To describe the characteristics of sudden arrhythmic death syndrome (SADS) and compare its incidence with official national mortality statistics for unascertained deaths.
Design and setting
Sudden unexplained deaths were prospectively surveyed through 117 coroners' jurisdictions in England. Consecutive cases meeting the following criteria were included: white Caucasian, aged 4–64 years, no history of cardiac disease, last seen alive within 12 h of death, normal coroner's autopsy, cardiac pathologist's confirmation of a normal heart and negative toxicology.
Main outcome measures
The estimated mortality from SADS was calculated and the official mortality statistics for unascertained causes of deaths in 4–64‐year‐olds was identified for the same time period.
115 coroner's cases were reported and 56 (49%) SADS victims were identified: mean age 32 years, range 7–64 years and 35 (63%) male. 7 of 39 cases (18%) had a family history of other premature sudden deaths (<45). The estimated mortality from SADS was 0.16/100 000 per annum (95% CI 0.12 to 0.21), compared with an official mortality of 0.10/100 000 per annum for International Classification of Diseases 798.1 (sudden death, cause unknown—instantaneous death) or 1.34/100 000 per annum for unascertained causes of death.
Deaths from SADS occur predominantly in young males. When compared with official mortality, the incidence of SADS may be up to eight times higher than estimated: more than 500 potential SADS cases per annum in England. Families with SADS carry genetic cardiac disease, placing them at risk of further sudden deaths. SADS should therefore be a certifiable cause of death prompting specialised cardiological evaluation of families.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetically determined heart muscle disorder presenting clinically with even lethal ventricular arrhythmias, particularly in the young and athletes. It is reported familial with recessive and most commonly dominant inheritance. Disease‐causing genes are increasingly recognised among desmosomal proteins plakoglobin, desmoplakin, plakophilin2, and desmoglein2 displaying phenotypic heterogeneity. Mutations in the plakoglobin and desmoplakin genes have been identified to underlie recessive ARVC associated with woolly hair and palmoplantar keratoderma (Naxos disease), while mutations in plakophilin2, desmoglein2 as well as desmoplakin have been identified to underlie the dominant non‐syndromic form. Preliminary genotype–phenotype assessment indicates that mutations affecting the outer dense plaque of desmosome (desmoglein2, plakoglobin, plakophilin2 and the N‐terminal of desmoplakin) result in ARVC with the ordinary described phenotype. However, mutations at the inner dense plaque, particularly affecting the desmin‐binding site of desmoplakin, may result in ARVC with predominantly left ventricular involvement and clinical overlapping with dilated cardiomyopathy. The interesting finding of abnormal distribution of plakoglobin, independently of the primarily affected protein, might suggest a common pathway for plakoglobin in ARVC pathogenesis.
arrhythmogenic right ventricular dysplasia/cardiomyopathy; Naxos disease; cell‐adhesions; desmosomal proteins; sudden death
To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series.
956 adult (⩾ 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16–88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non‐referral centres published between 1960 and January 2003.
The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n = 48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter‐defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p = 0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy‐myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)).
Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres.
prognosis; hypertrophic cardiomyopathy; referral bias
dilated cardiomyopathy; left ventricular enlargement; Doppler tissue imaging; ventricular function
To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson‐Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT).
Methods and results
Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 μg/kg/min) was measured in 10 male, non‐smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non‐smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant).
The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.
cardiomyopathy; coronary circulation; myocardial blood flow; myocardial ischaemia; cardiac imaging
The majority of sudden deaths in young athletes occur in the context of underlying inherited or genetic cardiac disorders. The evaluation of every athlete regarding underlying cardiac disease is impractical and therefore needs to be targeted at those who are at a higher risk. A practical approach would be to channel efforts towards athletes with cardiac symptoms, those with a family history of inherited cardiac disease, and those with a family history of premature sudden death. There are potential pitfalls in the evaluation of young athletes using non-invasive tests when making the distinction between physiological adaptations to exercise and cardiac pathology. Physicians evaluating young athletes need to be aware of the spectrum of physiological adaptations and to be familiar with conditions responsible for sudden death in this population.
young athlete; sudden death; cardiovascular evaluation; competitive sports; cardiomyopathy
The diagnosis of hypertrophic cardiomyopathy has relied on echocardiographic demonstration of unexplained left ventricular hypertrophy. The prevalence of hypertrophic cardiomyopathy defined in this way has been estimated to be 1:500 and experience indicates that these criteria are relatively specific when other causes of left ventricular hypertrophy are absent. In recent years, however, the systematic evaluation of pedigrees performed in the context of molecular genetic studies revealed that in some families with hypertrophic cardiomyopathy up to 20% of adults who carry a disease causing gene defect do not fulfil conventional echocardiographic criteria. None the less, most of these individuals show symptoms, electrocardiographic alterations, and/or minor echocardiographic abnormalities. Revised diagnostic criteria in members of families with hypertrophic cardiomyopathy are proposed, including major and minor criteria based on symptoms, and electrocardiographic and echocardiographic abnormalities. Given that the chance of inheriting the gene defect is 1:2, the likelihood that symptoms plus electrocardiographic or echocardiographic abnormalities are the expression of a disease causing gene is high.
OBJECTIVE--To determine whether Borrelia burgdorferi is implicated in the pathogenesis of dilated cardiomyopathy in the United Kingdom. DESIGN--A controlled prospective study. Patients' notes were reviewed for evidence of Lyme disease and serum samples were tested by enzyme linked immunoadsorbent assay (ELISA) for antibodies to B burgdorferi. Samples with raised antibody concentrations were subsequently analysed by immunoblotting to determine their antibody binding specificity. SETTING--Tertiary referral centre. PATIENTS--97 consecutive patients with dilated cardiomyopathy diagnosed according to World Health Organisation criteria were studied. Serum samples were taken from two matched control groups. The first group (n = 38) was age, sex, and geographically matched. The second control group (n = 39) was environmentally matched and consisted of members of the patients' own households. MAIN OUTCOME MEASURES--Clinical evidence of Lyme disease. Presence of raised antibody concentrations to B burgdorferi. RESULTS--No patients had a previous illness compatible with Lyme disease. Analysis of the ELISA data showed eight of 97 patients with dilated cardiomyopathy (8.2%) and two of 77 controls (3.9%) had raised antibody concentrations. Immunoblot analysis, however, did not show binding patterns consistent with the presence of IgG specific for B burgdorferi in any of these samples. CONCLUSIONS--There was no clinical or serological evidence to implicate B burgdorferi in the pathogenesis of idiopathic dilated cardiomyopathy in the United Kingdom. In the absence of specific symptoms or likely exposure to B burgdorferi routine serological testing for Lyme disease in this group of patients is not recommended. Furthermore, raised antibodies to B burgdorferi are not diagnostic of active infection and ELISA results should be interpreted with caution unless specific B burgdorferi antibody bands have been found by immunoblot analysis.
Objective: To examine the influence of genotype on late gadolinium enhancement (LGE) and the potential of cardiovascular magnetic resonance (CMR) to detect preclinical hypertrophic cardiomyopathy.
Design: Prospective, blinded cohort study of myocardial LGE in a genetically homogeneous population.
Patients: 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−).
Main outcome measures: CMR measures of regional left ventricular function, wall thickness, and mass, and the extent and distribution of LGE.
Results: 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% with ⩾ 2 risk factors v 7% with ⩽ 1 risk factor, p = 0.02) and left ventricular mass (r = 0.56, p < 0.001) and was inversely associated with ejection fraction (r = −0.58, p < 0.001). Segmental analysis showed that as regional wall thickness increased, LGE was more prevalent (p < 0.0001) and more extensive (r = 0.98, p = 0.001).
Conclusion: 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.
hypertrophic cardiomyopathy; magnetic resonance imaging; fibrosis; gadolinium
Objectives: To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM).
Methods: 1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS) ⩽ 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported.
Results: 26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p = 0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p < 0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p = 0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p = 0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p = 0.001). Patients with SI had greater wall thinning (p = 0.001), left ventricular cavity enlargement (p < 0.0005), and deterioration in New York Heart Association functional class (p = 0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function.
Conclusions: SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.
cardiomyopathy; end stage; hypertrophy; systolic impairment
Images in cardiology
Objectives: To define physiological upper limits of left ventricular (LV) cavity size in trained adolescent athletes.
Design: Cross sectional echocardiographic study.
Setting: British national sports training grounds and Olympic Medical Institute.
Subjects: 900 elite adolescent athletes (77% boys) aged 15.7 (1.2) years participating in ball, racket, and endurance sports and 250 healthy controls matched for age, sex, and size.
Main outcome measures: LV end diastolic cavity size.
Results: Compared with controls, athletes had a larger LV cavity (50.8 (3.7) v 47.9 (3.5) mm), a difference of 6%. The LV cavity was > 54 mm in 18% athletes, whereas none of the controls had an LV cavity > 54 mm. The LV cavity exceeded predicted sizes in 117 (13%) athletes. Among the athletes with LV dilatation, 78% were boys, LV size ranged from 52–60 mm, and left atrial diameter and LV wall thickness were enlarged. Systolic and diastolic function were normal. None of the athletes in the study had an LV cavity size > 60 mm. LV cavity size correlated with age, sex, heart rate, and body surface area.
Conclusion: Highly trained junior athletes usually have only modest increases in LV cavity size. A proportion of trained adolescent athletes have LV cavity size exceeding predicted values but, in absolute terms, LV cavity rarely exceeds 60 mm as in patients with dilated cardiomyopathy. In highly trained adolescent athletes with an LV cavity size > 60 mm and any impairment of systolic or diastolic function, the diagnosis of dilated cardiomyopathy should be considered.
adolescent; elite athlete; athlete’s heart; cardiomyopathy; ventricular cavity dilatation
Objective: To investigate the role of cardiovascular magnetic resonance (CMR) in a series of patients with ECG repolarisation changes and normal echocardiography.
Patients and design: 10 patients with anterolateral T wave inversion for which there was no obvious pathological cause who had normal routine echocardiography without contrast for the exclusion of hypertrophic cardiomyopathy (HCM) also had CMR that was diagnostic of apical HCM.
Results: Apical HCM detected by CMR could be morphologically severe with wall thickness up to 28 mm, or mild. The extent of repolarisation abnormalities did not correlate to the morphological severity.
Conclusions: In patients with unexplained repolarisation abnormalities, a normal routine echocardiogram without contrast does not exclude apical HCM. Further imaging with CMR or contrast echocardiography may be required. The reliance on routine echocardiography to exclude apical HCM may have led to underreporting of this condition.
cardiovascular magnetic resonance; echocardiography; apical hypertrophic cardiomyopathy
hypertrophic cardiomyopathy; Leber’s hereditary optic atrophy; mitochondria
Objectives: To determine whether pregnancy is well tolerated in hypertrophic cardiomyopathy.
Setting: Referral clinic.
Design: The study cohort comprised 127 consecutively referred women with hypertrophic cardiomyopathy. Forty (31.5%) underwent clinical evaluation before pregnancy. The remaining 87 (68.5%) were referred after their first pregnancy. All underwent history, examination, electrocardiography, and echocardiography. Pregnancy related symptoms and complications were determined by questionnaire and review of medical and obstetric records where available.
Results: There were 271 pregnancies in total. Thirty six (28.3%) women reported cardiac symptoms in pregnancy. Over 90% of these women had been symptomatic before pregnancy. Symptoms deteriorated during pregnancy in fewer than 10%. Of the 36 women with symptoms during pregnancy, 30 had further pregnancies. Symptoms reoccurred in 18 (60%); symptomatic deterioration was not reported. Heart failure occurred postnatally in two women (1.6%). No complications were reported in 19 (15%) women who underwent general anaesthesia and in 22 (17.4%) women who received epidural anaesthesia, three of whom had a significant left ventricular outflow tract gradient at diagnosis after pregnancy. Three unexplained intrauterine deaths occurred in women taking cardiac medication throughout pregnancy. No echocardiographic or clinical feature was a useful indicator of pregnancy related complications.
Conclusions: Most women with hypertrophic cardiomyopathy tolerate pregnancy well. However, rare complications can occur and therefore planned delivery and fetal monitoring are still required for some patients.
hypertrophic cardiomyopathy; pregnancy; complications
Background: 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.
Objective: To determine the relation between diastolic annular velocities combined with conventional Doppler indices and symptoms or exercise capacity in hypertrophic cardiomyopathy.
Methods: 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.
Results: 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, p < 0.0001; septal Ea: 7 (2) v 12 (3) cm/s, p < 0.0001). 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, p < 0.0001). 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), p < 0.005) or class I (6.6 (2.6), p < 0.0001).
Conclusions: 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.
Doppler tissue imaging; mitral annular velocity; hypertrophic cardiomyopathy
Background: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere characterised clinically by myocardial hypertrophy and its consequences. Phenotypic expression is heterogeneous even within families with the same aetiological mutation and may be influenced by additional genetic factors.
Objective: To determine the influence of genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on ECG and two dimensional echocardiographic left ventricular hypertrophy (LVH) in genetically identical patients with HCM.
Patients and methods: Polymorphisms of five RAAS components were determined in 26 gene carriers from a single family with HCM caused by a previously identified myosin binding protein C mutation. Genotypes associated with a higher activation status of the RAAS were labelled “pro-LVH genotypes”.
Results: There was a non-biased distribution of pro-LVH genotypes in the gene carriers. Those without pro-LVH genotypes did not manifest cardiac hypertrophy whereas gene carriers with pro-LVH genotypes did (mean (SD) left ventricular muscle mass 190 (48) v 320 (113), p = 0.002; interventricular septal thickness 11.5 (2.0) v 16.4 (6.7), p = 0.01; pathological ECG 0% (0 of 10) v 63% (10 of 16), respectively). Multivariate analysis controlling for age, sex, and hypertension confirmed an independent association between the presence of pro-LVH polymorphisms and left ventricular mass. When each polymorphism was assessed individually, carriers of each pro-LVH genotype had a significantly greater left ventricular mass than those with no pro-LVH mutation; these associations, with the exception of cardiac chymase A AA polymorphism (p = 0.06), remained significant in multivariate analysis.
Conclusion: Genetic polymorphisms of the RAAS influence penetrance and degree of LVH in 26 gene carriers from one family with HCM caused by a myosin binding protein C mutation.
hypertrophic cardiomyopathy; polymorphisms; renin-angiotensin-aldosterone system
OBJECTIVES: To evaluate the spectrum of electrocardiographic (ECG) changes in 1000 junior (18 or under) elite athletes. METHODS: A total of 1000 (73% male) junior elite athletes (mean (SD) age 15.7 (1.4) years (range 14-18); mean (SD) body surface area 1.73 (0.17) m2 (range 1.09-2.25)) and 300 non-athletic controls matched for gender, age, and body surface area had a 12 lead ECG examination. RESULTS: Athletes had a significantly higher prevalence of sinus bradycardia (80% v 19%; p<0.0001) and sinus arrhythmia (52% v 9%; p<0.0001) than non-athletes. The PR interval, QRS, and QT duration were more prolonged in athletes than non-athletes (153 (20) v 140 (18) milliseconds (p<0.0001), 92 (12) v 89 (7) milliseconds (p<0.0001), and 391 (27) v 379 (29) milliseconds (p = 0.002) respectively). The Sokolow voltage criterion for left ventricular hypertrophy (LVH) and the Romhilt-Estes points score for LVH was more common in athletes (45% v 23% (p<0.0001) and 10% v 0% (p<0.0001) respectively), as were criteria for left and right atrial enlargement (14% v 1.2% and 16% v 2% respectively). None of the athletes with voltage criteria for LVH had left axis deviation, ST segment depression, deep T wave inversion, or pathological Q waves. ST segment elevation was more common in athletes than non-athletes (43% v 24%; p<0.0001). Minor T wave inversion (less than -0.2 mV) in V2 and V3 was present in 4% of athletes and non-athletes. Minor T wave inversion elsewhere was absent in non-athletes and present in 0.4% of athletes. CONCLUSIONS: ECG changes in junior elite athletes are not dissimilar to those in senior athletes. Isolated Sokolow voltage criterion for LVH is common; however, associated abnormalities that indicate pathological hypertrophy are absent. Minor T wave inversions in leads other than V2 and V3 may be present in athletes and non-athletes less than 16 but should be an indication for further investigation in older athletes.
OBJECTIVE: To determine the skeletal muscle metabolic manifestations of familial hypertrophic cardiomyopathy. DESIGN: A case-control study. SETTING: 31P magnetic resonance spectroscopy of the calf muscle was performed on volunteers from a centre specialising in familial hypertrophic cardiomyopathy. PATIENTS: Five patients with abnormal beta myosin heavy chain protein in cardiac and skeletal muscle and five patients with a troponin T abnormality in cardiac muscle were compared with healthy controls. RESULTS: High energy phosphate metabolism in vivo was examined in a non-invasive manner. In resting muscle, the beta myosin heavy chain group had a higher ratio of phosphocreatine to ATP concentration (4.51 (SD 0.17)) than either the troponin T group (3.88 (0.42)) or controls (n = 16; 4.04 (0.40)). Exercise duration was reduced compared to controls, and during the fourth minute of exercise phosphocreatine depletion and muscle acidification were greater in both patient groups. After exercise, the recovery of phosphocreatine-an index of oxidative metabolic capacity of the muscle-was slower in the beta myosin heavy chain group (mean half time 0.65 (0.08) minutes) than in the troponin T group (0.60 (0.17) minutes) or controls (0.48 (0.14) minutes). CONCLUSIONS: Exercise metabolism was abnormal in both groups of subjects, and the affected contractile protein determined the metabolic changes in muscle at rest and during recovery. In patients with abnormal beta myosin heavy chain protein, there was a decrease in oxidative capacity consistent with the reduction in mitochondria reported in muscle biopsy studies of similar patients.
OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up. METHODS: Antibody status was assessed by indirect immunofluorescence in 110 patients with dilated cardiomyopathy (85 male, mean (SD) age 44 (13) years) at diagnosis and at follow up (mean (SD) 14 (12) months); in 57 of them cardiac specific anti-alpha myosin antibody titres were also measured by an enzyme-linked immunosorbent assay (ELISA). Patients underwent complete evaluation at diagnosis and clinical and non-invasive assessment at follow up, including exercise testing with maximal oxygen consumption measurements. RESULTS: The frequency of cardiac specific antibodies by immunofluorescence was lower at follow up than at diagnosis (28 (25%) v 11 (10%), P = 0.002). Mean (SEM) anti-alpha myosin antibody titres at follow up were also lower than at diagnosis (0.24 (0.02) v 0.30 (0.02), P = 0.038); 24% of patients at diagnosis and 14% at follow up had an abnormal ELISA result. None of the patients who were negative by immunofluorescence or ELISA at diagnosis became positive at follow up. Presence of antibody at diagnosis was associated with milder symptoms and greater exercise capacity at follow up and persistence of antibody at follow up was associated with stable disease and milder symptoms at diagnosis. CONCLUSIONS: Cardiac specific autoantibodies in dilated cardiomyopathy become undetectable with disease progression; this is a recognised feature of other autoimmune conditions, such as type 1 diabetes. Detection of these antibodies at diagnosis and at follow up may provide a non-invasive marker of early dilated cardiomyopathy.
OBJECTIVE--To use an enzyme linked immunoassay (ELISA) technique to assess frequency and disease specificity of anti-alpha-myosin antibodies in patients with dilated cardiomyopathy and their relatives. METHODS--Evaluation was performed on sera (dilution 1/320) from 123 consecutive patients with dilated cardiomyopathy (WHO criteria) (age 42 (SD 14) years), 252 of their relatives (35 (17) years), 203 healthy controls (45 (16) years), and 92 patients with ischaemic heart disease (63 (11) years). RESULTS--Abnormal antibody levels were commoner in patients with dilated cardiomyopathy (25, 20%) than in ischaemic heart disease (4, 4%), or normal controls (4, 2%, P = 0.001). Forty one (16%) of the relatives had abnormal results compared to the controls (4, 2%, P < 0.001) and antibodies were detected in 20 (38%) of pedigrees. Relatives from non-familial kindreds had higher antibody levels than those with familial disease (P << 0.001), and higher antibody levels were identified in 53 relatives of probands who had abnormal results compared to 116 relatives for whom the proband had a normal result (0.37 (SEM 0.02) v 0.22 (0.01); P < 0.001). CONCLUSIONS--The finding of anti-alpha-myosin antibodies in 20% of patients with dilated cardiomyopathy, in 16% of their asymptomatic relatives, and in 38% of families (particularly those with non-familial disease and where proband also had an abnormal result) provides additional evidence for autoimmunity against alpha myosin in a subset of patients.
OBJECTIVES--To determine the frequency and mode of inheritance of familial dilated cardiomyopathy in the United Kingdom. BACKGROUND--Two recent prospective studies have suggested that familial forms of dilated cardiomyopathy are common but have been limited by selective screening methods, inadequate diagnostic criteria, and low rates of ascertainment. METHODS--Prospective screening study of 236 relatives from 40 families of patients with dilated cardiomyopathy. Screening consisted of clinical examination, 12 lead electrocardiogram, and two-dimensional Doppler echocardiography. Relatives with systemic hypertension and other cardiac diseases were excluded from the study. All echocardiograms were performed by an experienced echocardiographer who was blinded to clinical information. Relatives were classified as having dilated cardiomyopathy, left ventricular enlargement (method of Henry), depressed fractional shortening, or as being normal. Relatives with abnormal investigations underwent further evaluation as appropriate. RESULTS--Twenty five cases of dilated cardiomyopathy were identified and came from 10 (25%) of the 40 families screened. Pedigree analysis was most consistent with autosomal dominant inheritance and variable penetrance (65-95%). Of the remaining apparently healthy relatives, 37 (18%) were found to have left ventricular enlargement and nine (4%) depressed fractional shortening; these values were significantly higher than those observed in 239 healthy controls (24 (10%), P = 0.02 and one (0.4%), P = 0.01, respectively). CONCLUSIONS--Patients with dilated cardiomyopathy commonly have an affected family member and a high proportion of apparently healthy relatives with minor echocardiographic abnormalities. Segregation analysis suggests that familial dilated cardiomyopathy is the result of the transmission of a rare autosomal dominant gene. Further studies are currently underway to characterise the molecular basis of familial dilated cardiomyopathy and identify early disease within these families.