Effects of interval training on inflammatory biomarkers in patients with ischemic heart failure.

Objectives. Exercise training has been proposed to have anti-inflammatory effects. We examined whether aerobic interval training (AIT) can attenuate the inflammatory response in ischemic heart failure (HF) as measured by serum biomarkers representing a broad spectrum of activated inflammatory pathways. Design. We conducted a controlled prospective trial recruiting 30 patients (19 in the AIT group and 11 in the control group) with ischemic HF and an implantable cardioverter defibrillator (ICD). This study is a sub study of the previously reported "Aerobic interval training in patients with heart failure and an ICD" (Eur J Prev Cardiol. 22 March 2015; 22:296-303). Patients in the AIT group exercised for 12-weeks completing a total of 36 AIT sessions. We analyzed serum levels of C-reactive protein, pentraxin-3, osteoprotegerin, brain natriuretic peptide, neopterin, and soluble tumor necrois factor type 1 and 2, all known to predict an adverse outcome in HF, at baseline and following the 12-week AIT intervention. Results. The AIT group significantly increased peak oxygen uptake and improved endothelial function compared to the sedentary control group. No statistically significant changes in serum levels of the biomarkers were detected from baseline following the AIT intervention and, there were no significant differences in changes of these mediators between the AIT and the control group. Conclusions. A 12-week AIT intervention, although improving exercise capacity and endothelial function, did not attenuate serum inflammatory biomarkers in stable ischemic HF patients with an ICD on optimal medical therapy.

Impact of an exercise training program on cardiac neuronal function in heart failure patients on optimal medical therapy : A randomized Iodine-123 metaiodobenzylguanidine scintigraphy study.

BACKGROUND: The syndrome of heart failure (HF) is characterized by left ventricular dysfunction and a compensatory chronic over activation of the sympathetic nervous system. We wanted to investigate if the beneficial effects of exercise training (ET) in HF patients on optimal medical therapy (OMT) are associated with alterations in cardiac sympathetic activity. METHODS: Cardiac sympathetic activity was evaluated at baseline and after 12 weeks using metaiodobenzylguanidine scintigraphy in 23 patients with stable HF participating in the SmartEx trial. Patients with HF in New York Heart Association class II or III and left ventricular ejection fraction <35 % were randomized to three different ET groups. RESULTS: We found no statistically significant changes in cardiac sympathetic activity after 12 weeks of ET. Heart to mediastinum (H/M) ratio at 15 minutes (0.00174 ± 0.0841, P = 0.922), H/M ratio at 4 hours (-0.00565 ± 0.1163, P = 0.818) and washout ratio (WR) (-1.2666 ± 16.5412, P = 0.717). A further group-wise analysis of the three ET groups did not show any difference between the groups. CONCLUSION: A 12-week ET program did not alter the abnormal cardiac sympathetic activity in stable HF patients on modern OMT.

EX-MET study: exercise in prevention on of metabolic syndrome - a randomized multicenter trial: rational and design.

BACKGROUND: Metabolic syndrome substantially increases risk of cardiovascular events. It is therefore imperative to develop or optimize ways to prevent or attenuate this condition. Exercise training has been long recognized as a corner-stone therapy for reducing individual cardiovascular risk factors constituting the metabolic syndrome. However, the optimal exercise dose and its feasibility in a real world setting has yet to be established. The primary objective of this randomized trial is to investigate the effects of different volumes of aerobic interval training (AIT) compared to the current exercise guideline of moderate-intensity continuous training (MICT) on the composite number of cardiovascular disease risk factors constituting the metabolic syndrome after a 16 week, 1-year, and 3-year follow-up. METHODS: This is a randomized international multi-center trial including men and women aged ≥30 years diagnosed with the metabolic syndrome according to the International Diabetes Federation criteria. Recruitment began in August 2012 and concluded in December 2016. This trial consists of supervised and unsupervised phases to evaluate the efficacy and feasibility of different exercise doses on the metabolic syndrome in a real world setting. This study aims to include and randomize 465 participants to 3 years of one of the following training groups: i) 3 times/week of 4 × 4 min AIT at 85-95% peak heart rate (HRpeak); ii) 3 times/week of 1 × 4 min AIT at 85-95% HRpeak; or iii) 5-7 times/week of ≥30 min MICT at 60-70% HRpeak. Clinical examinations, physical tests and questionnaires are administered to all participants during all testing time points (baseline, 16 weeks and after 1-, and 3-years). DISCUSSION: This multi-center international trial indeed aims to ease the burden in healthcare/economic cost arising from treating end-stage CVD related conditions such as stroke and myocardial infarction, that could eventually emerge from the metabolic syndrome condition. TRIAL REGISTRATION: Clinical registration number: NCT01676870 , ClinicalTrials.gov (August 31, 2012).

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.

Cardiac resynchronization therapy improves minute ventilation/carbon dioxide production slope and skeletal muscle capillary density without reversal of skeletal muscle pathology or inflammation.

AIMS: We evaluated the effects of cardiac resynchronization therapy (CRT) on skeletal muscle pathology and inflammation in patients with heart failure. METHODS AND RESULTS: Stable patients (n = 21, 14 males, mean age 70 ± 7 years) with symptomatic heart failure (mean left ventricular ejection fraction 24 ± 6%) and an indication for CRT were included. Ergospirometry, skeletal muscle open biopsy, and blood sampling were performed prior to implantation and after 6 months of CRT. After CRT there was a reduction in both left ventricular end-diastolic diameter (LVEDD; 6.8 ± 0.8 vs. 6.3 ± 0.7 cm, P < 0.001) and native QRS duration (D) minus biventricular paced QRSD (172.9 ± 23 vs. 136.3 ± 23 ms, P ≤ 0.001). These changes were associated with an increase in peak slope oxygen uptake (consumption) (VO2) (13.3 ± 2.2 vs. 14.5 ± 2.6 mL/kg/min, P = 0.07) and an improvement in the minute ventilation/carbon dioxide production slope (VE/VCO2) slope (41.6 ± 7.4 vs. 39.1 ± 5.6, P = 0.012). There were no statistically significant changes in levels of pro-inflammatory cytokines, in mediators of mitochondrial biosynthesis or skeletal muscle pathology, except for an increase in skeletal muscle capillary density (4.5 ± 2.4 vs. 7.7 ± 3.3%, P = 0.002). Both the reduction of QRS duration and the increase in peak VO2 correlated significantly with the change in mitochondrial density (r = 0.57, P = 0.008 and r = 0.54, P = 0.027, respectively). CONCLUSION: Cardiac resynchronization therapy, with improved functional status and reduced LVEDD resulted in increased peak VO2, improvement in VE/VCO2 slope and capillary density in skeletal muscle, with no reduction in systemic pro-inflammatory cytokines, increase in intramuscular levels of mediators of mitochondrial biosynthesis or improvement in skeletal muscle ultrastructure per se. ClinicalTrials.gov Identifier: NCT01019915.

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.

High intensity interval training reduces systemic inflammation in post-PCI patients.

BACKGROUND: Increased plasma levels of inflammatory markers and markers of endothelial cell activation have been associated with increased risk for cardiovascular events. Exercise training may lower the risk for coronary heart disease by attenuating inflammation and improving endothelial function. The objective of this study was to evaluate effects of regular high-intensity exercise training on a wide range of markers of inflammation and endothelial cell activation. MATERIALS AND METHODS: Consecutively, 40 patients were prospectively randomized to a 6 months supervised high-intensity interval training programme or to a control group following successful percutaneous coronary intervention (PCI). Blood samples of 36 patients with stable angina, drawn at baseline (before PCI) and at 6 months, were analysed. Late luminal loss was measured at 6 months using quantitative coronary angiography. RESULTS: At 6 months, levels of the inflammatory markers interleukin (IL)-6 and IL-8 were reduced and levels of the anti-inflammatory cytokine IL-10 increased in the training group only. The decrease in IL-6 and C-reactive protein levels were significantly correlated with the decrease in luminal loss following PCI. In contrast to these anti-inflammatory effects, training had no effect on markers of platelet-mediated inflammation, and the effect of training on markers on endothelial cell activation were rather complex showing attenuating (von Willebrand factor) and enhancing (E-selectin and vascular cell adhesion molecule 1) effects. CONCLUSIONS: Regular exercise training in stable angina patients following PCI may attenuate some, but not all, inflammatory pathways, potentially contributing to the beneficial effects of exercise training on restenosis.

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.

Blood Lactate AUC Is a Sensitive Test for Evaluating the Effect of Exercise Training on Functional Work Capacity in Patients with Chronic Heart Failure.

PURPOSE: Exercise training is an essential treatment option for patients with chronic heart failure (CHF). However, it remains controversial, which surrogate measures of functional work capacity are most reliable. The purpose of this paper was to compare functional capacity work measured as capillary lactate concentrations area under the curve (AUC) with standard cardiopulmonary exercise testing (CPET) with VO2peak and the 6-minute walk test (6 MWT). METHODS: Twenty-three patients in New York Heart Association (NYHA) class II/III with left ventricular ejection fraction (LVEF) <35% were randomised to home-based recommendation of regular exercise (RRE) (controls), moderate continuous training (MCT) or aerobic interval training (AIT). The MCT and AIT groups underwent 12 weeks of supervised exercise training. Exercise testing was performed as standard CPET treadmill test with analysis of VO2peak, the 6 MWT and a novel 30-minute submaximal treadmill test with capillary lactate AUC. RESULTS: All patients had statistically significant improvements in VO2peak, 6 MWT and lactate AUC after 12 weeks of exercise training: 6 MWT (p =0.035), VO2peak (p =0.049) and lactate AUC (p =0.002). Lactate AUC (p =0.046) and 6MWT (p =0.035), but not VO2peak revealed difference between the exercise modalities regarding functional work capacity. CONCLUSION: 6-MWT and lactate AUC, but not VO2peak, were able to reveal a statistically significant improvement in functional capacity between different exercise modalities.

[Inflammation and C-reactive protein in cardiovascular disease]. / Inflammasjon og C-reaktivt protein ved hjerte- og karsykdom.

BACKGROUND: This article reviews the role of inflammation in development of atherosclerosis and associated complications and discusses use of the inflammatory marker - high-sensitivity C-reactive protein (hs-CRP) - in risk stratification. MATERIAL AND METHODS: The article is based on selected publications retrieved from a non-systematic search of PubMed and the authors' experience within the field. RESULTS: Both chronic inflammatory disease and acute infections are associated with an increased risk of cardiovascular events. Influenza vaccination reduces the risk of coronary ischaemic events in patients with coronary artery disease, but the effect on cardiovascular mortality is not documented. Hs-CRP is an independent predictor of cardiovascular events in populations with and without established cardiovascular disease. Treatment with Rosuvastatin led to decreased hs-CRP-levels and a reduced risk for cardiovascular events in subjects without known cardiovascular disease, with normal serum cholesterol and hs-CRP-levels above 2 mg/l. INTERPRETATION: Individuals with chronic inflammatory disease and those with high risk and acute infection are at risk for cardiovascular events and should be evaluated for primary prevention. In patient groups at moderate risk for cardiovascular disease, hs-CRP can be a valuable supplement to established factors for risk stratification. Despite numerous studies confirming hs-CRP's role as an independent risk marker, hs-CRP has not found its place in international guidelines. This should be reconsidered on the background of new study results.

[Contrast-enhanced cardiac magnetic resonance in patients with acute myocarditis]. / Kontrastbasert MR-undersøkelse av hjerte ved akutt myokarditt.

BACKGROUND: Acute myocarditis is a serious condition that is challenging to diagnose. Recent developments in contrast-enhanced cardiac magnetic resonance imaging (ce-MRI) enable visualization of myocardial damage in patients with myocarditis. The objective of this study was to identify patients in whom ce-MRI could be useful to reach such a diagnosis. METHODS: We reviewed data from 37 patients referred to ce-MRI with suspected acute myocarditis at Stavanger University Hospital from July 2004 to May 2007. RESULT: 20 patients had epicardial contrast enhancement compatible with myocarditis. The contrast enhancement was focal and most frequently localized to the inferolateral wall (n = 12). No patient with Troponin T < 0.1 microg/L (n = 7) showed epicardial contrast enhancement. It was not possible to distinguish patients with acute myocarditis from the other patients on the basis of clinical signs, symptoms, C-reactive protein levels, ECG- or echocardiography. INTERPRETATION: Ce-cardiac MRI is important in the diagnosis of acute myocarditis. If troponin T levels are < 0.1 microg/L during the acute phase, it is unlikely that a contrast enhancement pattern will be compatible with myocarditis.

[Training after percutaneous coronary intervention- an undervalued treatment option?]. / Trening etter perkutan koronar intervensjon--en undervurdert behandlingsmulighet?

BACKGROUND: Even though regular exercise training after myocardial infarction reduces morbidity and mortality, training after percutaneous coronary intervention (PCI) is still not part of the standard treatment. This article reviews the documentation on exercise training with coronary artery disease and examines the effect on pathophysiological mechanisms that play an important role in the progression of coronary artery disease and restenosis after PCI with stent implantation. MATERIAL AND METHODS: The article is based on a search in PubMed and the Cochcrane database. RESULTS AND INTERPRETATION: The effect of regular exercise training on morbitity and mortality in coronary artery disease without myocardial infarction is not well documented. But the data indicate that training has an antiinflammatory effect in the vessel wall. Regular exercise training in these patients increases the bioavailibility of nitric oxide and is a non-pharmacological option to improve the endothelial function. Prospective, randomised, controlled trials are needed to evaluate whether there is a beneficial clinical effect of training after PCI treatment.

Acute occlusion of the left subclavian artery causing a non-ST-elevation myocardial infarction with subacute lung edema due to a coronary subclavian steal syndrome--a case report.

Subclavian artery occlusion causing an anterior non-ST-elevation myocardial infarction in a patient with a left internal mammary artery bypass to the left anterior descending artery. Presentation of a case not previously described in the literature to our knowledge.

Effects of aerobic interval training on measures of anxiety, depression and quality of life in patients with ischaemic heart failure and an implantable cardioverter defibrillator: A prospective non-randomized trial.

OBJECTIVE: To evaluate the short- and long-term effects of aerobic interval training on quality of life and on symptoms of anxiety and depression among patients with ischaemic heart failure and an implantable cardioverter defibrillator. DESIGN: Prospective, non-randomized controlled study. SUBJECTS: Patients with ischaemic heart failure and an implantable cardioverter defibrillator, willing to undergo an aerobic interval training programme. A total of 31 patients were enrolled (19 were assigned to the aerobic interval training group and 12 to the control group). METHODS: The aerobic interval training group performed a 12-week exercise training programme. All patients were evaluated with the Short Form-36 (SF-36), the Hospital Anxiety and Depression Scale (HADS) and the International Physical Activity Questionnaire at baseline, after 12 weeks and at 2 years. RESULTS: The aerobic interval training group showed significant improvements in several SF-36 subscores at 12 weeks. There was an unadjusted significant reduction in the HADS depression (HADS-D) score. At follow-up, results in the aero-bic interval training group moved towards baseline or remained stable, whereas in the control group HADS-D scores and some SF-36 subscores deteriorated. CONCLUSION: Participation in a 12-week aerobic interval training programme resulted in significant improvements in several measures of quality of life and the unadjusted HADS-D score in patients with ischaemic heart failure with an implantable cardioverter defibrillator. At follow-up there was significantly less sedentary activity in the aerobic interval training group, while psychometric measures were no longer significantly different from baseline.

Exercise training and cardiac rehabilitation in patients with implantable cardioverter defibrillators: a review of current literature focusing on safety, effects of exercise training, and the psychological impact of programme participation.

BACKGROUND: Indications for implantable cardioverter defibrillators (ICDs) have been widened considerably during the last decade due to the well-documented effect in the heart failure population. Exercise training (ET) has a 1A recommendation in heart failure. However, data on safety and efficacy of ET in patients with ICDs is sparse. ICD shocks are associated with reduced quality of life and increased mortality. Whether ET may have a beneficial effect in heart failure patients with an ICD is not well documented. METHODS: This review is based on a systematic search in the Pub Med database using the terms 'exercise training', 'implantable cardioverter defibrillator', and 'cardiac rehabilitation'. RESULTS: Nine studies were identified, comprising 1889 patients. The average duration of exercise-based cardiac rehabilitation (CR) was 9.6 weeks. Ten ICD therapies (seven shocks) were reported in the 834 patients with ICD during ET. Between exercise sessions and during follow up 182 events were recorded including 166 shocks. Three studies (2 randomized) showed that the control group representing sedentary patients were more prone to ICD discharge than patients undergoing CR/ET. In all studies the ICD patients improved their aerobic fitness following ET. Few studies report data on the effect of ET on anxiety and depression. CONCLUSION: Based on the current literature, ET in patients with an ICD seems to be safe and is not associated with increased risk of shocks. ET improves aerobic capacity in ICD patients, while effects on anxiety, depression and quality of life are still under debate.

Reversible fetal renal failure after maternal treatment with Candesartan: a case report.

Despite data suggesting that angiotensin-receptor blockers (ARBs) are associated with increased risk to the fetus, there has been an increasing exposure of ARBs in pregnancy. We report a case report regarding a woman, who accidentally was treated with Candesartan during the first 22 weeks of pregnancy. At 22 weeks of gestation the fetal kidneys were oedematous with very little amniotic fluid. The prognosis for the fetus was considered poor. Five weeks after discontinuation of Candesartan normal quantities of amnionic fluid and a visible fetal bladder was registered. After delivery at week 31, creatinine clearance, diuresis and urine examination of the neonate were within normal limits. Ultrasound examinations of the kidneys showed bilaterally marked calices, small cysts and parenchymal increased echogenety at 1 week with complete sonographic normalization at 6 weeks. However, experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood.

Lyme carditis: persistent local delayed enhancement by cardiac magnetic resonance imaging.

Lyme borreliosis (LB) is the most common tick-born disease in the Northern Hemisphere. During early disseminated Lyme disease cardiac manifestation can occur. We report a case of isolated Lyme myocarditis with transitory total atrioventricular (AV)-block and myocardial necrosis indicated by a rise in Troponin-T (TNT). Antibiotic treatment resulted in complete resolution of the AV-block, but a local epimyocardial contrast enhancement persisted as shown by cardiac magnetic resonance imaging (MRI).