| 1. |
- Hansen-Schwartz, Jacob, et al.
(författare)
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Endothelium-Dependent Relaxant Responses to Selective 5-HT(1B/1D) Receptor Agonists in the Isolated Middle Cerebral Artery of the Rat.
- 2003
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 40:6, s. 561-566
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Tidskriftsartikel (refereegranskat)abstract
- The vasomotor effects of triptans in the middle cerebral artery (MCA) of rats were studied using the pressurised arteriography method and in vitro vessel baths. Using the arteriograph, MCAs from Sprague-Dawley rats were mounted on two glass micropipettes, pressurised to 85 mm Hg and luminally perfused. Luminally added 5- hydroxytryptamine (5-HT), sumatriptan and rizatriptan induced maximal dilatations of 22 ± 4, 10 ± 2 and 13 ± 5%, respectively, compared to the resting diameter. The relaxant effect of sumatriptan was blocked by the 5- HT<sub>1B/1D</sub> receptor selective antagonist GR 55562 (10<sup>–6</sup><i>M</i>). The use of N<sup>ω</sup>-nitro-<i>L</i>-arginine and charybdotoxin revealed that the dilatation involved both nitric oxide and endothelially derived hyperpolarising factor. Thus, the earlier demonstrated expression of 5-HT<sub>1B/1D</sub> immunoreactivity in the endothelium may well translate into a relaxant response to 5-HT and triptans. Using the vessel bath technique, MCA segments were mounted on two metal wires. The relaxant responses to sumatriptan could not be reproduced using this model; instead, weak contractile responses (6 ± 3% of submaximal contractile capacity) were observed. The difference in observations between the experimental models may be related to the maintenance of shear stress in the arteriograph.
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| 2. |
- Ravn Jacobsen, Mia, et al.
(författare)
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Potassium Disturbances and Risk of Ventricular Fibrillation Among Patients With ST-Segment-Elevation Myocardial Infarction
- 2020
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Potassium disturbances per se increase the risk of ventricular fibrillation (VF). Whether potassium disturbances in the acute phase of ST-segment-elevation myocardial infarction (STEMI) are associated with VF before primary percutaneous coronary intervention (PPCI) is uncertain. Methods and Results All consecutive STEMI patients were identified in the Eastern Danish Heart Registry from 1999 to 2016. Comorbidities and medication use were assessed from Danish nationwide registries. Potassium levels were collected immediately before PPCI start. Multivariate logistic models were performed to determine the association between potassium and VF. The main analysis included 8624 STEMI patients of whom 822 (9.5%) had VF before PPCI. Compared with 6693 (77.6%) patients with normokalemia (3.5-5.0 mmol/L), 1797 (20.8%) patients with hypokalemia (<3.5 mmol/L) were often women with fewer comorbidities, whereas 134 (1.6%) patients with hyperkalemia (>5.0 mmol/L) were older with more comorbidities. After adjustment, patients with hypokalemia and hyperkalemia had a higher risk of VF before PPCI (odds ratio 1.90, 95% CI 1.57-2.30, P<0.001) and (odds ratio 3.36, 95% CI 1.95-5.77, P<0.001) compared with normokalemia, respectively. Since the association may reflect a post-resuscitation phenomenon, a sensitivity analysis was performed including 7929 STEMI patients without VF before PPCI of whom 127 (1.6%) had VF during PPCI. Compared with normokalemia, patients with hypokalemia had a significant association with VF during PPCI (odds ratio 1.68, 95% CI 1.01-2.77, P=0.045) after adjustment. Conclusions Hypokalemia and hyperkalemia are associated with increased risk of VF before PPCI during STEMI. For hypokalemia, the association may be independent of the measurement of potassium before or after VF.
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| 3. |
- Ashar, Foram N., et al.
(författare)
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A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39:44, s. 3961-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
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| 4. |
- Corrado, Domenico, et al.
(författare)
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Proposed diagnostic criteria for arrhythmogenic cardiomyopathy : European Task Force consensus report
- 2024
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Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 395
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Tidskriftsartikel (refereegranskat)abstract
- Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right-and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late-gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnor-malities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.
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| 5. |
- Glinge, Charlotte, et al.
(författare)
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Familial clustering of unexplained heart failure – A Danish nationwide cohort study
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Ingår i: International Journal of Cardiology. - 0167-5273.
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine whether a family history of unexplained heart failure (HF) in first-degree relatives (children or sibling) increases the rate of unexplained HF. Methods and results: Using Danish nationwide registry data (1978–2017), we identified patients (probands) diagnosed with first unexplained HF (HF without any known comorbidities) in Denmark, and their first-degree relatives. All first-degree relatives were followed from the HF date of the proband and until an event of unexplained HF, exclusion diagnosis, death, emigration, or study end, whichever occurred first. Using the general population as a reference, we calculated adjusted standardized incidence ratios (SIR) of unexplained HF in the three groups of relatives using Poisson regression models. We identified 55,110 first-degree relatives to individuals previously diagnosed with unexplained HF. Having a family history was associated with a significantly increased unexplained HF rate of 2.59 (95%CI 2.29–2.93). The estimate was higher among siblings (SIR 6.67 [95%CI 4.69–9.48]). Noteworthy, the rate of HF increased for all first-degree relatives when the proband was diagnosed with HF in a young age (≤50 years, SIR of 7.23 [95%CI 5.40–9.68]) and having >1 proband (SIR of 5.28 [95%CI 2.75–10.14]). The highest estimate of HF was observed if the proband was ≤40 years at diagnosis (13.17 [95%CI 8.90–19.49]. Conclusion: A family history of unexplained HF was associated with a two-fold increased rate of unexplained HF among first-degree relatives. The relative rate was increased when the proband was diagnosed at a young age. These data suggest that screening families of unexplained HF with onset below 50 years is indicated.
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| 6. |
- Glinge, Charlotte, et al.
(författare)
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Seasonality of ventricular fibrillation at first myocardial infarction and association with viral exposure
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Aims To investigate seasonality and association of increased enterovirus and influenza activity in the community with ventricular fibrillation (VF) risk during first ST-elevation myocardial infarction (STEMI). Methods This study comprised all consecutive patients with first STEMI (n = 4,659; aged 18–80 years) admitted to the invasive catheterization laboratory between 2010–2016, at Copenhagen University Hospital, Rigshospitalet, covering eastern Denmark (2.6 million inhabitants, 45% of the Danish population). Hospital admission, prescription, and vital status data were assessed using Danish nationwide registries. We utilized monthly/weekly surveillance data for enterovirus and influenza from the Danish National Microbiology Database (2010–2016) that receives copies of laboratory tests from all Danish departments of clinical microbiology. Results Of the 4,659 consecutively enrolled STEMI patients, 581 (12%) had VF before primary percutaneous coronary intervention. In a subset (n = 807), we found that VF patients experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with the patients without VF (OR 3.39, 95% CI 1.76–6.54). During the study period, 2,704 individuals were diagnosed with enterovirus and 19,742 with influenza. No significant association between enterovirus and VF (OR 1.00, 95% CI 0.99–1.02), influenza and VF (OR 1.00, 95% CI 1.00–1.00), or week number and VF (p-value 0.94 for enterovirus and 0.89 for influenza) was found. Conclusion We found no clear seasonality of VF during first STEMI. Even though VF patients had experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with patients without VF, no relationship was found between enterovirus or influenza exposure and occurrence of VF.
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| 7. |
- Glinge, Charlotte, et al.
(författare)
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Sibling history is associated with heart failure after a first myocardial infarction
- 2020
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Ingår i: Open Heart. - : BMJ. - 2398-595X .- 2053-3624. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Morbidity and mortality due to heart failure (HF) as a complication of myocardial infarction (MI) is high, and remains among the leading causes of death and hospitalisation. This study investigated the association between family history of MI with or without HF, and the risk of developing HF after first MI. Methods: Through nationwide registries, we identified all individuals aged 18-50 years hospitalised with first MI from 1997 to 2016 in Denmark. We identified 13 810 patients with MI, and the cohort was followed until HF diagnosis, second MI, 3 years after index MI, emigration, death or the end of 2016, whichever occurred first. HRs were estimated by Cox hazard regression models adjusted for sex, age, calendar year and comorbidities (reference: patients with no family history of MI). Results: After adjustment, we observed an increased risk of MI-induced HF for those having a sibling with MI with HF (HR 2.05, 95% CI 1.02 to 4.12). Those having a sibling with MI without HF also had a significant, but lower increased risk of HF (HR 1.39, 95% CI 1.05 to 1.84). Parental history of MI with or without HF was not associated with HF. Conclusion: In this nationwide cohort, sibling history of MI with or without HF was associated with increased risk of HF after first MI, while a parental family history was not, suggesting that shared environmental factors may predominate in the determination of risk for developing HF.
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| 8. |
- Hesselkilde, Eva Zander, et al.
(författare)
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Longitudinal study of electrical, functional and structural remodelling in an equine model of atrial fibrillation
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Large animal models are important in atrial fibrillation (AF) research, as they can be used to study the pathophysiology of AF and new therapeutic approaches. Unlike other animal models, horses spontaneously develop AF and could therefore serve as a bona fide model in AF research. We therefore aimed to study the electrical, functional and structural remodelling caused by chronic AF in a horse model. Method: Nine female horses were included in the study, with six horses tachypaced into self-sustained AF and three that served as a time-matched sham-operated control group. Acceleration in atrial fibrillatory rate (AFR), changes in electrocardiographic and echocardiographic variables and response to medical treatment (flecainide 2 mg/kg) were recorded over a period of 2 months. At the end of the study, changes in ion channel expression and fibrosis were measured and compared between the two groups. Results: AFR increased from 299 ± 33 fibrillations per minute (fpm) to 376 ± 12 fpm (p < 0.05) and atrial function (active left atrial fractional area change) decreased significantly during the study (p < 0.05). No changes were observed in heart rate or ventricular function. The AF group had more atrial fibrosis compared to the control group (p < 0.05). No differences in ion channel expression were observed. Conclusion: Horses with induced AF show signs of atrial remodelling that are similar to humans and other animal models.
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| 9. |
- Jabbari, Reza, et al.
(författare)
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Association of common genetic variants related to atrial fibrillation and the risk of ventricular fibrillation in the setting of first ST-elevation myocardial infarction
- 2017
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). Methods: We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case-control study among first STEMI-patients of Danish ancestry. Results: We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p < 0.001). All 24 selected SNPs have previously been associated with AF. None of the 24 SNPs were associated with the risk of VF after adjustment for age and sex under additive genetic model of inheritance in the logistic regression model. Conclusion: In this study, we found that the 24 AF-associated SNPs may not be involved in increasing the risk of VF. Larger VF cohorts and use of new next generation sequencing and epigenetic may in future identify additional AF and VF risk loci and improve our understanding of genetic pathways behind the two arrhythmias.
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| 10. |
- Jansweijer, Joeri A., et al.
(författare)
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Heritability in genetic heart disease : the role of genetic background
- 2019
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Ingår i: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ‘modifier genes’. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.
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| 11. |
- Kalarus, Zbigniew, et al.
(författare)
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Cardiac arrhythmias in the emergency settings of acute coronary syndrome and revascularization : an European Heart Rhythm Association (EHRA) consensus document, endorsed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Acute Cardiovascular Care Association (ACCA)
- 2019
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 21:10, s. 1603-1604
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Tidskriftsartikel (refereegranskat)abstract
- Despite major therapeutic advances over the last decades, complex supraventricular and ventricular arrhythmias (VAs), particularly in the emergency setting or during revascularization for acute myocardial infarction (AMI), remain an important clinical problem. Although the incidence of VAs has declined in the hospital phase of acute coronary syndromes (ACS), mainly due to prompt revascularization and optimal medical therapy, still up to 6% patients with ACS develop ventricular tachycardia and/or ventricular fibrillation within the first hours of ACS symptoms. Despite sustained VAs being perceived predictors of worse in-hospital outcomes, specific associations between the type of VAs, arrhythmia timing, applied treatment strategies and long-term prognosis in AMI are vague. Atrial fibrillation (AF) is the most common supraventricular tachyarrhythmia that may be asymptomatic and/or may be associated with rapid haemodynamic deterioration requiring immediate treatment. It is estimated that over 20% AMI patients may have a history of AF, whereas the new-onset arrhythmia may occur in 5% patients with ST elevation myocardial infarction. Importantly, patients who were treated with primary percutaneous coronary intervention for AMI and developed AF have higher rates of adverse events and mortality compared with subjects free of arrhythmia. The scope of this position document is to cover the clinical implications and pharmacological/non-pharmacological management of arrhythmias in emergency presentations and during revascularization. Current evidence for clinical relevance of specific types of VAs complicating AMI in relation to arrhythmia timing has been discussed.
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| 12. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 13. |
- Lundström, Anna, 1984-
(författare)
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Autonomic cardiac control in long QT syndrome : clinical studies of arrhythmogenic triggers
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Long QT syndrome (LQTS) is an inherited cardiac disease characterized by prolonged cardiac repolarization and an increased risk for life-threatening arrhythmias. These arrhythmias are typically triggered by adrenergic stimuli, such as physical activity and intense emotions, implicating that the sympathetic part of the autonomic nervous system (ANS) is involved in arrhythmogenesis. However, symptoms also commonly occur swimming and diving, situations associated with dual activation of both branches of the ANS. This observation suggests that both sympathetic and parasympathetic physiological responses may contribute to the initiation of arrhythmias in individuals with LQTS.Aim: The overall aim of this thesis was to describe the cardiac autonomic response in LQTS patients during daily activities, exercise, and swimming, as well as to assess the presence of arrhythmias during activities in water. Methods: In all 4 studies electrocardiograms (ECGs) were recorded. In study I and II, a 24-hour ECG (Holter) system was used. In study III and IV, a waterproof 2-lead ECG device (Actiwave-Cardio) was used. In study I, ECGs were collected from adult LQTS patients (n = 44) and healthy controls (n = 44) during a submaximal bicycle exercise stress test. In study II, annual 24-hour ECG recordings (n = 575) during ordinary daily living was retrospectively collected in children with LQTS (n = 116). In study III, children with LQTS type 1 (LQT1) (n = 15) and age and sex matched healthy controls (n = 15) performed face immersion (FI), swimming, diving, and whole-body submersion (WBS). In study IV, healthy adolescents aged 15 years performed FI (n = 54) and ice-water immersion (IWI) of the body (n = 20).Heart rate responses and spectral analysis of heart rate variability (HRV) were assessed. HRV measures the beat-to-beat variation of the RR intervals of the heart, making it possible to non-invasively analyze the cardiac autonomic influence on the heart. The total power (PTOT) reflects all the variation during the recorded period. The high frequency (HF) component reflects parasympathetic activity, while the low frequency (LF) is influenced by both the sympathetic and parasympathetic activity.Results: In study I, LQTS patients had a decreased heart rate reduction and a lower PTOT, LF and HF than controls during the post-exercise phase. LQTS patients off beta-blocker (BB) treatment showed a lower HF and higher LF/HF ratio compared to LQTS patients on BB treatment. In study II, a correlation between heart rate and changes in HRV parameters was observed. At higher heart rates, the whole cohort of LQTS patients, as well as the subgroup of LQTS patients off BB, had lower HRV values than controls. A pattern was observed indicating that LQT1 patients had lower HF in the age group of 1-10 years, with this trend shifting as age increased, resulting in lower HF in the LQT2 patients aged 15-18 years. LQT1 girls aged 10-18 years had lower PTOT than LQT1 boys. Study III showed that LQT1 patients had a smaller reduction in heart rate during FI and WBS than controls. LQT1 patients had a lower HRV before, during and after FI and WBS than controls. In study IV, in healthy adolescents, supraventricular extrasystoles were relatively common during both FI and IWI, and 2 of 54 had ventricular bigeminy during FI. FI resulted in a more pronounced heart rate reduction compared to IWI.Conclusions: The results of these studies indicate that individuals with LQTS have an aberrant cardiac response to activities that affects the ANS. After exercise and in response to water activities, the parasympathetic effect on both the heart rate and HRV appears depressed in LQTS patients. Additionally, during everyday activities, LQTS patients generally have lower HRV values at higher heart rates compared to controls. These findings suggest that both branches of the ANS might be involved in arrhythmogenesis in this patient group, and that an increased understanding of the ANS role could improve patient management and treatment. The results from the ice-water study indicate that the ventricular arrhythmia risk is likely higher during whole-body submersion with apnea. The absence of arrhythmias in beta-blocked LQT1 patients indicates effective protection by their current treatment.
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| 14. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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| 15. |
- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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