Rajesh Thaman

Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria.

OBJECTIVES We sought to ascertain the prevalence and mode of expression of familial disease in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). BACKGROUND Autosomal-dominant inheritance is recognized in ARVC. The prevalence and mode of expression of familial disease in consecutive, unselected families is uncertain. METHODS First- and second-degree relatives of 67 ARVC index patients underwent cardiac evaluation with history and examination, 12-lead and signal-averaged electrocardiogram (ECG), two-dimensional and Doppler echocardiography, metabolic exercise testing and Holter monitoring. Diagnoses were made in accordance with published criteria. RESULTS Of 298 relatives, 29 (10%; mean age 37.4 +/- 16.4 years) had ARVC. These were from 19 of the 67 families, representing familial involvement in 28%. Of these affected relatives, 72% were asymptomatic, 17% had ventricular tachycardia (sustained VT 10%, nonsustained VT 7%) and 21% had left ventricular involvement. A further 32 relatives (11%; 37.7 +/- 12.4 years) exhibited nondiagnostic ECG, echocardiographic or Holter abnormalities. Fifteen of these relatives were from families with only the proband affected, and inclusion of this subset of relatives would have resulted in familial ARVC in 48% of index cases. Four additional relatives (1% to 3%) fulfilled diagnostic criteria for dilated cardiomyopathy without any features of right ventricular disease. CONCLUSIONS By using current diagnostic criteria, familial disease was present in 28% of index patients. A further 11% of their relatives had minor cardiac abnormalities, which, in the context of a disease whose mode of inheritance is autosomal dominant, are likely to represent early or mild disease expression. We advocate that the current ARVC diagnostic criteria are modified to reflect the broader spectrum of disease that is observed in family members.

Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy

Background: Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain. Methods and results: 87 symptomatic patients (43.3 (13.7) years, 67.8% males) with HCM and no previously documented LVOTO (defined as a gradient ⩾30 mm Hg) underwent echocardiography during upright cardiopulmonary exercise testing: 54 patients (62.1%; 95% CI 51.5 to 71.6) developed LVOTO during exercise (latent LVOTO); 33 (37.9%; 95% CI 28.4 to 48.5) had neither resting nor exercise LVOTO (non-obstructive). Patients with latent LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM) at rest (relative risk 2.1, 95% CI 1.2 to 3.8; p = 0.01), and higher peak oxygen consumption (mean difference: 10.3%, 95% CI 2.1 to 18.5; p = 0.02) than patients with non-obstructive HCM. The only independent predictors of Δ gradient during exercise were a history of presyncope/syncope, incomplete/complete SAM at rest and Wigle score (all p<0.05). Subsequent invasive reduction of LVOTO in 10 patients with latent obstruction and drug refractory symptoms resulted in improved functional class and less syncope/presyncope (all p<0.05). Conclusions: Approximately two-thirds of patients with symptomatic non-obstructive HCM have latent LVOTO. This study suggests that all patients with symptomatic non-obstructive HCM should have exercise stress echocardiography.

Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy

Objective: 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. Methods: 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. Results: 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)). Conclusion: 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.

Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with α galactosidase A

Objective: 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). Conclusions: 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.

Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy

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.

Pregnancy related complications in women with hypertrophic cardiomyopathy

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.