second patient had subclinical episodes with chest pain after DES implantation. The patient died from stent thrombosis in a DES. Postmortem histological examination of the coronary arteries revealed stent struts with little or no neointimal coverage, persistent peri-strut fibrin deposition, inflammatory cells, malapposition, and small luminal platelet-rich thrombi. Old spotty myocardial infarctions were found in the supplied territory possibly caused by earlier episodes of embolizing thrombus. CONCLUSIONS: In patients with previous implanted DES presenting with ACS, OCT may detect abnormalities and thrombus formation not visible on CAG. Such findings may impact the treatment strategy in these patients.

Endothelial dysfunction predicts clinical restenosis after percutaneous coronary intervention.

BACKGROUND: Endothelial dysfunction is associated with increased risk for cardiovascular events in patients with coronary artery disease and may predict in-stent restenosis after percutaneous coronary intervention. We evaluated if endothelial dysfunction could predict clinical and angiographic restenosis in patients after percutaneous coronary intervention with stent implantation for angina pectoris or acute coronary syndrome. METHODS: One hundred patients were consecutively included after successful percutaneous coronary intervention with stenting for angiographic single vessel disease. All patients were evaluated with ultrasound detection of brachial artery reactivity at four weeks and with a symptom limited exercise stress test at six months and were followed for the occurrence of clinical or angiographic restenosis for 18 ± 6 months. RESULTS: Twenty patients showed clinical signs of restenosis during 18 months follow-up and were referred to re-angiography. Patients with clinical restenosis had impaired flow mediated vasodilation compared to patients without clinical restenosis (5.8 ± 3.4 vs. 9.0 ± 4.8, p = 0.005). In multivariate analysis flow mediated vasodilation was the only independent predictor for the risk of clinical restenosis (OR 4.5, 95% CI 1.11 to 17.8). CONCLUSIONS: Impaired flow mediated vasodilation four weeks after percutaneous coronary intervention independently predicts the risk of clinical restenosis.

Response of growth differentiation factor-15 to percutaneous coronary intervention and regular exercise training.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is considered to be a cardioprotective cytokine possessing antiapoptotic and antiproliferative properties. If GDF-15 plasma levels are influenced by percutanenous coronary intervention (PCI) or regular exercise training is currently not known. METHODS: After successful revascularization by PCI with stent implantation 36 consecutive patients with stable angina pectoris were randomized to an exercise training program or to a control group. Patients were followed by serial measurements of GDF-15, high-sensitivity Troponin T (hsTNT) and N-terminal pro brain natriuretic peptide (NT-proBNP) levels in peripheral blood after PCI and during six months follow-up. RESULTS: Plasma levels of GDF-15 showed an early response to PCI with a modest, but significant increase after 30 minutes (p = 0.007) peaking three hours after PCI. Levels of hsTNT rose 5-fold from baseline to 24 hours (p < 0.001) with a normalization at seven days post PCI. Changes in plasma levels of GDF-15, hsTNT and NT-proBNP were not significantly different between the training and control group during follow-up. CONCLUSIONS: GDF-15 levels show a modest transient increase in response to coronary intervention with stent implantation. Exercise training over six months does not affect plasma levels of GDF-15, hsTNT or NT-proBNP in patients with stable coronary artery disease.

High-intensity interval exercise training improves heart rate variability in patients following percutaneous coronary intervention for angina pectoris.

BACKGROUND: Low time domain measures of heart rate variability (HRV) have been shown to predict outcome after myocardial infarction (MI). The predictive value of HRV, when measured in patients with coronary artery disease (CAD) without MI is less clear. Further, little is known about the mechanisms of how autonomic imbalance affects outcome. METHODS AND DESIGN: Forty patients following percutaneous coronary intervention (PCI) with stent implantation for angina pectoris were prospectively randomized to a six month supervised high-intensity interval training program (n=20) or to a control group (n=20). All patients underwent a 24-hour Holter monitoring to assess measures of HRV at baseline and at six months. RESULTS: At baseline there were no significant differences between groups. In the training group all time domain indices and the frequency domain indices, total power and ultralow frequency of HRV, increased significantly during the training period. Mean heart rate decreased significantly. In the control group only the root mean square of differences between successive NN intervals (ln RMSSD) increased significantly. Changes in standard deviations of the average NN intervals (SDANN) and ln RMSSD were significantly correlated to changes in peak VO(2) (R=0.47 and 0.39; p<0.01 and p=0.03 respectively). HRV measures were not significantly correlated to endothelial function. CONCLUSIONS: High-intensity exercise training over 6 months significantly improved time and frequency domain measures of HRV in patients following PCI with stent implantation. The effect on HRV was correlated to changes in peak VO(2), but not to changes in endothelial function.

High-intensity interval training may reduce in-stent restenosis following percutaneous coronary intervention with stent implantation A randomized controlled trial evaluating the relationship to endothelial function and inflammation.

BACKGROUND: High-intensity interval training has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with coronary artery disease. The objective of this study was to evaluate this training model on in-stent restenosis following percutaneous coronary intervention for stable or unstable angina. METHODS AND RESULTS: We prospectively randomized 40 patients after percutaneous coronary intervention with implantation of a bare metal stent (n = 30) or drug eluting stent (n = 32) to a 6-month supervised high-intensity interval exercise training program (n = 20) or to a control group (n = 20). At six months, restenosis, measured as in-segment late luminal loss of the stented coronary area, was smaller in the training group 0.10 (0.52) mm compared to the control group 0.39 (0.38) mm (P = .01). Reduction of late luminal loss in the training group was consistent with both stent types. Peak oxygen uptake increased in the training and control group by 16.8% and 7.8%, respectively (P < .01). Flow-mediated dilation improved 5.2% (7.6) in the training group and decreased -0.1% (8.1) in the control group (P = .01). Levels of high-sensitivity C-reactive protein decreased by -0.4 (1.1) mg/L in the training group and increased by 0.1 (1.2) mg/L in the control group (P = .03 for trend). CONCLUSIONS: Regular high-intensity interval exercise training was associated with a significant reduction in late luminal loss in the stented coronary segment. This effect was associated with increased aerobic capacity, improved endothelium function, and attenuated inflammation.

[Modern treatment of acute myocardial infarction without ST elevation]. / Moderne behandling av akutt hjerteinfarkt uten ST-elevasjon.

The term unstable coronary syndromes represents a continuum of patients with unstable chest pain with or without small or large acute myocardial infarctions. There is a tendency towards an epidemiological shift to fewer large infarctions with ST elevation in the ECG (STEMI) to increased numbers of small infarctions without ST elevation (nSTEMI). Patients with unstable angina or nSTEMI should start antithrombotic medication with aspirin, heparin and clopidogrel upon arrival in hospital. Patients with medium or high risk of death or cardiac events will benefit from therapy with IIb/IIIa glycoprotein receptor inhibitors and should be referred for coronary angiography within 6-48 hours after arrival. Final therapy with percutaneous coronary intervention or coronary artery bypass surgery is indicated immediately after angiography or within a few days. Close follow-up with respect to epidemiological risk factors, diet, use of medication according to the results of large randomised studies will further reduce mortality and morbidity, in the short as well as the long term.