Molecular Mechanisms of Myocardial Hypertrophy and Heart Failure : Experimental Studies on Cardiac G Protein-Coupled Receptor Signaling with Emphasis on Endothelin-1

Lege og forsker Thomas Gero von Lueder har i sitt doktorgradsarbeid funnet nye mekanismer bak hjertesvikt, og identifisert nye potensielle mål for behandling. Forekomsten av hjertesvikt øker betydelig i hele den vestlige hemisfæren, og påfører samfunnet enorme kostnader. Hjertesvikt er en uhelbredelig tilstand som kjennetegnes ved at hjertemuskelens evne til å pumpe blod blir svekket, f.eks etter et hjerteinfarkt. Leveutsikten ved hjertesvikt er redusert på linje med alvorlig kreftsykdom, selv med de mest moderne medisiner. Man antar at kroniske endringer i signalsystemer som endrer hjertets muskelmasse, pumpekraft og slagfrekvens over tid spiller en viktig rolle. I sin avhandling "Molecular Mechanisms of Myocardial Hypertrophy and Heart Failure ; Experimental studies on cardiac G protein-coupled receptor signalling with emphasis on endothelin-1" har Thomas Gero von Lueder og medarbeidere studert slike omdannelsesprosesser i hjertet, såkalt remodellering. Som en av flere involverte hormonsystemer er plasmanivåer av endothelin-1 betydelig økt ved hjertesvikt, og gruppen kunne nå i en grisemodell fastslå at lungene er den viktigste endothelin-1 kilde. I et oppfølgende arbeid ble betennelsesceller i lungenene (makrofager) som har evne til endothelin-1 produksjon hemmet. Hemming av makrofager reduserte endothelin-1 nivåer og bedret hjertefunksjon hos rotter med alvorlig hjertesvikt. Signalstoffer som adrenalin innvirker på hjertet via mottagermolekyler (receptorer). Effekten slas av etter kort tid av enyzmer kalt GRK. Transgene mus der denne "bryter" funksjon via enzymet GRK3 var blokkert hadde styrket hjertefunksjon sammenlignet med normale kontrollmus. GRK3 hemming førte dessuten til at musene tolererte kraftig og langvarig overbelastning på hjertet mye bedre, og var beskyttet mot utvikling av hjertesvikt. Avhandlingen har ført til økt kunnskap om årsaksforhold ved hjertesvikt og samtidig identifisert en rekke nye potensielle angrepspunkter for bedret behandling

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction:An individual patient-level analysis of double-blind randomized trials

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials.  Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis.  Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%

The Prognostic Role of Serum Uric Acid (SUA) in Coronary Artery Disease: PerSUAsive Data Plea for a Large Morbidity-Mortality Trial

International audienc

Left ventricular biomechanics in professional football players

Chronic exercise induces adaptive changes of left ventricular (LV) ejection and filling capacities which may be detected by novel speckle‐tracking echocardiography (STE) and tissue Doppler imaging (TDI)‐based techniques. A total of 103 consecutive male elite Norwegian soccer players and 46 age‐matched healthy controls underwent echocardiography at rest. STE was used to assess LV torsional mechanics and LV systolic longitudinal strain (LS). Diastolic function was evaluated by trans‐mitral blood flow, mitral annular velocities by TDI, and LV inflow propagation velocity by color M‐mode. Despite similar global LS, players displayed lower basal wall and higher apical wall LS values vs controls, resulting in an incremental base‐to‐apex gradient of LS. Color M‐mode and TDI‐derived data were similar in both groups. Peak systolic twist rate (TWR) was significantly lower in players (86.4±2.8 vs controls 101.9±5.2 deg/s, P<.01). Diastolic untwisting rate (UTWR) was higher in players (−124.5±4.2 vs −106.9±6.7 deg/s) and peaked earlier during the cardiac cycle (112.7±0.8 vs 117.4±2.4% of systole duration, both P<.05). Untwisting/twisting ratio (−1.48±0.05 vs −1.11±0.08; P<.001) and untwisting performance (=UTR/TW; −9.25±0.34 vs −7.38±0.40 s−1, P<.01) were increased in players. Augmented diastolic wall strain (DWS), a novel measure of LV compliance in players, was associated with improved myocardial mechanical efficiency. The described myocardial biomechanics may underlie augmented exertional cardiac function in athletes and may have a potential role to characterize athlete′s heart by itself or to distinguish it from hypertensive or hypertrophic cardiomyopathy

Cardiac Dimensions and Function are not Altered among Females with the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CSF and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance. In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production. Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine transthoracic echocardiography, and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables. Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups. Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls

Late Pseudoaneurysm After Access Site Closure with Manta in Transfemoral Aortic Valve Implantation

Introduction: Access site vascular complications in transfemoral transcatheter aortic valve implantation (TF-TAVI) are still a major concern. Recently, a novel collagen plug based closure device (Manta) was introduced. The results from the first reports on Manta are very promising, but not much is known about the long-term patency. Report: A case of late pseudoaneurysm after access site arterial closure with Manta in TF-TAVI is described. The patient presented five weeks after left sided TF-TAVI with pain and claudication like symptoms in the left leg. CT angiography revealed a pseudoaneurysm at the puncture site. The patient was successfully treated by vascular surgery. Discussion: The results from recent peri-operative reports on the Manta vascular closure device (VCD) are promising, but not much is known about the long-term patency. In the present report a patient is described who developed a pseudoaneurysm several weeks after access site closure with Manta. To the authors’ knowledge, no such late access site complications after use of the Manta VCD have been reported previously. Keywords: TAVI, Access site closure, Manta, Pseudoaneurys