Andrew A. Grace

The accuracy of central SBP determined from the second systolic peak of the peripheral pressure waveform.

Background Recent evidence suggests that central aortic blood pressure may be a better predictor of cardiovascular risk than peripheral blood pressure. The central SBP (cSBP) can be estimated from the late systolic shoulder of the radial pulse waveform. We compared the second systolic peak of the radial waveform (pSBP2) with the central systolic pressure derived by a generalized transfer function in a large cohort, across a wide age range, of patients from the Anglo-Cardiff Collaborative Trial. We also compared pSBP2 with the true cSBP measured by cardiac catheterization [invasively measured cSBP (cSBPi)]. Methods Noninvasive measurements were made by applanation tonometry using the SphygmoCor device. The aortic pressure waveform was derived from the radial waveform using a validated transfer function. Invasive measures of cSBPi were carried out in a group of 38 patients undergoing diagnostic cardiac angiography, and radial artery pressure waveforms were simultaneously recorded using the SphygmoCor device. Results Overall, there was a strong correlation (r = 0.99, P < 0.001) and good agreement between pSBP2 and the derived cSBP (mean difference ± SD 1 ± 4 mmHg). However, there was a systematic bias with a greater difference between these measures at lower average pressures. There was also a strong correlation and good agreement between the invasively measured cSBPi and pSBP2 (r = 0.92, P < 0.001, mean difference 2 ± 6 mmHg). Conclusion The second systolic shoulder of the peripheral pressure waveform approximates the cSBP in a large cohort of patients across a wide age range, but this may be inaccurate at low SBP values.

The learning curve associated with the introduction of the subcutaneous implantable defibrillator

Abstract Aims The subcutaneous implantable cardioverter defibrillator (S-ICD) was introduced to overcome complications related to transvenous leads. Adoption of the S-ICD requires implanters to learn a new implantation technique. The aim of this study was to assess the learning curve for S-ICD implanters with respect to implant-related complications, procedure time, and inappropriate shocks (IASs). Methods and results In a pooled cohort from two clinical S-ICD databases, the IDE Trial and the EFFORTLESS Registry, complications, IASs at 180 days follow-up and implant procedure duration were assessed. Patients were grouped in quartiles based on experience of the implanter and Kaplan–Meier estimates of complication and IAS rates were calculated. A total of 882 patients implanted in 61 centres by 107 implanters with a median of 4 implants (IQR 1,8) were analysed. There were a total of 59 patients with complications and 48 patients with IAS. The complication rate decreased significantly from 9.8% in Quartile 1 (least experience) to 5.4% in Quartile 4 (most experience) (P = 0.02) and non-significantly for IAS from 7.9 to 4.8% (P = 0.10). Multivariable analysis demonstrated a hazard ratio of 0.78 (P = 0.045) for complications and 1.01 (P = 0.958) for IAS. Dual-zone programming increased with experience of the individual implanter (P < 0.001), which reduced IAS significantly in the multivariable model (HR 0.44, P = 0.01). Procedure time decreased from 75 to 65 min (P < 0.001). The complication rate and procedure time stabilized after Quartile 2 (>13 implants). Conclusion There is a short and significant learning curve associated with physicians adopting the S-ICD. Performance stabilizes after 13 implants.

Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine RyR2-P2328S hearts.

RyR2 mutations are associated with catecholaminergic polymorphic tachycardia, a condition characterized by ventricular and atrial arrhythmias. The present experiments investigate the atrial electrophysiology of homozygotic murine RyR2‐P2328S (RyR2S/S) hearts for ectopic triggering events and for conduction abnormalities that might provide a re‐entrant substrate.

Loss of Nav1.5 expression and function in murine atria containing the RyR2-P2328S gain-of-function mutation.

AIMS Recent studies reported slowed conduction velocity (CV) in murine hearts homozygous for the gain-of-function RyR2-P2328S mutation (RyR2(S/S)) and associated this with an increased incidence of atrial and ventricular arrhythmias. The present experiments determined mechanisms contributing to the reduced atrial CV. METHODS AND RESULTS The determinants of CV were investigated in murine RyR2(S/S) hearts and compared with those in wild-type (WT) and slow-conducting Scn5a(+/-) hearts. Picrosirius red staining demonstrated increased fibrosis only in Scn5a(+/-) hearts. Immunoblot assays showed similar expressions of Cx43 and Cx40 levels in the three genotypes. In contrast, Nav1.5 expression was reduced in both RyR2(S/S) and Scn5a(+/-) atria. These findings correlated with intracellular microelectrode and loose-patch-clamp studies. Microelectrode measurements showed reduced maximum rates of depolarization in Scn5a(+/-) and RyR2(S/S) atria compared with WT, despite similar diastolic membrane potentials. Loose-patch-clamp measurements demonstrated reduced peak Na(+) currents (INa) in the Scn5a(+/-) and RyR2(S/S) atria relative to WT, with similar normalized current-voltage relationships. In WT atria, reduction in INa could be produced by treatment with high extracellular Ca(2+), caffeine, or cyclopiazonic acid, each expected to produce an acute increase in [Ca(2+)]i. CONCLUSION RyR2(S/S) atria show reduced levels of Nav1.5 expression and Na(+) channel function. Reduced Na(+) channel function was also observed in WT atria, following acute increases in [Ca(2+)]i. Taken together, the results suggest that raised [Ca(2+)]i produces both acute and chronic inhibition of Na(+) channel function. These findings may help explain the relationship between altered Ca(2+) homeostasis, CV, and the maintenance of common arrhythmias such as atrial fibrillation.

Conduction Slowing Contributes to Spontaneous Ventricular Arrhythmias in Intrinsically Active Murine RyR2-P2328S Hearts

Conduction Changes in RyR2‐P2328S Hearts. Introduction: The familial condition catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic bidirectional ventricular tachycardia (BVT), polymorphic ventricular tachycardia (PVT), and ventricular fibrillation following adrenergic challenge. It is associated with mutations involving the cardiac ryanodine receptor (RyR2).

Systems biology and cardiac arrhythmias

During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell-based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence.

Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a+/- hearts: the effects of ageing and sex.

Highlights ► Scn5a+/− hearts showed an electrocardiographic bundle branch block. ► Epicardial activation analysis demonstrated increased late conducting components. ► This paralleled a myocardial regional fibrosis preferentially involving the RV. ► Such changes were greatest in ageing and male Scn5a+/− hearts. ► We propose a fibrotic mechanism slowing impulse conduction in ageing Scn5a+/− hearts.

Cardiac resynchronisation therapy: pacemaker versus internal cardioverter-defibrillator in patients with impaired left ventricular function

Objective Studies have shown beneficial effects of cardiac resynchronisation therapy (CRT) on mortality among patients with heart failure. However the incremental benefits in survival from CRT with a defibrillator (CRT-D) are unclear. The choice of appropriate device remains unanswered. Method This is a single-centre observational study in a tertiary cardiac centre. Patients (n=500) implanted with a CRT device with pacing alone (CRT-P) (n=354) and CRT-D (n=146) were followed for at least 2 years (mean 29 months, SD 14 months). The primary end point was all-cause mortality. Results A total of 116 deaths (23.2%) were recorded: 88 (24.8%) and 28 (19.2%), in the CRT-P and CRT-D groups, respectively. At 1 year there was a trend favouring CRT-D (HR 0.54, 95% CI 0.27 to 1.07, p=0.08) but this was attenuated by the 2nd year and became insignificant at the end of follow-up (HR 0.76, 95% CI 0.50 to 1.170, p=0.21). There was no survival benefit from having an internal cardioverter-defibrillator if patients were deemed non-responders to CRT. 27% of the CRT-P patients with ischaemic cardiomyopathy met indications for potential internal cardioverter-defibrillator implantation for primary prevention. These were older patients with poorer baseline function in comparison with CRT-D patients with devices for primary prevention. Once these differences were adjusted for, there was no difference in outcome between the groups. Conclusions CRT-D did not offer additional survival advantage over CRT-P at longer-term follow-up, as the clinical benefit of a defibrillator attenuated with time. Further work is needed to define which subset of patients benefit from CRT-D.

Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a+/− hearts

•  Mice which are haploinsufficient in the Scn5a+/− gene have reduced cardiac sodium channel (Nav1.5) density and are used to model the Brugada syndrome. •  Conduction velocity restitution showed lower initial values and earlier points of failure during incremental pacing in the murine Scn5a+/− right ventricle (RV) epicardium particularly when treated with flecainide. •  The broadness of the conduction velocity restitution function was a poor indicator of arrhythmia or alternans. Conduction velocity alternans occurred abruptly and was more marked in the flecainide‐treated Scn5a+/− RV epicardium. •  Introduction of wavelength restitution yielded functions that converged to a common instability condition in contrast to action potential duration (APD) or conduction velocity restitution. •  This occurred at significantly lower heart rates in Scn5a+/− RV epicardium following flecainide or quinidine challenge, corresponding to a smaller total wavelength (basic cycle distance) resulting from a reduction in conduction velocity. •  Wavelength restitution was superior at predicting alternans than either APD or conduction velocity restitution.

Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis.

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage‐gated, sodium (Na+) channel α‐subunits (Nav1.5). We summarize experimental studies of physiological and clinical consequences of loss‐of‐function Na+ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a+/− hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav1.5 haploinsufficient males in producing clinical arrhythmia.