Jan Otto Beitnes

Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study

Objective: To investigate long-term safety and efficacy after intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) in acute myocardial infarction (AMI). Design: Randomised, controlled trial. Setting: Two university hospitals in Oslo, Norway. Patients: Patients from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study were re-assessed 3 years after inclusion. Interventions: 100 patients with anterior wall ST-elevation myocardial infarction treated with acute percutaneous coronary intervention (PCI) were randomised to receive intracoronary injection of mBMCs (n = 50) or not (n = 50). Main outcome measures: Change in left ventricular (LV) ejection fraction (primary). Change in exercise capacity (peak VO2) and quality of life (secondary). Infarct size (additional aim), and safety. Results: The rates of adverse clinical events in the groups were low and equal. There were no significant differences between groups in change of global LV systolic function by echocardiography or magnetic resonance imaging (MRI) during the follow-up. On exercise testing, the mBMC-treated patients had larger improvement in exercise time from 2–3 weeks to 3 years (1.5 minutes vs 0.6 minutes, p = 0.05), but the change in peak oxygen consumption did not differ (3.0 ml/kg/min vs 3.1 ml/kg/min, p = 0.75). Conclusion: The results indicate that intracoronary mBMC treatment in AMI is safe in the long term. A small improvement in exercise time in the mBMC group was found, but no other effects of treatment could be identified 3 years after cell therapy.

Intramyocardial Injections of Human Mesenchymal Stem Cells Following Acute Myocardial Infarction Modulate Scar Formation and Improve Left Ventricular Function

Cell therapy is a promising treatment modality to improve heart function in acute myocardial infarction. However, the mechanisms of action and the most suitable cell type have not been finally determined. We performed a study to compare the effects of mesenchymal stem cells (MSCs) harvested from different tissues on LV function and explore their effects on tissue structure by morphometry and histological staining for species and lineage relationship. MSCs from skeletal muscle (SM-MSCs) and adipose tissue (ADSCs) were injected in the myocardium of nude rats 1 week after myocardial infarction. After 4 weeks of observation, LVEF was significantly improved in the SM-MSCs group (39.1%) and in the ADSC group (39.6%), compared to the placebo group (31.0%, p < 0.001 for difference in change between groups). Infarct size was smaller after cell therapy (16.3% for SM-MSCs, 15.8% for ADSCs vs. 26.0% for placebo, p < 0.001), and the amount of highly vascularized granulation tissue in the border zone was significantly increased in both groups receiving MSCs (18.3% for SM-MSCs, 22.6% for ADSCs vs. 13.1% for placebo, p = 0.001). By in situ hybridization, moderate engraftment of transplanted cells was found, but no transdifferentiation to cardiomyocytes, endothelial cells, or smooth muscle cells was observed. We conclude that MSC injections lead to improved LVEF after AMI in rats predominantly by reduction of infarct size. After 4 weeks, we observed modulation of scar formation with significant increase in granulation tissue. Transdifferentiation of MSCs to cardiomyocytes or vascular cells did not contribute significantly in this process. MSCs from skeletal muscle and adipose tissue had similar effects.

Assessment of left ventricular function in ST-elevation myocardial infarction by global longitudinal strain: a comparison with ejection fraction, infarct size, and wall motion score index measured by non-invasive imaging modalities

AIMS We aimed to compare two-dimensional global longitudinal strain (GS) with different non-invasive imaging modalities for the assessment of left ventricular function in an ST-elevation myocardial infarction population. METHODS AND RESULTS GS was compared with ejection fraction (EF) determined by magnetic resonance imaging (MRI), standard echocardiography (echo), contrast echo, and electrocardiography-gated single-photon emission computed tomography (SPECT), as well as with MRI-determined relative infarct size and echo-determined wall motion score index (WMSI), in 163 patients participating in the NORwegian Study on District Treatment of ST-Elevation Myocardial Infarction (NORDISTEMI). The linear relation between GS and standard echo (r(2)= 0.43, P <0.001), contrast echo (r(2)= 0.38, P <0.001), and SPECT-determined EF (r(2)= 0.52, P <0.001) was almost identical as that between GS and the gold standard MRI-determined EF (r(2)= 0.47, P <0.001). GS was best associated with WMSI by echo (r(2)= 0.55, P <0.001), while the associations between GS and relative infarct size were weaker (r = 0.43, P <0.001). Receiver operator characteristics curves, used to analyse the ability of GS to discriminate low EF (≤ 40%) measured by the four different modalities, large myocardial infarction (MI ≥ 15.7%), and high WMSI (≥ 1.5), were significant for all. GS was shown to be the best predictor of low EF measured by MRI [area under the curve (AUC) 0.965], while the lowest AUC was found between GS and large MI (0.814). CONCLUSION Global strain is associated well with EF measured by all modalities. Global strain was found to be the best predictor of low EF measured by the gold standard MRI. Since global strain is an inexpensive test, these data may be of health economic interest.

Krill oil attenuates left ventricular dilatation after myocardial infarction in rats

BackgroundIn the western world, heart failure (HF) is one of the most important causes of cardiovascular mortality. Supplement with n-3 polyunsaturated fatty acids (PUFA) has been shown to improve cardiac function in HF and to decrease mortality after myocardial infarction (MI). The molecular structure and composition of n-3 PUFA varies between different marine sources and this may be of importance for their biological effects. Krill oil, unlike fish oil supplements, contains the major part of the n-3 PUFA in the form of phospholipids. This study investigated effects of krill oil on cardiac remodeling after experimental MI. Rats were randomised to pre-treatment with krill oil or control feed 14 days before induction of MI. Seven days post-MI, the rats were examined with echocardiography and rats in the control group were further randomised to continued control feed or krill oil feed for 7 weeks before re-examination with echocardiography and euthanization.ResultsThe echocardiographic evaluation showed significant attenuation of LV dilatation in the group pretreated with krill oil compared to controls. Attenuated heart weight, lung weight, and levels of mRNA encoding classical markers of LV stress, matrix remodeling and inflammation reflected these findings. The total composition of fatty acids were examined in the left ventricular (LV) tissue and all rats treated with krill oil showed a significantly higher proportion of n-3 PUFA in the LV tissue, although no difference was seen between the two krill oil groups.ConclusionsSupplement with krill oil leads to a proportional increase of n-3 PUFA in myocardial tissue and supplement given before induction of MI attenuates LV remodeling.

Stem cells for cardiac repair in acute myocardial infarction

Despite recent advances in medical therapy, reperfusion strategies, implantable cardioverter-defibrillators and cardiac assist devices, ischemic heart disease is a frequent cause of morbidity and mortality worldwide. Cell therapy has been introduced as a new treatment modality to regenerate lost cardiomyocytes. At present, several cell types seem to improve left ventricular function in animal models as well as in humans, but evidence for true generation of new myocardium is confined to the experimental models. In the clinical perspective, myocardial regeneration has been replaced by myocardial repair, as other mechanisms seem to be involved. Clinical studies on adult stem cells suggest, at best, moderate beneficial effects on surrogate end points, but some applications may qualify for evaluation in larger trials. Complete regeneration of the myocardium by cell therapy after a large myocardial infarction is still visionary, but pluripotent stem cells and tissue engineering are important tools to solve the puzzle.

Comparison of patients with early-phase arrhythmogenic right ventricular cardiomyopathy and right ventricular outflow tract ventricular tachycardia

Aims Differentiation between early-phase arrhythmogenic right ventricular cardiomyopathy (ARVC) and right ventricular outflow tract (RVOT)-ventricular tachycardia (VT) can be challenging, and correct diagnosis is important. We compared electrocardiogram (ECG) parameters and morphological right ventricular (RV) abnormalities and investigated if ECG and cardiac imaging can help to discriminate early-phase ARVC from RVOT-VT patients. Methods and results We included 44 consecutive RVOT-VT (47 ± 14 years) and 121 ARVC patients (42 ± 17 years). Of the ARVC patients, 77 had definite ARVC and 44 had early-phase ARVC disease. All underwent clinical examination, ECG, and Holter monitoring. Frequency of premature ventricular complexes (PVC) was expressed as percent per total beats/24 h (%PVC), and PVC configuration was recorded. By echocardiography, we assessed indexed RV basal diameter (RVD), indexed RVOT diameter, and RV and left ventricular (LV) function. RV mechanical dispersion (RVMD), reflecting RV contraction heterogeneity, was assessed by speckle-tracking strain echocardiography. RV ejection fraction (RVEF) was assessed by cardiac magnetic resonance imaging (CMR). Patients with early-phase ARVC had lower %PVC by Holter and PVC more frequently originated from the RV lateral free wall (both P < 0.001). RVD was larger (21 ± 3 vs. 19 ± 2 mm, P < 0.01), RVMD was more pronounced (22 ± 15 vs. 15 ± 13 ms, P = 0.03), and RVEF by CMR was decreased (41 ± 8 vs. 49 ± 4%, P < 0.001) in early-phase ARVC vs. RVOT-VT patients. Conclusion Patients with early-phase ARVC had structural abnormalities with lower RVEF, increased RVD, and pronounced RVMD in addition to lower %PVC by Holter compared with RVOT-VT patients. These parameters can help correct diagnosis in patients with unclear phenotypes.

Automatic measurement of aortic annulus diameter in 3-dimensional Transoesophageal echocardiography

BackgroundTranscatheter aortic valve implantation involves percutaneously implanting a biomechanical aortic valve to treat severe aortic stenosis. In order to select a proper device, precise sizing of the aortic valve annulus must be completed.MethodsIn this paper, we describe a fully automatic segmentation method to measure the aortic annulus diameter in patients with aortic calcification, operating on 3-dimensional transesophageal echocardiographic images. The method is based on state estimation of a subdivision surface representation of the left ventricular outflow tract and aortic root. The state estimation is solved by an extended Kalman filter driven by edge detections normal to the subdivision surface.ResultsThe method was validated on echocardiographic recordings of 16 patients. Comparison against two manual measurements showed agreements (mean ±SD) of -0.3±1.6 and -0.2±2.3 mm for perimeter-derived diameters, compared to an interobserver agreement of -0.1±2.1 mm.ConclusionsWith this study, we demonstrated the feasibility of an efficient and fully automatic measurement of the aortic annulus in patients with aortic disease. The algorithm robustly measured the aortic annulus diameter, providing measurements indistinguishable from those done by cardiologists.

Morbidity outcomes after surgical aortic valve replacement

Objective In patients with mild to moderate operative risk, surgical aortic valve replacement (SAVR) is still the preferred treatment for patients with severe symptomatic aortic stenosis (AS). Aiming to broaden the knowledge of postsurgical outcomes, this study reports a broad set of morbidity outcomes following surgical intervention. Methods Our cohort comprised 442 patients referred for severe AS; 351 had undergone SAVR, with the remainder (91) not operated on. All patients were evaluated using the 6-minute walk test (6MWT), were assigned a New York Heart Association class (NYHA) and Canadian Cardiovascular Society class (CCS), with additional scores for health-related quality of life (HRQoL), cognitive function (Mini-Mental State Examination (MMSE)) and myocardial remodelling (at inclusion and at 1-year follow-up). Adverse events and mortality were recorded. Results Three-year survival after SAVR was 90.0%. SAVR was associated with an improved NYHA class, CCS score and HRQoL, and provoked reverse ventricular remodelling. The 6MWT decreased, while the risks of major adverse cardiovascular events (death, non-fatal stroke/transient ischaemic attack or myocardial infarction) and all-cause hospitalisation (incidence rate per 100 patient-years) were 13.5 and 62.4, respectively. The proportion of cognitive disability measured by MMSE increased after SAVR from 3.2% to 8.8% (p=0.005). Proportion of patients living independently at home, having attained NYHA class I, was met by 49.1% at 1 year. Unoperated individuals had a poor prognosis in terms of any outcome. Conclusion This study provides knowledge of outcomes beyond what is known about the mortality benefit after SAVR to provide insight into the morbidity burden of modern-day SAVR.

Long axis strain by MRI and echocardiography in a postmyocardial infarct population

To compare long axis strain (LAS) by magnetic resonance imaging (MRI) and echocardiography in a postinfarct patient population. Long axis left ventricle (LV) function is a sensitive index of incipient heart failure by echocardiography, but is less well established in MRI. LAS is an index of global LV function, which is easily assessed in cine loops provided by most cardiac MRI protocols.

Tetradecylthioacetic Acid Increases Fat Metabolism and Improves Cardiac Function in Experimental Heart Failure

Changes in myocardial metabolism, including a shift from fatty acid to glucose utilization and changes in fatty acid availability and composition are characteristics of heart failure development. Tetradecylthioacetic acid (TTA) is a fatty acid analogue lacking the ability to undergo mitochondrial β-oxidation. TTA promotes hepatic proliferation of mitochondria and peroxisomes and also decreases serum triglycerides and cholesterol in animals. We investigated the effect of TTA, in combination with a high-fat or regular diet, in a rat model of post-myocardial infarction heart failure. TTA had a beneficial effect on cardiac function in post-myocardial infarction heart failure without affecting myocardial remodeling. These effects of TTA on myocardial function were accompanied by decreased free fatty acids in plasma, increased myocardial proportion of n-3 polyunsaturated fatty acids (PUFA) and a decreased proportion of n-6 PUFA. Myocardial enzyme gene expression during TTA treatment suggested that the increase in n-3 PUFA could reflect increased n-3 PUFA synthesis and inadequately increased n-3 PUFA β-oxidation. Based on our data, it is unlikely that the changes are secondary to alterations in other tissues as plasma and liver showed an opposite pattern with decreased n-3 PUFA during TTA treatment. The present study suggests that TTA may improve myocardial function in heart failure, potentially involving its ability to decrease the availability of FFA and increase the myocardial proportion of n-3 PUFA.