Search

Learning objectives Phenotype is defined as a set of observable characteristics of an individual resulting from the interaction of their genotype with the environment. It differs from ‘disease’ in that it does not reflect the mechanism by which it is produced. In 1982, the term arrhythmogenic right ventricular dysplasia was first used to describe a clinical phenotype characterised by ventricular arrhythmias of left bundle branch block (LBBB) configuration accompanied by right ventricular dilatation, wall motion abnormalities and fibrofatty replacement of the myocardium.1 Arrhythmogenic right ventricular cardiomyopathy (ARVC) became the preferred descriptor when subsequent histopathological analysis revealed that myocyte atrophy as a consequence of progressive cell death occurred after birth.2 3 Initial clinical diagnostic criteria for ARVC were based on descriptions of patients with advanced disease,4 but discovery of its genetic basis, and the phenotyping of large patient cohorts including relatives, revealed a broader disease spectrum in which right ventricle (RV) and left ventricle (LV) can be involved.5 The disease paradigm has expanded further with the recognition of new disease genes causing similar phenotypes. Hence, terms such as left-dominant arrhythmogenic cardiomyopathy , arrhythmic dilated cardiomyopathy or simply arrhythmogenic cardiomyopathy (AC) are increasingly used to describe the clinical phenotype observed in a family of disorders in which frequent ventricular arrhythmia and dysfunction of one or both ventricles are the defining features. In this article, we review this emerging concept with a focus on the …

Lamins A and C are intermediate filament nuclear envelope proteins encoded by theLMNAgene. Mutations inLMNAcause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding anLMNAmutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible forLMNA, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to excludeLMNAmutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping ourLMNAknowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

Objective Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) and is associated with a high risk of stroke. The efficacy and safety of catheter ablation in this setting is poorly characterised. We aimed to systematically review the existing literature and to perform a meta-analysis to determine the efficacy and safety of catheter ablation of AF in patients with HCM. Methods Random-effects meta-analysis of studies comparing HCM versus non-HCM controls. The outcomes of freedom from AF/atrial tachycardia, and acute procedure-related complications were assessed. Studies were searched on MEDLINE, EMBASE, COCHRANE and clinicaltrials.gov. Results Fourteen studies were considered eligible for the systematic review, of which five were included in the meta-analysis. Freedom from AF/atrial tachycardia relapse was higher in patients without HCM (after a single procedure: 38.7% HCM vs 49.8% controls, OR=2.25, 95% CI 1.09 to 4.64, p=0.03; after ≥1 procedure: 51.8% HCM vs 71.2% controls, OR=2.62, 95% CI 1.52 to 4.51, p=0.0006; I 2 =33% and 26%, respectively). Risk of procedure-related adverse events was low. Repeat procedures (mean difference=0.16, 95% CI 0.0 to 0.32, p=0.05, I 2 =53%) and antiarrhythmic drugs (OR=4.70, 95% CI 2.31 to 9.55, p 2 =0%) are more frequently needed in patients with HCM to prevent arrhythmia relapse. Sensitivity analyses suggested that the outcome in patients with HCM with less dilated atria and paroxysmal AF may be more comparable to the general population. Conclusions The observed complication rate of catheter ablation of AF in patients with HCM was low. Even though the risk of relapse is twofold higher, catheter ablation can be effective in patients with HCM and AF, particularly in patients with paroxysmal AF and smaller atria.

Background Anderson–Fabry Disease (AFD) is an X linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Some mutations are associated with prominent and, in many cases, exclusive cardiac involvement. The primary aims of this study were to determine the incidence of major cardiac events in AFD and to identify clinical and genetic predictors of adverse outcomes. Methods and results We studied 207 patients with AFD (47% male, mean age 44 years, mean follow-up 7.1 years). Fifty-eight (28%) individuals carried mutations that have been previously associated with a cardiac predominant phenotype. Twenty-one (10%) developed severe heart failure (New York Heart Association functional class (NYHA) ≥3), 13 (6%) developed atrial fibrillation (AF), 13 (6%) received devices for the treatment of bradycardia; there were a total of 7 (3%) cardiac deaths. The incidence of the primary endpoint (a composite of new onset AF, NYHA ≥ 3 symptoms, device insertion for bradycardia and cardiac death) was 2.64 per 100 person-years (CI 1.78 to 3.77). Age (HR 1.04, CI 1.01 to 1.08, p=0.004), Mainz Severity Score Index score (HR 1.05, CI 1.01 to 1.09, p=0.012) and QRS duration (HR 1.03, CI 1.00 to 1.05, p=0.020) were significant independent predictors of the primary endpoint. The presence of a cardiac genetic variant did not predict the primary end point. Conclusions AFD is associated with a high burden of cardiac morbidity and mortality. Adverse cardiac outcomes are associated with age, global disease severity and advanced cardiac disease but not the presence of cardiac genetic variants.

Objective A predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype. Methods Unrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival. Results 874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values

The sarcomere is the principal contractile unit of striated muscle. Mutations in genes encoding sarcomeric proteins are responsible for a range of diseases including hypertrophic, dilated and restrictive cardiomyopathies and ventricular non-compaction. The downstream molecular pathways leading to these heterogeneous phenotypes include changes in acto-myosin cross-bridge kinetics, altered mechanosensation, disturbed calcium sensitivity, de-regulated signalling pathways, inefficient energetics, myocardial ischaemia and fibrosis. The elucidation of the genetic causes of cardiomyopathy has helped in understanding the structure and function of the sarcomere and a more detailed knowledge of the sarcomere and its associated proteins has suggested additional gene candidates. The new hope is that these advances will stimulate the discovery of disease-modifying drugs.

Introduction Left ventricular noncompaction (LVNC) is characterised by prominent ventricular myocardial trabeculations, composed of sheets of cardiomyocytes. They form early during cardiogenesis but their development is complex. Measuring trabecular complexity in animal models of cardiac disease is important as abnormal trabecular patterns are increasingly been recognised to coexist with several other cardiac conditions, not just LVNC. We describe an innovative approach that utilises fractal algorithms and high-resolution episcopic microscopy (HREM) to study the developmental timing of myocardial trabeculation in mouse and we validate it using a recently described LVNC mouse model (NOTCH pathway regulator Mib1 mutant). Methods HREM (2–3 μm resolution) analysis was performed prospectively on 123 embryonic mouse hearts consisting of wild-type (WT) NIMR:Parkes, WT C57BL/6 and Mib1 flox ; cTnT-cre mutant and WT littermates. HREM permits the 2D/3D imaging of tissue samples as they are physically sectioned. Datasets underwent fractal analysis using a box-counting approach (Figure 1). Results LV trabecular complexity showed a significant drop between E14.5 and E18.5 (Figure 2). Across all embryonic stages, the apical half of the LV retained the highest fractal dimensions (FD) when compared to the base. By E18.5 the myocardium was almost fully compacted registering the lowest FD. For the first time, we demonstrate that strain-specific differences in LV trabecular patterning exist in mouse because NIMR:Parkes compacts earlier than C57BL/6 (Figure 3). Reslicing experiments (Figure 4) and separate validation tests on Mib1 mutants and WT littermates (Fig.5) confirmed how the proposed methodology is a reliable and effective tool for the detection of mutagenesis-related differences in trabeculation. Conclusion Reported here is a method in which sequential, 2D sections of mouse embryo hearts may be analysed using a fractal algorithm to calculate ventricular trabecular complexity – a technique so sensitive, that small inter-strain differences in somitogenesis are detectable in mouse pups. Precise knowledge of the trabecular architecture as it presents itself in WT, is a prerequisite for the correct identification of pathological trabecular phenotypes in mouse models of cardiac disease, explaining the need for a quantitative fractal atlas of trabecular development. Fractal mathematics in combination with HREM has the potential to answer to many developmental biology questions in the heart, with future applicability to other organ systems and to other species.

ObjectiveReduction of left ventricular outflow tract obstruction (LVOTO) often improves symptoms in hypertrophic cardiomyopathy (HCM), but the correlation between exercise performance and measured LVOT gradients is weak. We investigated the relationship between LVOTO and cardiorespiratory responses during exercise.MethodsThe study cohort included 70 patients with HCM (32 with LVOTO, 55 male, age 47±13) attending a dedicated cardiomyopathy clinic and 28 normal volunteers. All underwent cardiopulmonary exercise testing with simultaneous non-invasive haemodynamic assessment using finger plethysmography. Main outcome measures were peak oxygen consumption, cardiac index and arteriovenous oxygen difference.ResultsWhen compared with controls, patients had reduced peak exercise oxygen consumption (22.4±6.1 vs 34.7±7.7 mL/kg/min, p2, pConclusionsCardiac reserve is reduced in HCM because of failure of SV augmentation. LVOTO exacerbates this abnormal response, but haemodynamic responses vary significantly. Non-invasive exercise haemodynamic assessment may improve understanding of symptoms and help tailor therapy.

Hypertrophic cardiomyopathy (HCM) is a heart muscle disease that affects an estimated 1 in 500 adults in the general population. Many people with HCM live healthy lives, but its association with premature death in the young and heart failure in the middle aged raises its profile in the mind of the general public and make it a common cause for concern among healthcare professionals. To assist practitioners and patients manage the condition, The European Society of Cardiology (ESC) has recently published a new clinical practice guideline on HCM that replaces an earlier document produced jointly with the American College of Cardiology in 2003.1 From the outset, all members of the ESC writing committee agreed to three guiding principles while preparing their recommendations. The first was that guidance should be practical and firmly rooted in real-life clinical practice; second, there was a determination that recommendations should, where humanly possible, innovate and not slavishly reproduce previous statements; and finally–and perhaps most challenging of all—recommendations should, whenever possible, be based on the best scientific evidence. At first glance, the absence of large randomised clinical trials and the relative paucity of large cohort studies in this area of medicine might seem to render such ideals futile, but the experts on the committee were able to achieve consensus on an approach to diagnosis and management that shifts the emphasis towards multidisciplinary working and individualisation of patient care. Some of the most important areas covered in the guideline are discussed below. HCM is defined by a simple measurement of LV wall thickness on cardiac imaging. While this has been shown to be a robust and reproducible approach to clinical classification, it fails to describe the spectrum of genetic and non-genetic disorders than can present with LV thickening. One approach to rationalising this complexity is to …

HCM is commonly associated with AF. Current guidelines for AF management omit detailed advice for HCM because of a lack of clinical prediction tools that estimate the risk of developing AF and an absence of adequately powered treatment studies.To critically review current literature on atrial fibrillation (AF) and thromboembolism in hypertrophic cardiomyopathy (HCM) and meta-analyse prevalence and incidence.PubMed and Web of Science.Studies investigating AF and stroke in HCM as primary or secondary endpoint.Two investigators independently reviewed and extracted data from the identified articles. A random effect meta-regression model and I(2) statistics were used for analysis.A population of 7381 patients (33 studies) revealed overall AF prevalence of 22.45% (95% CI 20.13% to 24.77%), I(2)=78.9% (p0.001). Overall prevalence of thromboembolism in HCM patients with AF was 27.09% (95% CI 20.94% to 33.25%), I(2)=61.4% ( p0.01). Overall AF incidence was 3.08% per 100 patients per year (95% CI 2.63% to 3.54%, I(2)=86.5%, p0.001) and incidence of thromboembolism in HCM patients with AF was 3.75% per 100 patients per year (95% CI 2.88% to 4.61%), I(2)=37.9% (p=0.1). Left atrial (LA) dimension and age were common predictors for AF and thromboembolism. Meta-analysis revealed an LA diameter of 38.03 mm (95% CI 34.62% to 41.44%) in sinus rhythm and 45.37 mm (95% CI 41.64% to 49.04%) in AF. There were no randomised controlled trials of therapy; anticoagulation was associated with lower stroke incidence but data on other interventions were limited and contradictory.AF is common in HCM and associated with high thromboembolic risk. LA dimension and age are independently associated with AF but the literature is insufficient to create robust clinical tools to predict AF or thromboembolism. Most data suggest that AF patients should be anticoagulated.

Objective Implantable cardioverter defibrillators (ICDs) are routinely used to prevent sudden cardiac death (SCD) in selected hypertrophic cardiomyopathy (HCM) patients, but the determinants of device-related complications, therapies and long-term cardiovascular mortality in ICD recipients are not known. Design Retrospective observational cohort study. Setting Single-centre tertiary referral cardiomyopathy clinic. Patients 334 consecutively evaluated HCM patients (median age 40 years, 62% male, 92% primary prevention) at risk of SCD treated with ICD. Thirty-six patients (11%) received concurrent cardiac resynchronisation therapy for heart failure symptoms. Results During the 1286 patient-years of follow-up, cardiovascular mortality (including transplantation) occurred in 22 (7%) patients (1.7%/year) and was associated with New York Heart Association (NYHA) class III/IV (adjusted HR=9.38, 95% CI 3.31 to 26.55, p≤0.001), percentage fractional shortening (HR=0.92, 95% CI 0.87 to 0.96, p=0.001) and implantation for secondary prevention (HR=0.07, 95% CI 0.01 to 0.86, p=0.04). There were no SCD. Twenty-eight (8%) patients received appropriate shocks (2.3%/year), which were predicted by baseline fractional shortening (HR=0.96, 95% CI 0.92 to 0.99, p=0.04). Fifty-five (16%) patients received inappropriate shocks (4.6%/year). Sixty (18%) patients experienced implant-related complications (5.1%/year), including two deaths. Adverse ICD-related events (inappropriate shocks and/or implant complications) were seen in 101 (30%) patients (8.6%/year). Patients with cardiac resynchronisation therapy were more likely to develop implant complications than those with single-chamber ICDs (HR=4.39, 95% CI 1.44 to 13.35, p=0.009) and had a higher 5-year cardiovascular mortality than did the rest of the cohort (21% vs 6%, p Conclusions HCM patients with an ICD have a significant cardiovascular mortality and are exposed to frequent inappropriate shocks and implant complications. These data suggest that new strategies are required to improve patient selection for ICDs and to prevent disease progression in those that receive a device.

Background and objectives Electrocardiographic (ECG) abnormalities of depolarisation and repolarisation contribute to the diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC). The development of diagnostic ECG features were investigated in a genotyped cohort with ARVC to provide more sensitive markers of early disease. Methods T-wave inversion (TWI) in right precordial leads, epsilon waves, localised QRS prolongation greater than 110 ms in V1–V3 and QRS dispersion greater than 40 ms were analysed from 317 ECG from 68 genotyped patients (34 with disease-causing mutations) during follow-up of 34±28 months. Results 16 patients (23%) had changes during follow-up, with the appearance of new ECG abnormalities in seven (10%) and dynamic changes in nine (13%). Four developed new and persistent TWI and eight had dynamic TWI in right precordial leads. Three developed new and another three had dynamic epsilon waves. No changes were observed in 10 with and 58 patients without localised QRS prolongation and in six patients with and 61 without QRS dispersion greater than 40 ms. An additional patient with QRS dispersion at baseline had normal depolarisation dispersion during follow-up. None of the nine ARVC patients with dynamic ECG changes had major structural or functional right ventricular abnormalities, suggesting an early stage of the disease. Conclusions New or dynamic ECG changes were observed in 23%. This underscores the importance of serial ECG in the diagnosis of individuals at risk of ARVC, in whom potentially lethal arrhythmia may develop before major abnormalities are detectable with conventional imaging.

Sudden death in young athletes is always a catastrophic event which focuses medical and public attention on the prevention of similar tragedies in other sporting participants. In this review article, we discuss the importance of evaluation of family members, who, by virtue of the familial nature of many of the diseases that cause sudden cardiac death, are potentially at risk of a similar outcome. We show that a systematic approach to the clinical evaluation of relatives of sudden death victims has a high yield in the identification of other affected family members and may prevent further catastrophic events in the same family.

Background: Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. Design: Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. Results: The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. Conclusion: These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

Lysosomal storage disorders (LSD) comprise a group of more than 40 diseases caused by a deficiency of lysosomal enzymes, membrane transporters or other proteins involved in lysosomal biology. The predominant inheritance pattern is autosomal recessive except for Anderson-Fabry disease, glycogen storage disease (GSD) type IIb (Danon disease) and mucopolysaccharidosis (MPS) type II (Hunter disease). While the metabolic defects affect all cells, clinical organ involvement usually occurs only in the presence of substrate excess or metabolic pathway activation. Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease). Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease (table 1). View this table: Table 1 Lysosomal storage disease causing cardiac disease Anderson-Fabry disease (AFD, synonyms Fabry disease, α-galactosidase A deficiency, angiokeratoma corporis diffusum) is an X-linked LSD caused by mutations in the gene encoding the lysosomal enzyme α-galactosidase A. The resultant deficiency in α-galactosidase A activity leads to intra-lysosomal accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3), in various organ systems. The disease is characterised by progressive clinical manifestations and premature death from renal failure, stroke and cardiac disease.1 ### Epidemiology The incidence of AFD has been estimated at 1 in 40 000 to 1 in 117 000 live births for males.1 Recently, studies in high risk patient cohorts suggest that it is much more common. The reported prevalence of AFD in patients with end-stage renal disease on haemodialysis ranges between 0.2–1.2%; in patients with cryptogenic stroke the prevalence may be as high as 4.9% in men and 2.8% in women. The prevalence of AFD in patients with heart disease varies depending on the population studied. In a survey of male patients with unexplained left ventricular hypertrophy (LVH) attending an echocardiography clinic, 3% had biochemical evidence for AFD2 …

When the number of events is low relative to the number of predictors, standard regression could produce overfitted risk models that make inaccurate predictions. Use of penalised regression may improve the accuracy of risk prediction

To examine the influence of genotype on late gadolinium enhancement (LGE) and the potential of cardiovascular magnetic resonance (CMR) to detect preclinical hypertrophic cardiomyopathy.Prospective, blinded cohort study of myocardial LGE in a genetically homogeneous population.30 patients with disease causing mutations in the recognised hypertrophic cardiomyopathy gene for cardiac troponin I (TNNI3): 15 with echocardiographically determined left ventricular hypertrophy (LVH+) and 15 without (LVH-).CMR measures of regional left ventricular function, wall thickness, and mass, and the extent and distribution of LGE.LGE was found in 12 (80%) LVH+ patients but with variable extent (mean 15%, range 3-48%). LGE was also found in two (13%) LVH- patients but the extent was limited (3.6%) and both patients were found to have an abnormal ECG and regional hypertrophy by cine CMR. The extent of LGE was positively associated with clinical markers of sudden death risk (21% withor = 2 risk factors v 7% withor = 1 risk factor, p = 0.02) and left ventricular mass (r = 0.56, p0.001) and was inversely associated with ejection fraction (r = -0.58, p0.001). Segmental analysis showed that as regional wall thickness increased, LGE was more prevalent (p0.0001) and more extensive (r = 0.98, p = 0.001).In patients with disease causing mutations in TNNI3, focal fibrosis was not detected by LGE CMR before LVH and ECG abnormalities were present. Once LVH is present, LGE is common and the extent correlates with adverse clinical parameters. This suggests that focal fibrosis is closely linked to disease development.

Conventional Doppler indices of left ventricular diastolic function do not correlate with symptoms or exercise capacity in patients with hypertrophic cardiomyopathy, because of their dependence on loading conditions. Diastolic mitral annular velocity measured using Doppler tissue imaging has been reported to be a preload independent index of left ventricular diastolic function.To determine the relation between diastolic annular velocities combined with conventional Doppler indices and symptoms or exercise capacity in hypertrophic cardiomyopathy.85 patients with hypertrophic cardiomyopathy and 60 normal controls were studied. Diastolic mitral annular velocities, transmitral left ventricular filling, and pulmonary venous velocities were measured.Early diastolic velocities at lateral and septal annulus were lower in patients with hypertrophic cardiomyopathy than in controls (lateral Ea: 10 (3) v 18 (4) cm/s, p0.0001; septal Ea: 7 (2) v 12 (3) cm/s, p0.0001). Unlike conventional Doppler indices alone, transmitral early left ventricular filling velocity (E) to lateral Ea ratio correlated inversely with peak oxygen consumption (r = -0.42, p0.0001). Patients in New York Heart Association (NYHA) class III had a higher transmitral E to lateral Ea ratio (12.0 (4.6)) than those in NYHA class II (7.6 (3.1), p0.005) or class I (6.6 (2.6), p0.0001).Early diastolic mitral annular velocities are reduced in patients with hypertrophic cardiomyopathy. Unlike conventional Doppler indices alone, the transmitral E to lateral Ea ratio correlates with NYHA functional class and exercise capacity.

BACKGROUND—Left ventricular enlargement with normal systolic function is common in asymptomatic relatives of patients with familial dilated cardiomyopathy, many of whom progress to overt dilated cardiomyopathy at follow up. OBJECTIVE—To examine maximal and submaximal gas exchange variables of cardiopulmonary exercise testing in asymptomatic relatives with left ventricular enlargement. DESIGN AND SETTING—Controlled evaluation of metabolic exercise performance of patients with dilated cardiomyopathy and asymptomatic relatives with left ventricular enlargement identified through prospective family screening in a cardiomyopathy outpatient clinic. METHODS—23 relatives with left ventricular enlargement, 33 normal controls, 29 patients with dilated cardiomyopathy, and 10 elite athletes with echocardiographic criteria of left ventricular enlargement ("physiological" enlargement) underwent symptom limited upright cycle ergometry using a ramp protocol. RESULTS—Peak oxygen consumption (pVO2; mean (SD)) was significantly reduced in relatives with left ventricular enlargement (78 (16.3)%) v normal controls (96%, p VO2 was less than 80% of predicted in 75% of patients, 58% of relatives, 22% of controls, and none of the athletes. Oxygen pulse (pVO2/heart rate) was less than 80% of predicted in 69% of patients, 35% of relatives, 6% of controls, and none of the athletes. The slope of minute ventilation v CO2 production (ΔVE/ΔVCO2) was > 30 in 68% of patients, 50% of relatives, and in none of the controls or athletes. Anaerobic threshold, occurring in relatives at 37 (14)% of the predicted VO2, was higher than in the patients (32%, p

AIM—To screen for a mutation of the cardiac troponin T gene in two families where there had been sudden deaths without an increase in left ventricular mass but with myocardial disarray suggesting hypertrophic cardiomyopathy. METHODS—DNA from affected individuals from both families was used to screen the cardiac troponin T gene on an exon by exon basis. Mutation screening was achieved by polymerase chain reaction and direct sequencing. Where appropriate, a mutation was confirmed by restriction digest. RESULTS—A novel missense mutation of exon 9 was found in the affected individuals of one of the families. This mutation at amino acid 94 resulted in the substitution of arginine for leucine and was not found in 100 normal control samples. A mutation of the cardiac troponin T gene was excluded in the second family. CONCLUSIONS—A mutation of the gene for the sarcomeric protein cardiac troponin T can cause familial hypertrophic cardiomyopathy with marked myocyte disarray and frequent premature sudden death in the absence of myocardial hypertrophy at clinical or macroscopic level. Keywords: hypertrophic cardiomyopathy; troponin T

Implantable cardioverter-defibrillators (ICDs) have been shown to successfully treat life-threatening arrhythmias in high-risk adults with hypertrophic cardiomyopathy (HCM).1 Children represent

Relapse rates, mortality rates and possible prognostic factors were assessed in women with early-stage, node-negative cervix cancer. We identified 194 women who had a radical hysterectomy with histopathologically confirmed negative lymph nodes as primary treatment for FIGO stages IB and IIA cervix cancer between 1981 and 1990, at a single tertiary referral oncology centre. Each patient’s pathology was reviewed by two pathologists blinded to patient outcome. Clinical and demographic details were abstracted from medical records by a single observer blinded to patient outcome. Median follow-up was 5.3 years and 95% were followed for longer than 2 years. Prognostic significance for relapse-free survival was assessed with Cox’s proportional hazards model. There were 27 relapses (relapse-free survival probability of 85% (95% confidence interval (CI): 79–90)) and 19 deaths (overall survival probability 86% (95% CI: 78–93)), of which 17 were due to cervix cancer (cervix cancer specific survival probability 87% (95% CI: 80–94)). Nuclear grade 2 or 3 (P = 0.02) and small-cell squamous histology (P = 0.01) were each associated with about a four-fold increase in the risk of recurrence, while lymphatic permeation (P = 0.02), age less than 36 years (P = 0.03) and either tumor size> 28 mm (P = 0.03) or surgical clearance < 5 mm (P = 0.02) were each associated with about a 2.5-fold increase in the risk of recurrence. Adverse histologic features, young age and large tumor size were independent predictors of increased recurrence rates in these women with early-stage cervix cancer.

Background Positron emission tomography (PET) performed utilising the glucose analogue and radiotracer 18F-FDG (FDG) to detect active inflammation, offers enormous potential for detecting disease presence and activity in myocarditis. However, the clinical utility of PET imaging is limited by the unpredictable nature of physiological FDG uptake within cardiac muscle. Methods to minimise physiological FDG uptake are necessary to depict active inflammation and to avoid avoid false negative and positive findings. Studies have suggested the use of fasting conditions to shift myocardial metabolism to primary free fatty acid (FFA) utilisation for energy and oxygen consumption to suppress physiological FDG uptake by normal myocardium. Specific dietary preparation regimens using a very high-fat content and low-carbohydrate diet prior to scanning have also been proposed, as has the administration of heparin to reduce FDG uptake through the activation of lipoprotein lipase (LPL) and hepatic lipase (HL) which enhances plasma lipolytic activity and leads to preferential free fatty acid consumption. This study was therefore performed to develop an optimal dietary preparation protocol for imaging in PET/CT. We sought to establish whether patient preparation using heparin in addition to a high fat, low carbohydrate diet and prolonged fast prior to scanning ncreases the diagnostic capability of PET scanning in myocarditis. Methods All patients referred for PET scans for the assessment of myocarditis were enrolled. We prospectively examined three preparation rationales to determine the optimal rationale for minimising physiological FDG-uptake. All subjects underwent strict preparation prior to scanning using one of the following protocols to enable comparison: A 6-hour fast only, no dietary preparation. Dietary preparation for 24 h prior to the scan with a high-fat content, low carbohydrate diet, followed by a prolonged fast for 12 h. Dietary preparation for 24 h prior to the scan with a high-fat content, low carbohydrate diet, followed by a prolonged fast for 12 h and the administration of 50IU/kg of heparin prior to scanning. The imaging findings were analysed by two independent and blinded clinicians. FDG uptake was categorised as none (complete suppression, no uptake = 0), focal (localised uptake, = 1), focal on diffuse (2) and diffuse (poor, failed suppression, = 4). Results A total of 280 PET scans were performed. 36 patients underwent preparation using a 6-hour fast only, 128 underwent dietary preparation and a 12-hour fast, and 118 underwent dietary preparation followed by a 12-hour fast and the administration of heparin prior to scanning. A 6-hour fast alone was associated with a 44% failure to suppress physiological metabolism – equivalent to almost one in every two scans being suboptimal or un-interpretable. In contrast, restriction of carbohydrate intake with high fat intake alongside a prolonged 12-hour fast was successful in supressing normal myocardial metabolism in 89% of subjects. Similarly, of those who also received heparin, there was a failure to suppress normal myocardial metabolism in 11% of subjects. Conclusion Strict patient preparation prior to PET scanning is key to ensuring an optimal diagnostic disease assessment in myocarditis. A short duration of fasting of 6-hours or less alone is suboptimal in suppressing physiological uptake. In contrast, strict dietary preparation (using a high fat, low carbohydrate diet) and prolonged fast of > 12 h increases the diagnostic capability by 75%. Interestingly, the addition of heparin to this regimen provided no additive benefit suggesting that the addition of heparin adds little to the diagnostic quality of scans and is therefore unnecessary.

Background Dilated cardiomyopathy (DCM) is the leading cause of non-ischaemic heart failure. It causes approximately 10,000 deaths in Europe per year. Studies suggest that up to 50% of patients with DCM have a genetic predisposition and that mutations within one of 40 genes coding for structural and functional cardiac proteins accounts for up to 40% of familial disease. The relevance of genotype to clinical phenotype, treatment and prognosis is poorly understood. This study aimed to clinically and genetically characterise probands with familial DCM using next-generation sequencing technology (NGS) to determine specific genotype-phenotype correlations in DCM. Methods 72 probands with DCM were consecutively recruited into this study within our centre. All received pre-test genetic counselling and provided written informed consent. All patients were clinically characterised using a standard phenotyping protocol. Genomic data isolated from peripheral blood lymphocytes using standardised protocols, was collected and screened for all major genes involved in cardiomyopathies and selected candidate genes using NGS. Eighty-six genes with 1528 exons representing 500kb of coding sequence, were studied using target enrichment methods (Agilent SureSelect System) followed by sequencing on the Illumina HiSeq 2000 platform. Clinical parameters were correlated with genotype findings. Results Variant calling from 72 probands (male 54%, age 41 years (mean 40.7, range 14 to 68 years) generated 1415 exonic and splice-site calls. After filtering, 420 distinct candidate variants were reported, 253 of which were published pathogenic mutations, 112 of which were frameshift insertion/deletion or splice-site variants predicted to cause loss of function (thus likely to be pathogenic). A further 55 novel variants were considered potentially pathogenic on the basis of preliminary in silico analysis. Each proband, on average, carried 3 published pathogenic variants which included known mutations associated with DCM and other forms of cardiomyopathy. Up to two further variants predicted to be pathogenic were identified per DCM proband illustrating genetic heterogeneity. However, there was no simple correlation between a specific mutation or the number of mutations and the clinical phenotype. Moreover, there was no evidence of a ‘poly-hit’ theory of multiple mutations contributing to a worsened phenotype nor of specific variant demonstrating causality of phenotype suggesting that genotype-phenotype correlations in DCM are complex and may be influenced by both genetic and epigenetic factors. Conclusion This study demonstrates the exciting potential for utilisation of next generation sequencing in routine clinical practice. However it highlights the genetic heterogeneity and high frequency of novel variants with uncertain effects on gene function in DCM. This presents considerable challenges for clinical interpretation. Large-scale phenotyping is therefore required to fully understand genotype-phenotype relations in DCM.

Introduction Myocardial perfusion scintigraphy (MPS) is one of the most commonly performed non-invasive imaging procedures for the diagnosis of Coronary Artery Disease (CAD). Two large trials evaluating over 21,000 patients with a normal SPECT study have demonstrated the safety of stress-only imaging as compared to traditional stress/rest imaging. Comparably low all-cause and cardiac mortality rates were observed with both imaging protocols. This was true irrespective of patient age, gender, cardiac risk factor profile, or stressor employed with SPECT. These results are consistent with earlier studies evaluating patient outcome following normal stress-only imaging. The best use of a stress-only imaging strategy is likely to be in the selected low or intermediate risk population, which forms the referral basis for myocardial perfusion imaging. In this study, we describe the introduction of stress only MPS in comparison to traditional stress/rest MPS. Old Pathway The traditional stress/rest MPS pathway requires two imaging sessions either the same day or on two separate days according to the patient’s Body Mass Index (BMI). For a 1 day protocol typically the injected activity is split in a 1:3 ratio between the first and second injections. For BMI 35, a total of 2000 MBq is administered 1:1. If the BMI is not provided by the requesting clinician then a letter is sent to the patient asking their height and weight. New Pathway From September 2014 through December 2014, we introduced selective stress only imaging. A single high dose MIBI stress dose of of 800 MBq, was authorised for all patients, regardless of BMI. After stress imaging, a decision was made regarding the necessity of rest imaging. Results Patients were referred from 10 hospitals. 407 patients were scanned. 55% were male and 45% female. Their average age was 66 years (+/-12.9). Their average BMI was 29.4 kg/m2 (+/-6.4). Of the total, 35% percent were normal at stress imaging and did not have rest imaging. Of the 65% who were abnormal, 60% of the combined rest/stress scans were interpreted as abnormal. As a result of this, the average time from request to appointment date for the stress scan reduced from 27 to 14 days. The average time between stress scan and rest scan was 2.5 (range: 1–21 days). The average report turn around time from request to report for MPS was 5 days, but 97% of normal stress only scans were reported the same day. Furthermore, the administered radiation dose was lower for 67% of all patients. In additional to scanning parameters being assessed, patients preferences were also assessed via a questionnaire. 49% expressed a preference for the test to be split across 2 days. 7% said either 1 day or 2 days. 20% of patients had to take a day off work to attend the hospital. Conclusion Stress only MPS reduces radiation exposure, increases efficiency and thereby reduces cost.

Objectives-To assess the relation between alcohol intake and blood pressure in men and women and in men at younger and older ages; to examine the influence of amount and pattern of alcohol consumption, as well as of acute effects, taking into account body mass index, smoking, and urinary sodium and potassium excretion. Design-Subjects reported alcohol consumption for each of seven days before standardised blood pressure measurement, and whether they had consumed any alcohol in the 24 hours before measurement. Setting-50 centres worldwide. Subjects-4844 men and 4837 women aged 20-59. Main outcome measures-Effect of alcohol on blood pressure estimated by taking a weighted average of regression coefficients from centres. Acute effect assessed by examining mean differences in blood pressure of non-drinkers and of heavy drinkers who had and had not consumed alcohol in the 24 hours before measurement. Effect of pattern of consumption assessed by examining mean in blood pressure of non-drinkers with drinkers (i) whose intake was concentrated in fewer days or who were drinking more frequently, and (ii) whose alcohol intake varied little over the seven days or varied more substantially, as indicated by the standard deviation of daily consumption Results-Of the 48 centres in which some people reported consuming at least 300 ml/week of alcohol, 35 had positive regression coefficients linking heavy alcohol consumption to blood pressure. Overall, alcohol consumption was associated with blood pressure, significantly-at the highest intake. After: account was taken of key confounders, men who drank 300-499 ml alcohol/week had systolic/diastolic blood pressure on average 2.7/1.6 mm Hg higher than non-drinkers, and men who drank greater than or equal to 500 ml alcohol/week had pressures of 4.6/3.0 mm Hg higher. For women, heavy drinkers (greater than or equal to 300 ml/week) had blood pressures higher by 3.9/3.1 mm Hg than non-drinkers. Heavy drinking and blood pressure were strongly associated in both sexes, and in men at both younger (20-39 years) and older (40-59 years) ages. In men who were heavy drinkers, episodic drinkers (those with great variation in daily alcohol consumption) had greater differences in blood pressure compared with non-drinkers than did regular drinkers of relatively constant amounts. Conclusion-The significant relation of heavy drinking (3-4 or more drinks/day) to blood pressure, observed in both men and women, and in younger and older men, was independent of and added to the effect on blood pressure of body mass index and urinary excretion of sodium and potassium. The findings indicate the usefulness of targeting those at high risk as well as the general population to reduce the adverse effects of alcohol on blood pressure.

Introduction The genetic background of hypertrophic cardiomyopathy (HCM) is well described; however it fails to explain the phenotypic diversity characteristic of the disease. By performing an unbiased label-free quantitative proteomics analysis of heart tissue, we have identified important proteins and pathways that contribute to the cytoskeletal and metabolic alterations of HCM. To verify and validate these findings we have developed a targeted and rapid peptide-based tandem mass spectrometry (MS/MS) assay to prospectively screen a large genotyped cohort of patients. Methods Heart tissue from 17 patients with HCM and 6 controls was homogenised and whole protein assayed, prior to tryptic digestion. Samples were analysed using PLGS Version 2.5 and quantified based on ion abundance using Progenesis LC-MS. Statistically significant differences were calculated by one-way ANOVA. Proteins were submitted for ontology and functional annotation bioinformatics. Selected differentially expressed proteins were validated in 59 patients by developing a targeted, high throughput, peptide-based multiple reaction monitoring (MRM) assay using a Waters Xevo TQ-S triple quadruple mass spectrometer. Further validation and localisation of proteins was confirmed with immunohistochemistry. Results 1672 unique proteins were identified of which 152 were differentially expressed between the 2 groups (p Conclusions This is the first comprehensive global proteomic study of human hypertrophic cardiomyopathy. We have identified differences in the expression of several proteins in the HCM heart, many of which are relevant to the disease process. By developing a targeted and multiplexed MS/MS based assay we have been able to prospectively validate potential biomarkers in tissue, and create an assay that can be applied to screen plasma. Increased myocardial expression of Lumican is a possible marker of progressive disease in HCM.

Disproportionate exercise limitation in patients with cardiovascular disease is a common problem faced by clinical cardiologists and other physicians. Symptoms may be attributed to psychological factors or hypothetical pathophysiological mechanisms that are difficult to confirm clinically. This case report describes how the use of metabolic exercise testing in a 28 year old woman with morphologically and haemodynamically mild hypertrophic cardiomyopathy and severe exercise limitation led to the diagnosis of an alternative cause for the patient's symptoms, namely a primary disturbance of the mitochondrial respiratory chain probably caused by a nuclear encoded gene defect. Keywords: metabolic exercise testing; mitochondrial disease; hypertrophic cardiomyopathy

Introduction Hypertrophic cardiomyopathy (HCM) is a genetic disorder with significant variability in its clinical phenotype. Most major studies in HCM to date have been largely based on Caucasian patients, but there are some indications that racial background may have an important effect on the disease course. In other areas (such as athletes and hypertensive patients) black patients have been shown to be significantly different to white patients in terms of ECG and echocardiographic appearances. In this study we have used a large single centre population to determine the effect of racial group on baseline phenotype and clinical outcomes in HCM. Methods The case records of sequential patients with hypertrophic cardiomyopathy referred to our cardiomyopathy clinic were reviewed. Patients were asked to identify their racial group using the standard Office of National Statistics classification. Patients who identified themselves as mixed race were excluded. Patients underwent comprehensive cardiac assessment at their baseline visit, and were followed up regularly, for a mean of 7 years. Results Records were available for 2248 patients (95 Black/African/Caribbean/Black British (B), 216 Asian/Asian British (A), 1937 White (W)). Asian patients were more likely to be male (W 66%, B 66%, A 78%, p At baseline assessment, there were differences in the morphological pattern of left ventricular hypertrophy on echo, with more B patients having apical and concentric distributions of hypertrophy, while W and A patients mostly displayed asymmetric septal hypertrophy (p During follow-up, there were significant differences between ethnic groups in a combined end-point of mortality and cardiac transplant (Annual rates W 1.4%, B 1.7%, A 0.6%, p 0.02), but there were no significant differences in a secondary combined end-point of sudden cardiac death, aborted sudden death, and appropriate ICD therapy (Annual rates W 0.4%, B 0.4%, A 0.2%, p 0.4). W patients were significantly more likely to receive a pacemaker (Annual rates W 1.8%, B 0.9%, A 0.8%, p Conclusions In this large single centre study of hypertrophic cardiomyopathy, there were significant differences between racial groups in terms of their clinical phenotype at presentation and their long term outcomes. Further work is required to try and understand the different genetic and social factors which lead to these different disease patterns.

Introduction Interstitial myocardial volume expansion is an important factor in cardiac disease but until recently could only be accurately assessed with myocardial biopsy. It is usually a result of diffuse fibrosis, but can also be caused by infiltration (such as by amyloid deposition) or oedema. We have used a new method, Equilibrium Contrast Cardiovascular Magnetic Resonance (EQ-CMR) to accurately quantify the interstitial space in normal subjects and across a broad spectrum of cardiac diseases. Methods The three steps in EQ-CMR are: (1) a primed gadolinium infusion to achieve contrast equilibrium, (2) Signal (T1) measurement pre and post equilibrium, (3) measurement of blood contrast volume (1−haematocrit). This allows calculation of the contrast volume of distribution, Vd(m), by: Vd ( m ) = ( 1 − haematocrit ) × Δ ( 1 / T1 ) myo ÷ Δ ( 1 / T1 ) blood . Vd(m) was measured in 278 subjects: 86 normal subjects (median age 43, range 24–81, 51% male) and 192 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) or myocardial infarction (MI, n=20). Results In normal subjects, mean Vd(m) was higher in females (0.274) than males (0.237, p Conclusions This study shows the ability of EQ-CMR to non-invasively quantify interstitial expansion using this novel technique in both the healthy population and a spectrum of differing cardiac diseases. Further work will build on this study to evaluate the potential role of Vd(m) as a clinical biomarker.

Background Exercise testing is commonly performed in patients with hypertrophic cardiomyopathy (HCM) to evaluate blood pressure response, a conventional risk factor for sudden cardiac death. The 2011 ACCF/AHA guidelines state “the role of metabolic stress testing in the evaluation of patients with HCM remains to be decided, particularly with regard to clinical outcome. Methods and results Between 1998 and 2010, 1,898 patients (age 47 ± 15 years, 67% male) with HCM underwent cardiopulmonary exercise testing (CPX). During a mean follow-up of 5.8 ± 4 years, 178 (9.4%) patients reached the primary endpoint of all-cause mortality or orthotropic heart transplant. Peak oxygen consumption, V˙O 2 (HR 0.91 95% CI 0.89–0.93, p 2 (HR 1.08 95% CI 1.06–1.09), and ventilatory anaerobic threshold V˙AT (HR 0.88 95% CI 0.84–0.92) were predictors of the primary outcome. A progressively worse prognosis was associated with higher ventilatory class (Figure 1). V˙EV˙CO 2 was a good predictor of heart failure death or transplantation (HR 1.1 95% CI 1.07–1.14 p Conclusions CPX provides important prognostic information in patients with HCM. Sub-maximal exercise parameters are potentially more useful than peak VO 2 alone. Patients with an enhanced ventilatory response have a substantially higher risk of death or transplantation. Reference 1 Gersh, et al . JACC 2011;58(25):212–60

Background Cardiac sarcoidosis (CS) is associated with poor outcomes, but detection remains difficult.Few studies evaluate 18-fluorodeoxyglucose positron emission tomography (PET) and cardiac magnetic resonance imaging (MRI) for CS diagnosis. None examine a novel hybrid PET-MR approach. We sought to examine the diagnostic accuracy of hybrid PET-MR imaging for CS detection. Methods 51 consecutive patients with biopsy-proven or clinically suspected CS (age 48 ± 13 years, 32% males) underwent hybrid PET-MR imaging. 18-FDG tracer uptake and late gadolinium enhancement (LGE) were qualitatively assessed on a binary scale and quantitatively by measuring standardised uptake value (SUV) and % LGE detected in each myocardial segment. Sensitivity and specificity of PET-MR for CS diagnosis was calculated. Inter-modality agreement was performed by the Cohen κ method. Coefficient of variance (COV) was performed to determine whether SUV quantification analysis discriminated between CS presence and absence. Results 37 (73%) of the patients had confirmed sarcoidosis; 46% were histologically proven and 59% had cardiac involvement according to JMHW guidelines. FDG uptake on PET-MR was equivalent to PET-CT (p When considered in isolation, sensitivity of PET and MR at detecting abnormalities was 0.65 and 0.6, respectively. In contrast, hybrid imaging had improved sensitivity of 0.89 in detecting probable cardiac sarcoidosis with specificity, positive and negative predictive values of 0.42, 0.8 and 0.6, respectively. Sensitivity for detecting confirmed CS using hybrid PET-MR was 100%. Notably, there was poor inter-modality agreement between the location of increased SUV and LGE (k = 0.021). This may reflect the natural history of CS with progression from inflammation to scar and also account for the sensitivity of hybrid imaging. Coefficient of variance analysis of SUV uptake suggested that a COV above 25% predicted CS. Conclusion This is the first study to describe the feasibility and improved diagnostic accuracy of novel hybrid cardiac PET-MR imaging in CS. This technique may allow for more accurate and earlier diagnoses and may also allow titration of therapy according to disease activity.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder of heart muscle characterised by myocardial hypertrophy in the absence of abnormal loading conditions.1 It occurs in about 1 in 500 people and is an important cause of sudden cardiac death in young people. Progression to an end-stage, or “burnt-out” phase occurs in 2–15% of patients every year and is associated with a mortality rate of up to 11% a year.2–4 Left ventricular outflow tract obstruction, caused by contact between one or both leaflets of the mitral valve and the interventricular septum during ventricular systole is present at rest in approximately 25% of patients. In some people, obstruction varies spontaneously (labile obstruction) and in others is present only during physical or pharmacological manoeuvres that change loading conditions or increase contractility (latent obstruction).5 Left ventricular outflow tract obstruction is associated with an increased incidence of sudden death and progression to heart failure.6 7 In this issue of the journal, Dimitrow and colleagues report an association between left ventricular outflow tract obstruction and markers of thrombin generation and platelet activation (specifically, thrombin–antithrombin complex, prothrombin fragment (1+2), …

In 1958, Donald Teare, a forensic pathologist in London, reported eight cases of sudden death caused by “asymmetrical hypertrophy or benign tumour” of the heart in the British Heart Journal. In this special issue of Heart, we celebrate the fiftieth anniversary of Teare’s paper and examine its importance in four specially commissioned reviews, written by clinicians whose careers span the half a century since his publication. Discussions on genetics, pathophysiology and treatment are brought up to date in a series of original papers written by contemporary investigators.

Anderson-Fabry disease (AFD), an X linked lysosomal storage disorder, results in glycoshingolipid deposition in multiple organ systems, including the heart. Recognised cardiac manifestations include conduction disease, valvar thickening, and left ventricular hypertrophy (LVH).1 Recent studies have shown that enzyme replacement therapy (ERT) reduces left ventricular (LV) mass in patients with AFD.2 It remains uncertain, however, whether LVH is a clinically relevant surrogate marker of disease severity. Weidemann and colleagues2 have shown that tissue Doppler derived strain rate improves during treatment with ERT, suggesting that contractile function is reversibly impaired in AFD cardiomyopathy. To determine the importance of systolic performance in the natural history of AFD we performed a retrospective analysis of an untreated cohort of patients followed for at least one year. Seventy five patients with AFD were evaluated at the Heart Hospital, London between 1 January 1993 and 1 December 2003. Diagnosis of AFD was based on low plasma α-galactosidase A (α-Gal) concentrations and DNA mutational analysis. The mean (SD) follow up from diagnosis of AFD was 5.8 (4.8) years. Twenty four patients had been followed up for more than one year; 12 were receiving ERT at the time of evaluation. The 12 untreated patients (nine male patients, three female patients, mean age 54.5 (12.2) years, range 42–82 …

Introduction Familial evaluation for the presence of left ventricular hypertrophy (LVH) is an important part of management in hypertrophic cardiomyopathy. However due to incomplete penetrance, the presence of LVH does not reliably identify all mutation carriers, with consequences for cascade screening. Previous studies in small genotyped populations have suggested that reduced myocardial tissue Doppler velocities in unaffected relatives may predate the development of LVH and may therefore be useful in identifying at risk relatives. The value of such techniques in a large cohort of genotyped relatives remains unknown however. This study sought to prospectively evaluate ECG and Echo markers of early disease expression in a large genotyped cohort of families with mutations in myosin binding protein C (MYBPC3). Methods Relatives of index cases with HCM related to mutations in MYBPC3 (4 insertion/deletion, 7 missense, 4 nonsense, 5 intronic, 2 double heterozygotes) were evaluated. Clinical examination, ECG and transthoracic Echo (operator blinded to genetic status) were performed and combined with genetic predictive testing. The clinical value of ECG and Echo derived indices in predicting genotype were assessed. Results Of 95 relatives, 40 did not carry the family mutation (Group 1, 22 males, 38.5±16.7 years), 39 were unaffected mutation carriers (Group 2, 17 males, 37.4±16.8 years) and 16 were clinically affected and excluded from the study. ECG evidence of left atrial enlargement (21 vs 3%, p=0.01) and non-pathological Q waves (64 vs 28%, p=0.001) were more common in group 2 than group 1. S wave amplitude in lead V2 was greater in group 2 than group 1 (16.6±7.9 vs 12.4±8.2 mV, p=0.02) and also lead V3 (12.7±6.9 vs 9.3±6.1 mV, p=0.02). ECG criteria for left ventricular hypertrophy were specific but not sensitive for identifying mutation carriers (Abstract 073 table 1). Lateral annular late diastolic velocities were increased in group 2 but all other tissue Doppler indices were similar between the two groups (Abstract 073 table 2). The proposed cut-off values (from previous studies) were tested in our larger study and found to be clinically unhelpful; lateral Ea velocity Conclusions In previous small studies, tissue Doppler indices have been reported to be both sensitive and specific for identifying unaffected mutation carriers. However in our larger study, tissue Doppler imaging was unhelpful in predicting genotype and with current imaging techniques it is not possible to reliably identify unaffected mutation carriers before the development of ventricular hypertrophy.

A Brugada pattern on routine electrocardiography is one of several features that can indicate the potential for life threatening rhythm disturbances. The authors describe such a scenario in an asymptomatic 38-year-old woman who required significant surgery under anaesthesia. The diagnosis and possible management routes are outlined with an emphasis on the incumbent psychosocial and familial issues that are encountered. The patient underwent her surgery and was then further investigated to 'prove' the diagnosis. Ultimately, the patient declined further investigations and interventions. This case highlights the dilemma faced by anaesthetists and clinicians, not to mention the patients and their family when a Brugada phenotype is identified on a routine ECG. Clinicians should seek an expert opinion but ultimately, as in this case, the patient should be positioned to make an informed decision on what route to follow.

Background Patients with hypertrophic cardiomyopathy (HCM) exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathogenesis of HCM remains unproven. We hypothesised that the metabolic modulator, perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods Forty-six consecutive patients with symptomatic exercise limitation (peak oxygen consumption – peak VO2 Results Perhexiline improved myocardial PCr/ATP ratios (from 1.27±0.02 to 1.73±0.02; p=0.003) and normalised the abnormal prolongation of nTTPF between rest and exercise (δ nTTPF: +0.11±0.008 s vs −0.01±0.005; p=0.03). These changes were accompanied by improvement in peak VO2 (22.2±0.2 to 24.29±0.2 ml/kg/min; p=0.003) and symptoms (NYHA class by 0.8 units p Conclusion In symptomatic HCM, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathogenesis and provides a rationale for further consideration of metabolic therapies in HCM.

Dilated cardiomyopathy is a heart muscle disorder defined by the presence of a dilated and poorly functioning left ventricle in the absence of abnormal loading conditions (hypertension, valve disease) or ischaemic heart disease sufficient to cause global systolic impairment. A large number of cardiac and systemic diseases can cause systolic impairment and left ventricular dilatation, but in the majority of patients no identifiable cause is found—hence the term “idiopathic” dilated cardiomyopathy (IDC). There are experimental and clinical data in animals and humans suggesting that genetic, viral, and immune factors contribute to the pathophysiology of IDC.#### Causes of dilated cardiomyopathy Young Adolescent/adults ### Clinical presentation The first presentation of IDC may be with systemic embolism or sudden death, but patients more typically present with signs and symptoms of pulmonary congestion and/or low cardiac output, often on a background of exertional symptoms and fatigue for many months or years before their diagnosis. Intercurrent illness or the development of arrhythmia, in particular atrial fibrillation, may precipitate acute decompensation in such individuals. Increasingly, IDC is diagnosed incidentally in asymptomatic individuals during routine medical screening or family evaluation of patients with established diagnosis. A careful family history facilitates diagnosis of inherited causes of IDC by characterising the family phenotype, and also defines the scope of family screening.1 At least 25% of patients have evidence for familial disease with predominantly autosomal dominant inheritance. Clinically, familial disease is defined by the presence of two or more affected individuals in a single family and should also be suspected in all patients with …