Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice

BACKGROUND: Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR(-/-)ApoB(100/100)). METHODS AND RESULTS: 18-month-old LDLR(-/-)ApoB(100/100 )(n = 12), diabetic LDLR(-/-)ApoB(100/100 )mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR(-/-)ApoB(100/100), n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR(-/-)ApoB(100/100 )mice, diabetic IGF-II/LDLR(-/-)ApoB(100/100 )mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR(-/-)ApoB(100/100 )and IGF-II/LDLR(-/-)ApoB(100/100 )mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. CONCLUSIONS: LDLR(-/-)ApoB(100/100 )mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals

Vascular Endothelial Growth Factor-B Induces a Distinct Electrophysiological Phenotype in Mouse Heart

Vascular endothelial growth factor B (VEGF-B) is a potentmediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. In vivo and ex vivo analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal. Neither the oxidative metabolism of isolated TG cardiomyocytes nor their energy substrate preference showed any difference to WT cardiomyocytes. Similarly, myocyte Ca2+ signaling showed only minor changes compared to WT myocytes. However, VEGF-B overexpression induced a distinct electrophysiological phenotype characterized by ECG changes such as an increase in QRSp time and decreases in S and R amplitudes. At the level of isolated TG cardiomyocytes, these changes were accompanied with decreased action potential upstroke velocity and increased duration (APD60-70). These changes were partly caused by downregulation of sodium current (INa) due to reduced expression of Nav1.5. Furthermore, TG myocytes had alterations in voltage-gated K + currents, namely decreased density of transient outward current (Ito) and total K + current (Ipeak). At the level of transcription, these were accompanied by downregulation of Kv channel-interacting protein 2 (Kcnip2), a knownmodulatory subunit for Kv4.2/3 channel. Cardiac VEGF-B overexpression induces a distinct electrophysiological phenotype including remodeling of cardiomyocyte ion currents, which in turn induce changes in action potential waveform and ECG.Peer reviewe

Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice

Aims Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR-/-), and LDLR-/- mice expressing apoB-100 only (LDLR-/- ApoB(100/100)) having a humanized lipoprotein profile. Methods and results LDLR-/- mice were fed a high-fat diet (HFD) for 6 or 12weeks and LDLR(-/-)ApoB(100/100) mice a regular chow diet for 6 or 12months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR-/- mice reduced total plasma cholesterol after 6weeks of HFD and triglycerides in LDLR(-/-)ApoB(100/100) mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR(-/-)ApoB(100/100) mice as it increased plaque calcification. Moreover, approximate to 36% of Nrf2(-/-)LDLR(-/-)ApoB(100/100) females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR(-/-)ApoB(100/100) female mice at age of 12months. Conclusions Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR(-/-)ApoB(100/100) mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.Peer reviewe

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Koronavirusinfektion ja koronarokottamisen sydänvaikutukset

COVID-19-infektiota sairastavien potilaiden sydäninfarktin, sydänlihastulehduksen, laskimo- ja keuhkoveritulpan, eteisvärinän ja sydämen vajaatoiminnan vaara on suurentunut. Sydänpotilailla todetaan vaikeampaa COVID-19-tautimuotoa ja sen komplikaatioita useammin kuin muussa väestössä. Kliinisesti merkittäviä sydänongelmia voi ilmetä vaikean sairaalahoitoisen COVID-19-infektion yhteydessä. Yleinen sydänsairauden vaikeutta heijasteleva löydös on suurentunut troponiinipitoisuus. Kirjallisuudessa kuvatuista vaikutuksista huolimatta COVID-19-potilaiden sydänkomplikaatiot eivät ole olleet Suomessa laajamittainen ongelma ehkäisevien toimien ja rokotusten myötä. COVID-19-infektioon liittyy etenkin sairaalahoidon aikana merkittävä tromboosiriski, mutta se osataan tunnistaa ja hoitaa asianmukaisella antikoagulaatiohoidolla. Koronarokotteiden jälkeisiä pääosin lieväoireisia ja nopeasti ohimeneviä sydänlihastulehduksia ilmenee nuorilla miespotilailla hieman muita enemmän. COVID-19-infektio aiheuttaa kuitenkin selvästi enemmän sydänlihastulehduksia kuin rokotukset.Peer reviewe