GWAS summary statistics, often publicly available, summarizes results from association testing and are ideal to identify the genome-wide significant genetic variants that are used as instrumental ...variables for MR. Causal effects of atrial fibrillation on lower white matter volume Using summary data from one of the newest GWAS on AF by Roselli et al., Park and colleagues found evidence of causal effects of AF on lower white matter volume assessed by brain MRI, using the fixed-effects inverse variance weighted MR method. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
Current treatments for type 2 diabetes fail to prevent the development of peripheral neuropathy. To examine insulin degludec’s effect on peripheral neuropathy in rats, we tested insulin 700, an ...analog identical to insulin degludec with the same pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but with the absence of the terminal threonine on the B-chain. Rats were fed a high fat diet for 8 weeks and then treated with a low dose of streptozotocin to induce hyperglycemia. After 2 weeks, diabetic rats were treated with I700 or a control basal insulin (IC) with similar PK twice daily for 18 weeks. A healthy reference group fed a chow diet and not subjected to streptozotocin treatment was also included. The endpoints evaluated included sensory and motor nerve conduction velocity, allodynia using von Frey’s test, thermal sensitivity using Hargreaves test and corneal sensitivity. We evaluated innervation of sensory nerves using corneal confocal microscopy and, in the skin, using histological methods. We also tested vascular reactivity of epineurial arterioles using pressure myography. The insulin analogues were equally effective at correcting hyperglycemia as determined by HbA1C levels of 4.1±0.1 and 4.1±0.1% for I700 and IC, respectively. Both insulin analogues improved all neuropathy related parameters. However, I700 was more effective in that by the end of the treatment period there was no difference in thermal sensitivity, corneal sensitivity, corneal nerve fiber length and sensory and motor nerve conduction velocity between the group treated with I700 and the healthy reference rats. Interestingly, vascular relaxation to acetylcholine improved more with IC treatment. In conclusion, this study demonstrates that I700 (a degludec-like insulin analog) is a more effective treatment for diabetic peripheral neuropathy than a comparable control insulin, independent of glycemic control.
Disclosure
T.C.A.Åkerström: Employee; Novo Nordisk. L.Andreasen: Employee; Novo Nordisk. E.Nishimura: Employee; Novo Nordisk A/S. M.A.Yorek: Consultant; Novo Nordisk.
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome ...sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10
). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10
). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
Introduction. Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) emphasize good glycemic control. However, this has limited effect on prevention of DPN in type 2 ...diabetic (T2D) patients. This study investigates the effect of insulin treatment on development of DPN in a rat model of T2D to assess the underlying causes leading to DPN. Methods. Twelve-week-old male Sprague-Dawley rats were allocated to a normal chow diet or a 45% kcal high-fat diet. After eight weeks, the high-fat fed animals received a mild dose of streptozotocin to induce hyperglycemia. Four weeks after diabetes induction, the diabetic animals were allocated into three treatment groups receiving either no insulin or insulin-releasing implants in a high or low dose. During the 12-week treatment period, blood glucose and body weight were monitored weekly, whereas Hargreaves’ test was performed four, eight, and 12 weeks after treatment initiation. At study termination, several blood parameters, body composition, and neuropathy endpoints were assessed. Results. Insulin treatment lowered blood glucose in a dose-dependent manner. In addition, both doses of insulin lowered lipids and increased body fat percentage. High-dose insulin treatment attenuated small nerve fiber damage assessed by Hargreaves’ test and intraepidermal nerve fiber density compared to untreated diabetes and low-dose insulin; however, neuropathy was not completely prevented by tight glycemic control. Linear regression analysis revealed that glycemic status, circulating lipids, and sciatic nerve sorbitol level were all negatively associated with the small nerve fiber damage observed. Conclusion. In summary, our data suggest that high-dose insulin treatment attenuates small nerve fiber damage. Furthermore, data also indicate that both poor glycemic control and dyslipidemia are associated with disease progression. Consequently, this rat model of T2D seems to fit well with progression of DPN in humans and could be a relevant preclinical model to use in relation to research investigating treatment opportunities for DPN.
ObjectiveCardiac MRI is quickly emerging as the gold standard for assessment of mitral regurgitation, most commonly with the indirect method subtracting forward flow in aorta from volumetric ...segmentation of the left ventricle. We aimed to investigate how aortic flow measurements with increasing distance from the aortic valve affect calculated mitral regurgitations and whether measurements were influenced by breath-hold regimen.MethodsFree-breathing and breath-hold phase contrast flows were measured in aorta at valve level, sinotubular (ST) junction, mid-ascending aorta and in the pulmonary trunk. Flow measurements were pairwise compared, and subsequently, after exclusion of patients with visible mitral and tricuspid regurgitations for left-sided and right-sided comparisons, respectively, flow-measured stroke volumes were compared with ventricular volumetric segmentations.ResultsThirty-nine participants without arrhythmias or structural abnormalities of the large vessels were included. Stroke volumes measured with free-breathing and breath-hold flow decreased equally with increasing distance to the aortic valves (breath-hold flow: aortic valve 105.6±20.8 mL, ST junction 101.5±20.7 mL, mid-ascending aorta 98.1±21.5 mL). After exclusion of atrioventricular regurgitations, stroke volumes determined by volumetric measurements were higher compared with values determined by flow measurements, corresponding to ‘false’ atrioventricular regurgitations of 8.0%±5.8% with flow measured at valve level, 11.6%±5.2% at the ST junction and 15.3%±5.0% at the mid-ascending aorta.ConclusionsStroke volumes determined by flow decrease throughout the proximal aorta and are systematically lower than volumetrically measured stroke volumes. The indirect method systematically overestimates mitral regurgitations, especially with increasing distance from the aortic valves.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF.
...We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population.
Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies.
Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P = .0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes.
We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown.
The purpose of this study was to ...investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF.
DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques.
No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2).
We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), ...which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (
= 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (
), actin-associated
protein (
), and fukutin (
)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (
= 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (
= 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.
A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, to increase the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general ...population is unknown, we aimed to investigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population.
A cohort of 6,161 individuals (median age 45 interquartile range (IQR) 40-50 years, 49% males), with available digital ECGs, was genotyped and subsequently followed for a median period of 13 IQR 12.6-13.4 years. Data on outcomes were collected from Danish administrative healthcare registries. Furthermore, ~400,000 persons from UK Biobank were investigated for associations between the three loci and cardiac arrest/ventricular fibrillation (VF).
Homozygote carriers of the C allele in rs6800541 intronic to
had a significantly larger J-point elevation (JPE) compared with wildtype carriers (11 vs. 6 μV,
< 0.001). There was an additive effect of carrying multiple BrS-associated risk alleles with an increased JPE in lead V1. None of the BrS-associated genetic loci predisposed to syncope, atrial fibrillation, or total mortality in the general Danish population. The rs9388451 genetic locus adjacent to the
gene was associated with cardiac arrest/VF in an analysis using the UK Biobank study (odds ratio = 1.13 (95% confidence interval: 1.08-1.18),
= 0.006).
BrS-associated risk alleles increase the JPE in lead V1 in an additive manner, but was not associated with increased mortality or syncope in the general population of Denmark. However, the
risk allele increased the risk of cardiac arrest/VF in the larger population study of UK Biobank indicating an important role of this common genetic locus.
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