Delayed conduction and its implications in murine Scn5a+/− hearts: independent and interacting effects of genotype, age, and sex

We explored for relationships between SCN5A haploinsufficiency, implicated in clinical arrhythmogenicity, and right ventricular (RV) conduction disorders in Langendorff-perfused, male and female, and young (3 months) and old (>12 month old) Scn5a+/− and wild type (WT) hearts. The investigated conditions of genotype, age, and sex affected latencies but not repolarization time courses of RV monophasic action potentials. This prompted examination of the patterns of RV epicardial activation, its dispersion, and their interrelationships as possible arrhythmic mechanisms using a 64-channel, multi-electrode array. Mean ventricular activation times (T*MEAN), spatial dispersions (D*S) between recording channels/cardiac cycle, and maximum activation times (T*MAX) representing the slowest possible conduction in any given heart were all higher in old male Scn5a+/− compared with young male and old female Scn5a+/− and old male WT. Temporal dispersions (D*T) of recording channels were similarly higher in old male Scn5a+/− compared with old male WT. All groupings of D*T, D*S, and T*MAX nevertheless linearly correlated with T*MEAN, with indistinguishable slopes. The variates explored thus influence D*T, D*S, and T*MAX through actions on T*MEAN. These findings in turn correlated with increased levels of fibrosis in young male, young female, and old male Scn5a+/− compared with the corresponding WTs. We thus demonstrate for the first time independent and interacting effects of genotype, age, and sex on epicardial conduction and its dispersions at least partially attributable to fibrotic change, resulting in the greatest effects in old male Scn5a+/− in an absence of alterations in repolarization time courses. This directly implicates altered depolarization in the clinical arrhythmogenicity associated with Scn5a+/−

Atrial arrhythmogenicity in aged Scn5a+/∆KPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/∆KPQ mice modeling long QT3 syndrome in relationship to cardiac Na+ channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/∆KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/ΔKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/ΔKPQ than young WT. These levels increased with age in WT but not Scn5a+/ΔKPQ. Both young and aged Scn5a+/ΔKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/ΔKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/ΔKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/ΔKPQ. Aged murine Scn5a+/ΔKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/ΔKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/ΔKPQ hearts

The survival time of chocolates on hospital wards:covert observational study

Objective To quantify the consumption of chocolates in a hospital ward environment. Design Multicentre, prospective, covert observational study. Setting Four wards at three hospitals (where the authors worked) within the United Kingdom. Participants Boxes of Quality Street (Nestlé) and Roses (Cadbury) on the ward and anyone eating these chocolates. Intervention Observers covertly placed two 350 g boxes of Quality Street and Roses chocolates on each ward (eight boxes were used in the study containing a total of 258 individual chocolates). These boxes were kept under continuous covert surveillance, with the time recorded when each chocolate was eaten. Main outcome measure Median survival time of a chocolate. Results 191 out of 258 (74%) chocolates were observed being eaten. The mean total observation period was 254 minutes (95% confidence interval 179 to 329). The median survival time of a chocolate was 51 minutes (39 to 63). The model of chocolate consumption was non-linear, with an initial rapid rate of consumption that slowed with time. An exponential decay model best fitted these findings (model R(2)=0.844, P<0.001), with a survival half life (time taken for 50% of the chocolates to be eaten) of 99 minutes. The mean time taken to open a box of chocolates from first appearance on the ward was 12 minutes (95% confidence interval 0 to 24). Quality Street chocolates survived longer than Roses chocolates (hazard ratio for survival of Roses v Quality Street 0.70, 95% confidence interval 0.53 to 0.93, P=0.014). The highest percentages of chocolates were consumed by healthcare assistants (28%) and nurses (28%), followed by doctors (15%). Conclusions From our observational study, chocolate survival in a hospital ward was relatively short, and was modelled well by an exponential decay model. Roses chocolates were preferentially consumed to Quality Street chocolates in a ward setting. Chocolates were consumed primarily by healthcare assistants and nurses, followed by doctors. Further practical studies are needed

The survival time of chocolates on hospital wards: covert observational study

Objective To quantify the consumption of chocolates in a hospital ward environment. Design Multicentre, prospective, covert observational study. Setting Four wards at three hospitals (where the authors worked) within the United Kingdom. Participants Boxes of Quality Street (Nestlé) and Roses (Cadbury) on the ward and anyone eating these chocolates. Intervention Observers covertly placed two 350 g boxes of Quality Street and Roses chocolates on each ward (eight boxes were used in the study containing a total of 258 individual chocolates). These boxes were kept under continuous covert surveillance, with the time recorded when each chocolate was eaten. Main outcome measure Median survival time of a chocolate. Results 191 out of 258 (74%) chocolates were observed being eaten. The mean total observation period was 254 minutes (95% confidence interval 179 to 329). The median survival time of a chocolate was 51 minutes (39 to 63). The model of chocolate consumption was non-linear, with an initial rapid rate of consumption that slowed with time. An exponential decay model best fitted these findings (model R(2)=0.844, P<0.001), with a survival half life (time taken for 50% of the chocolates to be eaten) of 99 minutes. The mean time taken to open a box of chocolates from first appearance on the ward was 12 minutes (95% confidence interval 0 to 24). Quality Street chocolates survived longer than Roses chocolates (hazard ratio for survival of Roses v Quality Street 0.70, 95% confidence interval 0.53 to 0.93, P=0.014). The highest percentages of chocolates were consumed by healthcare assistants (28%) and nurses (28%), followed by doctors (15%). Conclusions From our observational study, chocolate survival in a hospital ward was relatively short, and was modelled well by an exponential decay model. Roses chocolates were preferentially consumed to Quality Street chocolates in a ward setting. Chocolates were consumed primarily by healthcare assistants and nurses, followed by doctors. Further practical studies are needed

Very long-term survival and late sudden cardiac death in cardiac resynchronization therapy patients

International audienceAbstract Aims The very long-term outcome of patients who survive the first few years after receiving cardiac resynchronization therapy (CRT) has not been well described thus far. We aimed to provide long-term outcomes, especially with regard to the occurrence of sudden cardiac death (SCD), in CRT patients without (CRT-P) and with defibrillator (CRT-D). Methods and results A total of 1775 patients, with ischaemic or non-ischaemic dilated cardiomyopathy, who were alive 5 years after CRT implantation, were enrolled in this multicentre European observational cohort study. Overall long-term mortality rates and specific causes of death were assessed, with a focus on late SCD. Over a mean follow-up of 30 months (interquartile range 10–42 months) beyond the first 5 years, we observed 473 deaths. The annual age-standardized mortality rates of CRT-D and CRT-P patients were 40.4 [95% confidence interval (CI) 35.3–45.5] and 97.2 (95% CI 85.5–109.9) per 1000 patient-years, respectively. The adjusted hazard ratio (HR) for all-cause mortality was 0.99 (95% CI 0.79–1.22). Twenty-nine patients in total died of late SCD (14 with CRT-P, 15 with CRT-D), corresponding to 6.1% of all causes of death in both device groups. Specific annual SCD rates were 8.5 and 5.8 per 1000 patient-years in CRT-P and CRT-D patients, respectively, with no significant difference between groups (adjusted HR 1.0, 95% CI 0.45–2.44). Death due to progressive heart failure represented the principal cause of death (42.8% in CRT-P patients and 52.6% among CRT-D recipients), whereas approximately one-third of deaths in both device groups were due to non-cardiovascular death. Conclusion In this first description of very long-term outcomes among CRT recipients, progressive heart failure death still represented the most frequent cause of death in patients surviving the first 5 years after CRT implant. In contrast, SCD represents a very low proportion of late mortality irrespective of the presence of a defibrillator

The Importance of Mitral Valve Prolapse Doming Volume in the Assessment of Left Ventricular Stroke Volume with Cardiac MRI

There remains a debate whether the ventricular volume within prolapsing mitral valve (MV) leaflets should be included in the left ventricular (LV) end-systolic volume, and therefore factored in LV stroke volume (SV), in cardiac magnetic resonance (CMR) assessments. This study aims to compare LV volumes during end-systolic phases, with and without the inclusion of the volume of blood on the left atrial aspect of the atrioventricular groove but still within the MV prolapsing leaflets, against the reference LV SV by four-dimensional flow (4DF). A total of 15 patients with MV prolapse (MVP) were retrospectively enrolled in this study. We compared LV SV with (LV SVMVP) and without (LV SVstandard) MVP left ventricular doming volume, using 4D flow (LV SV4DF) as the reference value. Significant differences were observed when comparing LV SVstandard and LV SVMVP (p &lt; 0.001), and between LV SVstandard and LV SV4DF (p = 0.02). The Intraclass Correlation Coefficient (ICC) test demonstrated good repeatability between LV SVMVP and LV SV4DF (ICC = 0.86, p &lt; 0.001) but only moderate repeatability between LV SVstandard and LV SV4DF (ICC = 0.75, p &lt; 0.01). Calculating LV SV by including the MVP left ventricular doming volume has a higher consistency with LV SV derived from the 4DF assessment. In conclusion, LV SV short-axis cine assessment incorporating MVP dooming volume can significantly improve the precision of LV SV assessment compared to the reference 4DF method. Hence, in cases with bi-leaflet MVP, we recommend factoring in MVP dooming into the left ventricular end-systolic volume to improve the accuracy and precision of quantifying mitral regurgitation

Long-Term Impact of Body Mass Index on Survival of Patients Undergoing Cardiac Resynchronization Therapy: A Multi-Centre Study

Obesity is a risk factor for heart failure (HF), but its presence among HF patients may be associated with favorable outcomes. We investigated the long-term outcomes across different body mass index (BMI) groups, after cardiac resynchronization therapy (CRT), and whether defibrillator back-up (CRT-D) confers survival benefit. One thousand two-hundred seventy-seven (1,277) consecutive patients (mean age: 67.0 +/- 12.7 years, 44.1% women, and mean BMI: 28.3 +/- 5.6 Kg/m(2)) who underwent CRT implantation in 5 centers between 2000-2014 were followed-up for a median period of 4.9 years (IQR 2.4 to 7.5). More than 10% of patients had follow-up for &gt;10 years. Patients were classified according to BMI as normal: &lt;25.0 Kg/m(2), overweight: 25.0 to 29.9 Kg/m(2) and obese: &gt;= 30.0 Kg/m(2). 364 patients had normal weight, 494 were overweight and 419 were obese. CRT-Ds were implanted in &gt;75% of patients, but were used less frequently in obese individuals. The composite endpoint of all-cause mortality or cardiac transplant/left ventricular assist device (LVAD) occurred in 50.9% of patients. At 10-year follow-up, less than a quarter of patients in the lowest and highest BMI categories were still alive and free from heart transplant/LVAD. After adjustment BMI of 25 to 29.9 Kg/m(2) (HR = 0.73 [95%CI 0.56 to 0.96], p = 0.023) and use of CRT-D (HR = 0.74 [95% CI 0.55 to 0.98], p = 0.039) were independent predictors of survival free from LVAD/heart transplant. BMI of 25 to 29.9 Kg/m(2) at the time of implant was independently associated with favourable long-term 10-year survival. Use of CRT-D was associated with improved survival irrespective of BMI class. (C) 2021 Elsevier Inc. All rights reserved

Adding Defibrillation Therapy to Cardiac Resynchronization on the Basis of the Myocardial Substrate

International audienceBackground: Patients with nonischemic dilated cardiomyopathy (DCM) may be at lower risk for ventricular arrhythmias compared with those with ischemic cardiomyopathy (ICM). In addition, DCM has been identified as a predictor of positive response to cardiac resynchronization therapy (CRT).Objectives: The aim of this study was to investigate the impact of an additional implantable cardioverter-defibrillator over CRT, according to underlying heart disease, in a large study group of primary prevention patients with heart failure.Methods: This was an observational, multicenter, European cohort study of 5,307 consecutive patients with DCM or ICM, no history of sustained ventricular arrhythmias, who underwent CRT implantation with (n = 4,037) or without (n = 1,270) a defibrillator. Propensity-score and cause-of-death analyses were used to compare outcomes.Results: After a mean follow-up period of 41.4 ± 29.0 months, patients with ICM had better survival when receiving CRT with a defibrillator compared with those who received CRT without a defibrillator (hazard ratio for mortality adjusted on propensity score and all mortality predictors: 0.76; 95% confidence interval [CI]: 0.62 to 0.92; p = 0.005), whereas in patients with DCM, no such difference was observed (hazard ratio: 0.92; 95% CI: 0.73 to 1.16; p = 0.49). Compared with recipients of defibrillators, the excess mortality in patients who did not receive defibrillators was related to sudden cardiac death in 8.0% among those with ICM but in only 0.4% of those with DCM.Conclusions: Among patients with heart failure with indications for CRT, those with DCM may not benefit from additional primary prevention implantable cardioverter-defibrillator therapy, as opposed to those with ICM