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Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

ABSTRACT: The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes.Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis.The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494.

SUBMITTER: Seegers J

PROVIDER: S-EPMC3283222 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

Seegers Joachim J Vos Marc A MA Flevari Panagiota P Willems Rik R Sohns Christian C Vollmann Dirk D Lüthje Lars L Kremastinos Dimitrios T DT Floré Vincent V Meine Mathias M Tuinenburg Anton A Myles Rachel C RC Simon Dirk D Brockmöller Jürgen J Friede Tim T Hasenfuß Gerd G Lehnart Stephan E SE Zabel Markus M

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 20111123 3

<h4>Aims</h4>The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes ...[more]

PMID: 22117037

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Project description:IntroductionThe purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter defibrillator for primary prevention indication.Methods and analysisMulticentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained.Ethics and disseminationEthical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries.Trial registration numberNCT03022487.

Project description:BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. METHODS: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). RESULTS: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced “late” cardiac sodium current (INa), which were entirely corrected by editing G145R to wildtype. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A downregulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis and increased arrhythmia risk with disruption of PDGF sigaling were both conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P

Project description:Background: The relationship between thyroid function and cardiac disease is complex. Both hypothyroidism and thyrotoxicosis can predispose to ventricular arrhythmia and other major adverse cardiovascular events (MACE), so that a U-shaped relationship between thyroid signaling and the incidence of MACE has been postulated. Moreover, recently published data suggest an association between thyroid hormone concentration and the risk of sudden cardiac death (SCD) even in euthyroid populations with high-normal FT4 levels. In this study, we investigated markers of repolarization in ECGs, as predictors of cardiovascular events, in patients with a spectrum of subclinical and overt thyroid dysfunction. Methods: Resting ECGs of 100 subjects, 90 patients (LV-EF > 45%) with thyroid disease (60 overt hyperthyroid, 11 overt hypothyroid and 19 L-T4-treated and biochemically euthyroid patients after thyroidectomy or with autoimmune thyroiditis) and 10 healthy volunteers were analyzed for Tp-e interval. The Tp-e interval was measured manually and was correlated to serum concentrations of thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and thyroxine (FT4). Results: The Tp-e interval significantly correlated to log-transformed concentrations of TSH (Spearman's rho = 0.30, p < 0.01), FT4 (rho = -0.26, p < 0.05), and FT3 (rho = -0.23, p < 0.05) as well as log-transformed thyroid's secretory capacity (SPINA-GT, rho = -0.33, p < 0.01). Spearman's rho of correlations of JT interval to log-transformed TSH, FT4, FT3, and SPINA-GT were 0.51 (p < 1e-7), -0.45 (p < 1e-5), -0.55 (p < 1e-8), and -0.43 (p < 1e-4), respectively. In minimal multivariable regression models, markers of thyroid homeostasis correlated to heart rate, QT, Tp-e, and JT intervals. Group-wise evaluation in hypothyroid, euthyroid and hyperthyroid subjects revealed similar correlations in all three groups. Conclusion: We observed significant inverse correlations of Tp-e and JT intervals with FT4 and FT3 over the whole spectrum of thyroid function. Our data suggest a possible mechanism of SCD in hypothyroid state by prolongation of repolarization. We do not observe a U-shaped relationship, so that the mechanism of SCD in patients with high FT4 or hyperthyroidism seems not to be driven by abnormalities in repolarization.

Project description:Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca(2+) transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 ?m(2)) or low (1.5 × 1.5 cm(2)) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant ?f?s = 48 ± 9.2 s) and caused a secondary Ca(2+) release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca(2+) transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca(2+) release events leading to subcellular Ca(2+) waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P < 0.01, n = 5), enhanced DOR (r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 ?M), suppressed SCR and reduced APD at the base, thereby reducing DOR (P < 0.02, n = 5). Ventricular ectopy induced by bradycardia (n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca(2+) channel protein (Cav1.2?), Na(+)-Ca(2+) exchange (NCX1), voltage-gated Na(+) channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca(2+) ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.

Project description:It is estimated that seniors (?65 years old) account for >50% of acute inpatient hospital days and are presenting for surgical evaluation of acute illness in increasing numbers. Unfortunately, conventional acute care models rarely take into account needs of the elderly population. The failure to consider these special needs have resulted in poor outcomes, longer lengths of hospital stay and have likely increased the need for institutional care. Acute Care for the Elderly models on medical wards have demonstrated decreased cost, length of hospital stay, readmissions and improved cognition, function and patient/staff satisfaction. We hypothesize that specific Elder-friendly Approaches to the Surgical Environment (EASE) interventions will similarly improve health outcomes in a cost-effective manner.Prospective, before-after study with a concurrent control group. Four cohorts of 140 consecutively-screened older patients (?65 years old) will be enrolled (560 patients in total). The EASE interventions involves co-locating all older surgical patients on a single unit, involving an interdisciplinary care team (including a geriatric specialist) in the development of individual care plans, implementing evidence-informed elder-friendly practices, use of a reconditioning program, and optimizing discharge planning. Subjects will be followed via chart review for their hospital stay, and will then complete in-person or telephone interviews at 6 weeks and 6 months after discharge. Measured outcomes include clinical (postoperative major in-hospital complication or death [primary composite outcome]; death or readmission within 30-days of initial discharge; length of hospital stay), humanistic (quality of life; functional, cognitive, and nutritional status) and economic (health care resource utilization and costs) endpoints. Within-site mean change scores will be computed for the composite primary outcome and the overall covariate-adjusted between-site pre-post difference will be the dependent variable analyzed using generalized linear mixed model procedures including adjustment for clustering.Our findings will generate new knowledge on outcomes from acute surgical care in older patients and validate a novel elder-friendly surgical model including assessment of both clinical and economic benefits. If effective, we expect the EASE initiatives to be generalizable to other surgical centres.Clinicaltrials.govidentifier: NCT02233153.

Dataset Information

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

Publications

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

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