Giovanni Quarta

Ospedale Papa Giovanni XXIII

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Perry Elliott

University College London

William J. McKenna

University College London

James Moon

University College London

Andrew Flett

University Hospital Southampton NHS Foundation Trust

Petros Syrris

University College London

Antonios Pantazis

Royal Brompton & Harefield NHS Foundation Trust

Daniel Sado

King's College Hospital

Derek J. Hausenloy

University College London

Srijita Sen‐Chowdhry

University College London

Pier D. Lambiase

British Heart Foundation

Cooperative Institutions

University College London

Centro de Investigación Biomédica en Red

Centro de Investigación en Red en Enfermedades Cardiovasculares

University College Hospital at Westmoreland Street

Istituti di Ricovero e Cura a Carattere Scientifico

St Bartholomew's Hospital

Instituto de Salud Carlos III

Royal London Hospital

ERN GUARD-Heart

Barts Health NHS Trust

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Beyond late gadolinium enhancement: the key role of diffuse myocardial fibrosis in severe aortic stenosis - an Equilibrium Contrast CMR study

Journal of Cardiovascular Magnetic Resonance (2011)

Andrew Flett Dan Sado Giovanni Quarta Olivier Huttin Derek J. Hausenloy

Background In severe aortic stenosis (AS), hemodynamics and conventional indices do not fully explain symptoms, prognosis or treatment response. We hypothesize that diffuse myocardial fibrosis (DMF) is a key missing factor in AS. This can now be accurately measured non-invasively using equilibrium contrast CMR (EQ-CMR) [1] involving a primed gadolinium infusion, T1 measurement preand post-infusion, and direct measure of blood volume of distribution (1-hematocrit). The derived myocardial volume of distribution (Vd(m)) correlates strongly with histological diffuse myocardial fibrosisin AS and this calibration can convert Vd(m) to DMF%. Cell volume can be calculated as 1-DMF%*LV mass.

Angiology

Myocardial fibrosis

Nephrogenic Systemic Fibrosis

Cardiac magnetic resonance

10.1186/1532-429x-13-s1-o39

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Citations (3)

Dynamic Conduction and Repolarisation Changes in Early Arrhythmogenic Right Ventricular Cardiomyopathy versus Benign Outflow Tract Ectopy Demonstrated by High Density Mapping & Paced Surface ECG Analysis

PLoS ONE (2014)

Malcolm Finlay Akbar K. Ahmed Alan Sugrue Justine Bhar-Amato Giovanni Quarta

Aims The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy. Methods 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol. Results Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls. Conclusions Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.

Ventricular outflow tract

10.1371/journal.pone.0099125

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Citations (20)

Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease

Heart (2012)

Daniel Sado Andrew Flett Sanjay M Banypersad Steven K White Viviana Maestrini

Objective

To measure and assess the significance of myocardial extracellular volume (ECV), determined non-invasively by equilibrium contrast cardiovascular magnetic resonance, as a clinical biomarker in health and a number of cardiac diseases of varying pathophysiology.

Design

Prospective study.

Setting

Tertiary referral cardiology centre in London, UK.

Patients

192 patients were mainly recruited from specialist clinics. We studied patients with Anderson–Fabry disease (AFD, n=17), dilated cardiomyopathy (DCM, n=31), hypertrophic cardiomyopathy (HCM, n=31), severe aortic stenosis (AS, n=66), cardiac AL amyloidosis (n=27) and myocardial infarction (MI, n=20). The results were compared with those for 81 normal subjects.

Results

In normal subjects, ECV (mean (95% CI), measured in the septum) was slightly higher in women than men (0.273 (0.264 to 0.282 vs 0.233 (0.225 to 0.244), p<0.001), with no change with age. In disease, the ECV of AFD was the same as in normal subjects but higher in all other diseases (p<0.001). Mean ECV was the same in DCM, HCM and AS (0.280, 0.291, 0.276 respectively), but higher in cardiac AL amyloidosis and higher again in MI (0.466 and 0.585 respectively, each p<0.001). Where ECV was elevated, correlations were found with indexed left ventricular mass, end systolic volume, ejection fraction and left atrial area in apparent disease-specific patterns.

Conclusions

Myocardial ECV, assessed non-invasively in the septum with equilibrium contrast cardiovascular magnetic resonance, shows gender differences in normal individuals and disease-specific variability. Therefore, ECV shows early potential to be a useful biomarker in health and disease.

Hypertensive heart disease

Cardiac Amyloidosis

10.1136/heartjnl-2012-302346

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Citations (332)

Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

European Heart Journal (2012)

John Gomes Malcolm Finlay Akbar K. Ahmed Edward J. Ciaccio Angeliki Asimaki

Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

Desmoplakin

10.1093/eurheartj/ehr472

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Citations (181)

The evolution and clinical importance of scar in hypertrophic cardiomyopathy - a 7 year CMR follow-up study

Journal of Cardiovascular Magnetic Resonance (2011)

Giovanni Quarta Agata Grasso Ferdinando Pasquale Andrew Flett Dan Sado

Fibrosis is a key histopathological component of hypertrophic cardiomyopathy (HCM). Fibrosis, detected by CMR late gadolinium enhancement (LGE) contributes to diastolic dysfunction, ischaemia, atrial fibrillation, progression to heart failure, sudden cardiac death and is associated with exercise intolerance.

Angiology

Exercise intolerance

Restrictive cardiomyopathy

Myocardial fibrosis

Diastolic heart failure

10.1186/1532-429x-13-s1-p296

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Citations (0)

Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

European Heart Journal (2012)

Annika Haywood Nancy D. Merner Kathy Hodgkinson Jim Houston Petros Syrris

Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Bidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation.

Proband

Founder effect

Sudden Death

10.1093/eurheartj/ehs383

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Citations (51)

Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy

Circulation (2009)

Paolo Spirito Camillo Autore Claudio Rapezzi Paola Bernabò Roberto Badagliacca

Background— The prognostic significance of syncope has not been investigated systematically in hypertrophic cardiomyopathy, and treatment strategies have been based largely on intuition and experience. Methods and Results— We assessed the relationship between syncope and sudden death in 1511 consecutive patients with hypertrophic cardiomyopathy. Unexplained (n=153) or neurally mediated (n=52) syncope occurred in 205 patients (14%). Over a 5.6±5.2-year follow-up, 74 patients died suddenly. Relative risk of sudden death was 1.78 (95% confidence interval 0.88 to 3.51, P =0.08) in patients with unexplained syncope and 0.91 (95% confidence interval 0.00 to 3.83, P =1.0) in those with neurally mediated syncope compared with patients without syncope. In multivariable analysis, the temporal proximity of unexplained syncope to initial patient evaluation was independently associated with risk of sudden death ( P =0.006). Patients with unexplained syncope within 6 months before the initial evaluation showed a 5-fold increase in risk compared with patients without syncope (adjusted hazard ratio 4.89, 95% confidence interval 2.19 to 10.94), a relationship that was maintained throughout all age groups (<18, 18 to 39, and ≥40 years). Older patients (≥40 years of age) with remote episodes of syncope (>5 years before initial evaluation) did not show an increased risk of sudden death (adjusted hazard ratio 0.38, 95% confidence interval 0.05 to 2.74). Conclusions— In the present large cohort of patients with hypertrophic cardiomyopathy, unexplained syncope was a risk factor for sudden death. Patients with syncopal events that occurred in close temporal proximity to the initial evaluation showed a substantially higher risk of sudden death than patients without syncope. Older patients with remote syncopal events did not show an increased risk.

Sudden Death

10.1161/circulationaha.108.798314

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Citations (346)

Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation (2011)

Giovanni Quarta Alison Muir Antonios Pantazis Petros Syrris Katja Gehmlich

With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied.The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04).Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy.

Penetrance

Proband

Expressivity

Pedigree chart

10.1161/circulationaha.110.976936

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Citations (247)

Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele

Cardiovascular Pathology (2011)

Katja Gehmlich Petros Syrris Mareike Reimann Angeliki Asimaki Elisabeth Ehler

Plakoglobin

Adherens junction

Desmoplakin

Desmosome

Intercalated disc

10.1016/j.carpath.2011.09.005

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Citations (33)

The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy

EP Europace (2011)

Constantinos O’Mahony Pier D. Lambiase Shafiqur Rahman Montserrat Cardona Margherita Calcagnino

The triggers of ventricular arrhythmias (VAs) leading to sudden cardiac death in hypertrophic cardiomyopathy (HCM) are ill defined. We sought to examine the electrophysiological characteristics of VAs in HCM and study their relation to cardiac phenotype and circadian patterns using stored intracardiac electrocardiograms from implantable cardioverter defibrillators (ICDs).A single centre, observational cohort study of 230 consecutively evaluated ICD recipients with HCM [median age 42 years, 97% primary prevention, 51% with anti-tachycardia pacing (ATP)]. Fifty-six non-clustered VAs (39 initially treated with ATP and 17 with shocks) from 29 patients were analysed. Monomorphic ventricular tachycardia was the culprit arrhythmia in 86% of cases, ventricular fibrillation/flutter in 9%, and polymorphic ventricular tachycardia in 5%. Prior to the onset of VA the rhythm was sinus in 67%, atrial fibrillation/flutter in 19%, and 15% were paced ventricularly; tachycardia (cycle length <600 ms) was present in 25%. Ventricular arrhythmias were triggered by premature ventricular complexes (PVCs) in 72%, which were late-coupled (84%). Short-long-short initiation was seen in 2% and 26% of VAs were sudden-onset without preceding PVCs. Ventricular arrhythmia peaked at midday (with 20% occurring between 2300 and 0700), on Sundays and in May. The cardiac phenotype and time of the day did not predict the mode of initiation. Age at ICD implantation was the only independent predictor of VA cycle length (linear regression coefficient 0.67, 95% CI 0.02-1.32, P= 0.04). Anti-tachycardia pacing terminated 67% of VAs, but patients with ATP therapy had a similar incidence of appropriate shocks (log-rank test P= 0.25) and syncope (log rank P= 0.23) to patients with shock as initial therapy.Most VAs are monomorphic ventricular tachycardias triggered by late-coupled PVCs. They are frequently terminated by ATP, but ATP does not reduce the frequency of ICD shocks. Younger HCM patients have more rapid VAs, which may explain the peak of sudden cardiac death in early adulthood. The circadian periodicity is different from that observed in ischaemic heart disease, and is likely to relate to the distinct character of the arrhythmogenic substrate in HCM and its modulators.

10.1093/europace/eur362

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Citations (48)