Bert Vandenberk

Which QT Correction Formulae to Use for QT Monitoring

Background Drug safety precautions recommend monitoring of the corrected QT interval. To determine which QT correction formula to use in an automated QT‐monitoring algorithm in our electronic medical record, we studied rate correction performance of different QT correction formulae and their impact on risk assessment for mortality. Methods and Results All electrocardiograms (ECGs) in patients >18 years with sinus rhythm, normal QRS duration and rate <90 beats per minute (bpm) in the University Hospitals of Leuven (Leuven, Belgium) during a 2‐month period were included. QT correction was performed with Bazett, Fridericia, Framingham, Hodges, and Rautaharju formulae. In total, 6609 patients were included (age, 59.8±16.2 years; 53.6% male and heart rate 68.8±10.6 bpm). Optimal rate correction was observed using Fridericia and Framingham; Bazett performed worst. A healthy subset showed 99% upper limits of normal for Bazett above current clinical standards: men 472 ms (95% CI, 464–478 ms) and women 482 ms (95% CI 474–490 ms). Multivariate Cox regression, including age, heart rate, and prolonged QTc, identified Framingham (hazard ratio [HR], 7.31; 95% CI, 4.10–13.05) and Fridericia (HR, 5.95; 95% CI, 3.34–10.60) as significantly better predictors of 30‐day all‐cause mortality than Bazett (HR, 4.49; 95% CI, 2.31–8.74). In a point‐prevalence study with haloperidol, the number of patients classified to be at risk for possibly harmful QT prolongation could be reduced by 50% using optimal QT rate correction. Conclusions Fridericia and Framingham correction formulae showed the best rate correction and significantly improved prediction of 30‐day and 1‐year mortality. With current clinical standards, Bazett overestimated the number of patients with potential dangerous QTc prolongation, which could lead to unnecessary safety measurements as withholding the patient of first‐choice medication.

Changes in Implantation Patterns and Therapy Rates of Implantable Cardioverter Defibrillators over Time in Ischemic and Dilated Cardiomyopathy Patients.

Clinical guidelines on implantable cardioverter defibrillator (ICD) therapy changed significantly in the last decades with potential inherent effects on therapy efficacy. We aimed to study therapy rates in time and the association between therapies and mortality.

Inferior and anterior QRS fragmentation have different prognostic value in patients who received an implantable defibrillator in primary prevention of sudden cardiac death

AIMS QRS fragmentation (fQRS) has been proposed as a predictor of sudden cardiac death (SCD) and all-cause mortality in ischemic (ICM) and non-ischemic cardiomyopathy patients. However the value of fQRS in patients with a LVEF <35% is a matter of debate. METHODS All consecutive patients with an indication for an ICD in primary prevention of SCD were included in a retrospective registry from 1996 until 2013. Twelve lead electrocardiograms before implant were analyzed for the presence of fQRS in different regions. Adjusted Cox regression analysis for first appropriate ICD shock (AS) and all-cause mortality was performed. RESULTS In total 407 patients were included with a mean follow-up of 4.2±3.3y (age 60.6±11.9y, 15.7% female and 52.8% ICM). fQRS was present in 46.7% of patients, predominantly inferior (30.7%) followed by anterior (21.4%) and lateral (11.1%) coronary artery territories. fQRS was significantly more prevalent in ICM (p=0.004). Inferior fQRS was an independent predictor of a first AS within 1y (HR 2.55, 95%CI 1.28-5.07) and 3y (HR 1.90, 95%CI 1.14-3.18) after implantation. Whereas, anterior fQRS was an independent predictor of all-cause mortality within 1y (HR 4.58, 95%CI 1.29-16.19), 3y (HR 3.92, 95%CI 1.77-8.65) and the complete follow-up (HR 2.22, 95%CI 1.33-3.69). Lateral fQRS was only a predictor of late (>3y of follow-up) all-cause mortality (HR 2.04, 95%CI 1.09-3.81). CONCLUSIONS fQRS in a specific coronary artery territory might be promising to discriminate arrhythmic from mortality risk. Inferior fQRS was a predictor of early arrhythmia, while anterior fQRS was related to mortality.

Incidence of Torsade de Pointes in a tertiary hospital population

BACKGROUND Multiple risk factors play a role in the development of QTc-prolongation and Torsade de Pointes (TdP). Cases of TdP are underreported and data on the incidence of TdP is scarce. The aim of this study was to investigate the incidence of TdP in a Belgian university hospital and describe the characteristics of TdP-cases using a risk score. METHODS All cases from 2011 till 2013 coded with the ICD-9 code 427.1 in the University Hospitals of Leuven were selected. The medical files were reviewed and demographical, medical, medication and electrocardiographic data were collected. We focused on TdP-cases that were probably caused by the acquired long QT-syndrome. The RISQ-PATH score was used to quantify the risk in these cases (≥10 points as high risk for QTc-prolongation/TdP). RESULTS Over three years, 41 TdP-cases were identified of which 19 cases were secondary to the acquired long QT-syndrome (52.6% females, mean age of 74±12years). This corresponds with an incidence of 0.16‰/year in a hospital population. Most of the patients (N=17) were treated with at least one QTc-prolonging drug (most frequently amiodarone, sotalol and furosemide) of whom 12 patients with ≥1 QTc-prolonging drug of list 1 of CredibleMeds. Fifteen patients had an electrocardiogram in a 24-hours interval before the TdP with a prolonged QTc-interval (≥450/470ms). All the patients had a RISQ-PATH score≥10. CONCLUSIONS Although the incidence of 0.16‰/year might seem low, this means that approximately 173 possibly lethal TdP-cases can be expected in Belgian hospitals each year. All TdP-cases were associated with a high RISQ-PATH score.

Individualized corrected QT interval is superior to QT interval corrected using the Bazett formula in predicting mutation carriage in families with long QT syndrome

BACKGROUND Long QT syndrome (LQTS) is characterized by reduced penetrance and variable QT prolongation over time, resulting in an estimate of 25% carriers of a pathogenic mutation with a normal corrected QT (QTc) interval on the resting electrocardiogram (ECG). OBJECTIVE The purpose of this study was to test the hypothesis that an individualized corrected QT interval derived from 24-hour Holter data more accurately predicts carriage of a pathogenic LQTS mutation than did QT derived from a standard 12-lead ECG and corrected using the Bazett formula (QTc interval). METHODS Carriers of a pathogenic LQTS mutation and their genotype-negative family members who had both resting ECG and Holter recordings available were included. Automated and manual measurements of QTc were performed. QTi was derived from 24-hour Holter recordings and defined as the QT value at the intersection of an RR interval of 1000 ms, with the linear regression line fitted through QT-RR data points of each individual patient. RESULTS In total, 69 patients with LQTS (23 long QT type 1, 39 long QT type 2, and 7 long QT type 3) and 55 controls were selected. Demographic characteristics were comparable. A comparison of the receiver operating characteristic curves indicates that the test added diagnostic value compared to manual measurement (P = .02) or automated measurement (P = .005). The diagnostic accuracy of manually measured QTc using conventional cutoff criteria was 72%, while it was 92% using a sex-independent QTi cutoff of 445 ms. This was caused by a 39% increase in sensitivity without compromising the specificity. CONCLUSION QTi derived from Holter recordings is superior to conventional QTc measured from a standard 12-lead ECG in predicting the mutation carrier state in families with LQTS.

Appearance of QRS fragmentation late after Mustard/Senning repair is associated with adverse outcome

Objective To evaluate if development of fragmented QRS (fQRS) complexes, a marker of inhomogeneous ventricular activation due to myocardial fibrosis, is associated with adverse outcome in adults after Mustard/Senning repair for d-transposition of the great arteries (d-TGA). Methods Adults with atrial switch repair for d-TGA were selected from the database of a tertiary care hospital. Exclusion criteria were systemic right ventricular (RV) assist device or heart transplantation (HTx) before the age of 16, or fQRS already present at first visit to the Adult Congenital Heart Disease clinic. A blinded expert reader retrospectively analysed all available ECGs after the age of 16 for the presence of fQRS. The appearance of fQRS was modelled for each patient as a time-dependent variable. Cox regression was performed to assess the relationship between covariates and the composite endpoint of cardiovascular mortality, HTx or systemic RV assist device. Results Records of 89 patients (34% female, 42% Mustard repair) were analysed. At latest follow-up, fQRS was noted in 26 patients (29%). Over a median follow-up time of 16.9 (IQR 12.6–22.9) years, the composite endpoint occurred in nine patients (10%). In multivariable Cox analysis, appearance of fQRS (HR 14.11; 95% CI 1.42 to 140.12) and development of severe RV dysfunction (HR 11.36; 95% CI 2.08 to 62.17) were significantly associated with the composite endpoint. Conclusions Appearance of fQRS complexes on a 12-lead ECG is associated with adverse outcome in adults after atrial switch repair for d-TGA. In this population, fQRS detection might be a promising and easily implementable tool to identify patients at risk for adverse events.

Cases of drug-induced Torsade de Pointes: a review of Belgian cases in the EudraVigilance database

Objectives: Post-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database. Methods: The EudraVigilance database was searched for Belgian post-marketing cases of TdP reported between December 2001–April 2015. These cases were identified with MedDRA preferred terms. Duplicate reports were excluded. Each included case report was reviewed to collect data about age, gender, seriousness, suspected drug, concomitant drugs, causality, and other known risk factors for QTc-prolongation. Results: Between 2001 and 2015, only 31 cases coded as TdP were identified; 16 cases were also coded as ‘prolonged QT’ and 2 patients died. In total, 21 suspected drugs were implicated and most of them (N = 11) were part of list 1 of CredibleMeds. The most common suspected drugs were citalopram (N = 4) and amiodarone (N = 3). In 18 cases, a pharmacodynamic drug-drug interaction with risk of QTc-prolongation was present. Most patients (N = 25) had ≥2 other risk factors for QTc-prolongation. Conclusion: Over 15 years, only a low number of Belgian cases of TdP were identified in the EudraVigilance database. In most case reports, multiple risk factors for QTc-prolongation could be detected. This illustrates that there is a clear underreporting of QTc-prolongation and TdP in Belgium. Initiatives are needed to improve the awareness and knowledge of health care professionals regarding the risk of QTc-prolongation and TdP, both to prevent cases of TdP and to stimulate the reporting of these cases.

Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy

BACKGROUND AND OBJECTIVE We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS For 672 enrolled patients, we collected history, LVEF, EP study and T-wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS The 635 patients included in the final analyses were 63 ± 13 years old, 81% were male, LVEF averaged 40 ± 14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 ± 1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks.

Sex differences in outcomes of primary prevention implantable cardioverter-defibrillator therapy: combined registry data from eleven European countries

Abstract Aims Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials. Methods and results Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16–55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47–0.79; P = 0.0002). Conclusion Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons

Abstract Aims In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM). Methods and results Single LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation–contraction coupling. Conclusions In HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.