Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.

Local impedance-guided ablation and ultra-high density mapping versus conventional or contact force-guided ablation with mapping for treatment of cavotricuspid isthmus dependent atrial flutter.

INTRODUCTION: - Local impedance (LI) guided ablation as a method of judging lesion effectiveness for cavotricuspid isthmus dependent atrial flutter (CTI-AFL), and ultra-high density (UHD) mapping when breakthrough occurred across an ablation line has not previously been assessed. METHODS: This retrospective observational study evaluated patients undergoing CTI-AFL ablation using conventional, contact force (CF) and LI guided strategies. Ablation metrics were collected, and in the LI cohort, the use of UHD mapping for breakthrough evaluated. RESULTS: 30 patients were included, 10 per group. Mean total ablation time was significantly shorter with LI (3.2 ± 1.3min) vs conventional (5.6 ± 2.7min) and CF (5.7 ± 2.0min, p = 0.0042). Time from start of ablation to CTI block was numerically shorter with LI (14.2 ± 8.0min) vs conventional and CF (19.7 ± 14.1 and 22.5 ± 19.1min, p = 0.4408). Mean lesion duration was significantly shorter with LI, but there were no differences in the number of lesions required to achieve block, procedural success, complication rates or recurrence. 15/30 patients did not achieve block following first-pass ablation. UHD mapping rapidly identified breakthrough in the five LI patients, including epicardial-endocardial breakthrough (EEB). CONCLUSION: - The use of LI during ablation for real-time lesion assessment was as efficacious as the conventional and CF methods. UHD mapping rapidly identified breakthrough, including EEB.

Structural and Functional Properties of Subsidiary Atrial Pacemakers in a Goat Model of Sinus Node Disease.

BACKGROUND: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases. METHODS: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques. RESULTS: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT). CONCLUSIONS: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker.

Does rhythm matter in acute heart failure? An insight from the British Society for Heart Failure National Audit.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with acute heart failure (AHF). The presence of AF is associated with adverse prognosis in patients with chronic heart failure (CHF) but little is known about its impact in AHF. METHODS: Data were collected between April 2007 and March 2013 across 185 (> 95%) hospitals in England and Wales from patients with a primary death or a discharge diagnosis of AHF. We investigated the association between the presence of AF and all-cause mortality during the index hospital admission, at 30 days and 1 year post-discharge. RESULTS: Of 96,593 patients admitted with AHF, 44,642 (46%) were in sinus rhythm (SR) and 51,951 (54%) in AF. Patients with AF were older (mean age 79.8 (79.7-80) versus 74.7 (74.5-74.7) years; p < 0.001), than those in SR. In a multivariable analysis, AF was independently associated with mortality at all time points, in hospital (HR 1.15, 95% CI 1.09-1.21, p < 0.0001), 30 days (HR 1.13, 95% CI 1.08-1.19, p < 0.0001), and 1 year (HR 1.09, 95% CI 1.05-1.12, p < 0.0001). In subgroup analyses, AF was independently associated with worse 30-day outcome irrespective of sex, ventricular phenotype and in all age groups except in those aged between 55 and 74 years. CONCLUSION: AF is independently associated with adverse prognosis in AHF during admission and up to 1 year post-discharge. As the clinical burden of concomitant AF and AHF increases, further refinement in the detection, treatment and prevention of AF-related complications may have a role in improving patient outcomes.

Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia-A simulation study.

Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.

Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide-gated and ryanodine 2 channels.

BACKGROUND: Aging is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. OBJECTIVE: The aim of this study was to investigate the structural and functional remodeling in the atrioventricular junction (AVJ) with aging. METHODS: Electrophysiology, histology, and immunohistochemistry experiments on male Wistar Hannover rats aged 3 months (n = 24) and 2 years (n = 15) were performed. Atrio-His (AH) interval, Wenkebach cycle length (WBCL), and AVN effective refractory period (AVNERP) were measured. Cesium (2 mM) was used to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, while ryanodine (2 µM) was used to block ryanodine 2 (RyR2) channels. Protein expression from different regions of the AVJ was studied using immunofluorescence. The expression of connexins (connexin 43 and connexin 40), ion channels (Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), voltage sensitive sodium channel (Nav1.5), and L-Type calcium channel (Cav1.3)), and calcium handling proteins (RyR2 and sarco/endoplasmic reticulum calcium ATPaset type 2a (SERCA2a)) were measured. Morphological characteristics were studied with histology. RESULTS: Without drugs to block HCN and RyR2 channels, there was prolongation of the AH interval, WBCL, and AVNERP (P < .05) with aging. In young rats only, cesium prolonged the AH interval, WBCL, and AVNERP (P < .01). Ryanodine prolonged the AH interval and WBCL (P < .01) in both young and old rats. Immunofluorescence revealed that with aging, connexin 43, HCN4, Nav1.5, and RyR2 downregulate in the regions of the AVJ and connexin 40, SERCA2a, and Cav1.3 upregulate (P < .05). Aging results in cellular hypertrophy, loosely packed cells, a decrease in the number of nuclei, and an increase in collagen content. CONCLUSION: Heterogeneous ion channel expression changes were observed in the AVJ with aging. For the first time, we have shown that HCN and RyR2 play an important role in AVN dysfunction with aging.

Effective cascade screening through identification of a mutation in RYR2 in a large family with a history of sudden death.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder which usually presents in the first or second decade of life with syncope, which is typically induced by emotional stress or exercise. We describe a large family with a history of three sudden unexpected deaths. Investigations in the sibling of a deceased individual affected by emotion-induced syncope revealed ventricular bigeminy. Molecular genetic testing was performed on one symptomatic individual and a missense mutation in RYR2 was identified consistent with a diagnosis of CPVT. Subsequent cascade testing of family members excluded 37 of 43 individuals from risk and facilitated preventative intervention. This case highlights the value of genotyping in sudden cardiac death by defining the precise diagnosis and through the identification and exclusion of at-risk individuals. .

Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics - Insights from a 3D Model of the Human Atria.

AIMS: Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. METHODS AND RESULTS: A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2-3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished. CONCLUSIONS: This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients.

Fractionation of electrograms is caused by colocalized conduction block and connexin disorganization in the absence of fibrosis as AF becomes persistent in the goat model.

BACKGROUND: Electrogram fractionation and atrial fibrosis are both thought to be pathophysiological hallmarks of evolving persistence of atrial fibrillation (AF), but recent studies in humans have shown that they do not colocalize. The interrelationship and relative roles of fractionation and fibrotic change in AF persistence therefore remain unclear. OBJECTIVE: The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing or block due to changes in atrial connexin distribution in the absence of fibrotic change. METHODS: Of 12 goats, atrial burst pacemakers maintained AF in 9 goats for up to 3 consecutive 4-week periods. After each 4-week period, 3 goats underwent epicardial mapping studies of the right atrium and examination of the atrial myocardium for immunodetection of connexins 43 and 40 (Cx43 and Cx40) and quantification of connective tissue. RESULTS: Despite refractoriness returning to normal in between each 4-week period of AF, there was a cumulative increase in the prevalence of fractionated atrial electrograms during both atrial pacing (control and 1, 2, and 3 months period of AF 0.3%, 1.3% ± 1.5%, 10.6% ± 2%, and 17% ± 5%, respectively; analysis of variance, P < .05) and AF (0.3% ± 0.1%, 2.3% ± 1.2%, 14% ± 2%, and 23% ± 3%; P < .05) caused by colocalized areas of conduction block during both pacing (local conduction velocity <10 cm/s: 0.1% ± 0.1%, 0.3% ± 0.6%, 6.5% ± 3%, and 6.9% ± 4%; P < .05) and AF (1.5% ± 0.5%, 2.7% ± 1.1%, 10.1% ± 1.2%, and 13.6% ± 0.4%; P < .05), associated with an increase in the heterogeneity of Cx40 and lateralization of Cx43 (lateralization scores: 1.75 ± 0.89, 1.44 ± 0.31, 2.85 ± 0.96, and 2.94 ± 0.31; P < .02), but not associated with change in connective tissue content or net conduction velocity. CONCLUSION: Electrogram fractionation with increasing persistence of AF results from slow localized conduction or block associated with changes in atrial connexin distribution in the absence of fibrotic change.

Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria.

Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves.

Advantages of a subcutaneous implantable cardioverter-defibrillator in LAMP2 hypertrophic cardiomyopathy.

Danon disease is a rare X-linked lysosomal disease causing severe hypertrophic cardiomyopathy (LAMP2 cardiomyopathy) and an extremely poor prognosis in males, with several reported cases of sudden cardiac death despite the use of transvenous implantable cardioverter defibrillators (TV-ICD). We describe a case in which a TV-ICD was unable to defibrillate induced ventricular fibrillation (VF), but a wholly subcutaneous system (S-ICD) was successful in terminating induced VF and spontaneous ventricular tachycardia. These findings have relevance to the selection of device therapy in the management of these individuals and a wider group of young patients with severe hypertrophic cardiomyopathy.

Comparison of Atrial Fibrillation in the Young versus That in the Elderly: A Review.

The incidence and prevalence of atrial fibrillation (AF) are projected to increase significantly worldwide, imposing a significant burden on healthcare resources. The disease itself is extremely heterogeneous in its epidemiology, pathophysiology, and treatment options based on individual patient characteristics. Whilst ageing is well recognised to be an independent risk factor for the development of AF, this condition also affects the young in whom the condition is frequently symptomatic and troublesome. Traditional thinking suggests that the causal factors and pathogenesis of the condition in the young with structurally normal atria but electrophysiological "triggers" in the form of pulmonary vein ectopics leading to lone AF are in stark contrast to that in the elderly who have AF primarily due to an abnormal substrate consisting of fibrosed and dilated atria acting in concert with the pulmonary vein triggers. However, there can be exceptions to this rule as there is increasing evidence of structural and electrophysiological abnormalities in the atrial substrate in young patients with "lone AF," as well as elderly patients who present with idiopathic AF. These reports seem to be blurring the distinction in the pathophysiology of so-called idiopathic lone AF in the young versus that in the elderly. Moreover with availability of improved and modern investigational and diagnostic techniques, novel causes of AF are being reported thereby seemingly consigning the diagnosis of "lone AF" to a rather mythical existence. We shall also elucidate in this paper the differences seen in the epidemiology, causes, pathogenesis, and clinical features of AF in the young versus that seen in the elderly, thereby requiring clearly defined management strategies to tackle this arrhythmia and its associated consequences.

The Year in Cardiology 2012: arrhythmia and pacing.

This is a commissioned review for 'A Year in Cardiology 2012', focusing on recent developments in the field of arrhythmias and pacing.

Mimics of Hypertrophic Cardiomyopathy - Diagnostic Clues to Aid Early Identification of Phenocopies.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cause of cardiomyopathy worldwide. Significant advances and widespread availability of genetic testing have improved detection of the sarcomeric mutations that cause HCM, but have also highlighted the significance of inborn errors of metabolism (IEM) or metabolic storage disorders that can mimic HCM ('HCM phenocopies'). These conditions cannot always be reliably differentiated on the basis of imaging alone. Whilst HCM phenocopies are relatively rare, it is crucial to distinguish these conditions at an early stage as their natural history, management and prognosis vary significantly from that of HCM with sarcomeric mutations. This review illustrates the salient features of HCM phenocopies and stresses the need for a high level of suspicion for these conditions in the assessment of cardiac hypertrophy.

The clinical management of relatives of young sudden unexplained death victims; implantable defibrillators are rarely indicated.

OBJECTIVE: Following national guidance on management of sudden unexplained death (SUD) in the young, inherited cardiac conditions (ICC) clinics were established to identify and treat relatives thought to be at increased risk. Studies have examined diagnostic yield of these clinics but outcome of clinical management has not been reported. DESIGN: Observational outcome study of consecutively referred relatives of SUD victims. SETTING: Regional ICC clinic. PATIENTS: 193 individuals (108 families) referred to a regional ICC clinic following SUD/aborted cardiac arrest of a young relative (mean follow-up 16.5 months, range 0.1-61). INTERVENTIONS: All individuals underwent assessment by history, examination, ECG and echocardiography. Exercise electrocardiography, ajmaline provocation, further imaging techniques and genetic testing were performed in selected individuals. Implantable cardioverter-defibrillator (ICD) insertion based on national guidelines. MAIN OUTCOME MEASURES AND RESULTS: Forty-five patients (23%) from 38 families (35%) were diagnosed with an inheritable cause of sudden death. Eighteen had potentially prognostically important medication commenced and 4 had an ICD inserted on clinic recommendation (2 hypertrophic cardiomyopathy, 1 dilated cardiomyopathy, 1 arrhythmogenic right ventricular cardiomyopathy). Two other individuals had ICDs removed after negative testing for familial RYR2 mutations. No deaths have occurred during follow-up to date. CONCLUSION: A diagnosis of an inheritable cause of sudden death was obtained in a significant minority of those with a family history of SUD/aborted cardiac arrest. The number of ICDs inserted as a result of specialist assessment was very small (2%). A major function of the clinic is reassurance of the clinically normal and cessation of treatment after exclusion of familial disease by genetic testing.