| 1. |
- Baturova, Maria A., et al.
(författare)
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Usefulness of Electrocardiographic Left Atrial Abnormality to Predict Response to Cardiac Resynchronization Therapy in Patients With Mild Heart Failure and Left Bundle Branch Block (a Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy Substudy)
- 2018
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 122:2, s. 268-274
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac resynchronization therapy (CRT) has proven prognostic benefits in patients with heart failure (HF) with left bundle branch block (LBBB) QRS morphology. Electrocardiographic left atrial (LA) abnormality has been proposed as a noninvasive marker of atrial remodeling. We aimed to assess the impact of electrocardiographic LA abnormality for prognosis in patients with HF treated with CRT. Baseline resting 12-lead electrocardiograms recorded from 941 patients enrolled in the CRT arm of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy was processed automatically using Glasgow algorithm, which included automated assessment of P-wave terminal force in lead V1 (PTF-V1) as a marker of LA abnormality. A PTF-V1 of ≥0.04 mm⋅s was considered abnormal. The primary end point was HF event and/or death. Total mortality and appropriate defibrillator therapies were the secondary end points. At baseline 550, patients treated with CRT with a defibrillator had LBBB QRS morphology and normal PTF-V1. Normal PTF-V1 was associated with significant risk reduction for all assessed end points and for the primary end point comprised a hazard ratio of 0.55 (95% confidence interval 0.36 to 0.84) compared with patients with LBBB with abnormal PTF-V1 (n = 120), and a hazard ratio of 0.42 (95% confidence interval 0.32 to 0.55) compared with patients with implanted defibrillator (n = 729). In CRT-treated patients with HF, electrocardiographic LA abnormality appears to be an electrocardiographic indicator of poor long-term outcome in patients with LBBB. In conclusion, our data suggest that PTF-V1 bears additive prognostic information in the context of CRT, thus further strengthening the role of electrocardiographic diagnostics in risk stratification of patients with HF.
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| 2. |
- Cortez, Daniel, et al.
(författare)
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Quantitative T-wave morphology assessment from surface ECG is linked with cardiac events risk in genotype-positive KCNH2 mutation carriers with normal QTc values
- 2019
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Ingår i: Journal of Cardiovascular Electrophysiology. - : Wiley. - 1045-3873 .- 1540-8167. ; 30:12, s. 2907-2913
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Long QT syndrome (LQTS) mutation carriers have elevated the risk of cardiac events even in the absence of QTc prolongation; however, mutation penetrance in patients with normal QTc may be reflected in abnormal T-wave shape, particularly in KCNH2 mutation carriers. We aimed to assess whether the magnitude of a three-dimensional T-wave vector (TwVM) will identify KCNH2-mutation carriers with normal QTc at risk for cardiac events. Methods: Adult LQT2 patients with QTc < 460 ms in men and <470 ms in women (n = 113, age 42 ± 16 years, 43% male) were compared with genotype-negative family members (n = 1007). The TwVM was calculated using T-wave amplitudes in leads V6, II, and V2 as the square root of (TV62 + TII2 + (0.5*TV2)2). Cox regression analysis adjusted for gender and time-dependent beta-blocker use was performed to assess cardiac event (CE) risk, defined as syncope, aborted cardiac arrest, implantable cardioverter-defibrillator therapy, or sudden death. Results: Dichotomized by median of 0.30 mV, lower TwVM was associated with elevated CE risk compared to those with high TwVM (HR = 2.95, 95% CI, 1.25-6.98, P =.014) and also remained significant after including sex and time-dependent beta-blocker usage in the Cox regression analysis (HR = 2.64, 95% CI, 1.64-4.24, P <.001). However, these associations were found only in women but not in men who had low event rates. Conclusion: T-wave morphology quantified as repolarization vector magnitude using T-wave amplitudes retrieved from standard 12-lead electrocardiogram predicts cardiac events risk in LQT2 women and appears useful for risk stratification of KCNH2-mutation carriers without QTc prolongation.
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| 3. |
- Mann, Stefan A., et al.
(författare)
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Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes
- 2016
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Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 100, s. 25-34
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Tidskriftsartikel (refereegranskat)abstract
- In-silico models of human cardiac electrophysiology are now being considered for prediction of cardiotoxicity as part of the preclinical assessment phase of all new drugs. We ask the question whether any of the available models are actually fit for this purpose. We tested three models of the human ventricular action potential, the O'hara-Rudy (ORD11), the Grandi-Bers (GB10) and the Ten Tusscher (TT06) models. We extracted clinical QT data for LQTS1 and LQTS2 patients with nonsense mutations that would be predicted to cause 50% loss of function in I-Ks and I-Kr respectively. We also obtained clinical QT data for LQTS3 patients. We then used a global optimization approach to improve the existing in silico models so that they reproduced all three clinical data sets more closely. We also examined the effects of adrenergic stimulation in the different LQTS subsets. All models, in their original form, produce markedly different and unrealistic predictions of QT prolongation for LQTS1, 2 and 3. After global optimization of the maximum conductances for membrane channels, all models have similar current densities during the action potential, despite differences in kinetic properties of the channels in the different models, and more closely reproduce the prolongation of repolarization seen in all LQTS subtypes. In-silico models of cardiac electrophysiology have the potential to be tremendously useful in complementing traditional preclinical drug testing studies. However, our results demonstrate they should be carefully validated and optimized to clinical data before they can be used for this purpose.
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| 4. |
- Platonov, Pyotr G., et al.
(författare)
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Atrial Fibrillation in Long QT Syndrome by Genotype
- 2019
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Ingår i: Circulation: Arrhythmia and Electrophysiology. - 1941-3084. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Long QT syndrome (LQTS) is caused by the abnormal function of ion channels, which may also affect atrial electrophysiology and be associated with the risk of atrial fibrillation (AF). However, large-scale studies of AF risk among patients with LQTS and its relation to LQTS manifestations are lacking. We aimed to assess the risk of AF and its relationship to the LQTS genotype and the long-term prognosis in patients with LQTS. METHODS: Genotype-positive patients with LQTS (784 LQT1, 746 LQT2, and 233 LQT3) were compared with 2043 genotype-negative family members. Information on the occurrence of AF was based on physician-reported ECG-verified events. Multivariate Cox proportional hazards regression analyses were performed for ages 0 to 60 and after 60 years (reflecting an early and late-onset of AF) to assess the risk of incident AF by genotype and the relationship of AF to the risk of cardiac events defined as syncope, documented torsades de pointes, and aborted cardiac arrest or sudden cardiac death. RESULTS: In patients followed from birth to 60 years of age, patients with LQT3 had an increased risk of AF compared with genotype-negative family members (hazard ratio=6.62; 95% CI, 2.04-21.49; P<0.001), while neither LQT1 nor LQT2 demonstrated increased AF risk. After the age of 60 years, patients with LQT2 had significantly lower risk of AF compared with genotype-negative controls (hazard ratio=0.07; 95% CI, 0.01-0.53, P=0.011). AF was a significant predictor of cardiac events in patients with LQT3 through the age of 60 (hazard ratio=5.38; 95% CI, 1.17-24.82; P=0.031). CONCLUSIONS: Our data demonstrate an increased risk of early age AF in patients with LQT3 and also indicate a protective effect of the LQT2 genotype in it's association with a decreased risk of AF after the age of 60.
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| 5. |
- Platonov, Pyotr G., et al.
(författare)
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Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers with Normal QTc Interval : The Value of Sex, T-Wave Morphology, and Mutation Type
- 2018
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Ingår i: Circulation: Arrhythmia and Electrophysiology. - 1941-3149. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. Methods: LQT2 mutation carriers with QTc <460 ms in men and <470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of KCNH2, and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy, or sudden cardiac death. Sex-specific associations were estimated using interactions terms. Results: LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared with LQT2 female carriers with normal T waves (hazard ratio, 3.31; 95% confidence interval, 1.68-6.52; P=0.001), whereas this association was not significant in men. LQT2 men with pore location of mutations have significantly higher risk of cardiac events than those with nonpore mutations (hazard ratio, 6.01; 95% confidence interval, 1.50-24.08; P=0.011), whereas no such association was found in women. Conclusions: The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T-wave morphology in women and pore location of mutation in men. The findings further indicate sex-specific differences in phenotype and genotype relationship in LQT2 patients.
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| 6. |
- Svensson, Anneli, 1972-, et al.
(författare)
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Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers
- 2021
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Ingår i: Cardiology. - : S. Karger. - 0008-6312 .- 1421-9751. ; 146:6, s. 763-771
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2).METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed.RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731).CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.
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