Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.

OBJECTIVES: The purpose of this study was to examine the genotype-phenotype relation with respect to penetrance, age and severity of expression, disease progression and prognosis in a recessively inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. METHODS: Twelve families with Naxos disease underwent cardiac and molecular genetic investigation. Serial cardiac assessment with annual resting 12-lead and 24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardiography was performed during 1 to 16 years, median 7 +/- 6 years in all 78 surviving members. RESULTS: Twenty-eight surviving members were homozygous and 40 were heterozygous for the mutation. All adults who were homozygous (n = 26) fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. In eight who were heterozygous, minor ECG or echocardiographic abnormalities were observed. Of the 26 subjects who were affected homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right ventricular structural alterations and 27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmic events and 7 (27%) heart failure. The annual disease-related and sudden death mortality was 3% and 2.3%, respectively. CONCLUSIONS: Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by adolescence. Affected subjects who were homozygous experienced progressive disease with adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/echocardiographic changes, but clinically significant disease did not develop.

Fixed subaortic stenosis revisited. congenital abnormalities in 72 new cases and review of the literature.

Seventy-two patients aged 2-65 years (mean 20.2) with fixed subaortic stenosis (FSS) are reported. All patients underwent echocardiography and angiography prior to surgical intervention. Sixty-four (89%) had discrete subaortic stenosis (DSS) and 8 (11%) tunnel type stenosis (TSS). Patients with DSS aged 2-65 years (mean 29) while patients with TSS aged 10-34 years (mean 19) and had a distinct female preponderance (7:1). Twenty-five patients (39%) with DSS had other congenital abnormalities of which aortic stenosis associated with bicuspid aortic valve was slightly more common than ventricular septal defect (7:6). Five patients with TSS had a small aortic annulus and hypoplastic aorta. Our data and those in the literature indicate that TSS although related to DSS has certain features that may set it apart as a distinct entity. In addition DSS appears to be associated with aortic stenosis and bicuspid aortic valve as frequently as with ventricular septal defect.

Exercise capacity in patients with beta-thalassemia major: relation to left ventricular and atrial size and function.

OBJECTIVES: The objective of this study was to examine the association between exercise capacity and echocardiographic indexes of atrial and ventricular function and size in patients with beta-thalassemia major. BACKGROUND: In patients with beta-thalassemia major, the assessment of cardiac function with echocardiography alone does not always correspond to their functional status. Peak oxygen uptake and anaerobic threshold, on the other hand, constitute 2 objective and reproducible determinants of exercise capacity in patients with heart failure. METHODS AND RESULTS: Forty consecutive patients (22 women and 18 men, 18 to 30 years old) who were in stable condition while receiving regular transfusions and 30 age- and sex-matched control subjects were studied. At 2 to 3 days after the last transfusion, each subject underwent complete echocardiographic study followed by cardiopulmonary exercise testing. Left atrial volumes (maximal [Vmax], at onset of atrial systolic [Vp], and minimal [Vmin]) and left ventricular volumes were measured with the biplane area-length method, and left atrial active emptying fraction (ACTEF) and left ventricular ejection (LVEF) fraction were calculated. Peak oxygen uptake (Vo 2 max) and anaerobic threshold (AT) were also estimated. After transfusion, patients with beta-thalassemia major had reduced Vo 2 max and AT and greater left atrial volume in comparison with control subjects. Also, ACTEF and LVEF were significantly lower in the patient group. Moreover, Vo2 max and AT were inversely related to Vmax (r = -0.74 and r = -0.80, respectively) and directly related to ACTEF (r = 0.85 and r = 0.82, respectively) in beta-thalassemia major, whereas they were poorly related to LVEF (r = 0.50 and r = 0. 53, respectively). In the control group, Vo 2 max and AT parameters were related to Vmax and ACTEF in a similar way to that in the beta-thalassemia group. CONCLUSIONS: In patients with beta-thalassemia major, exercise capacity does not correlate with left ventricular dimensions and function. On the contrary, left atrial size and systolic dysfunction are probably predictors of decreased exercise capacity.

Left atrial mechanical function in the healthy elderly: new insights from a combined assessment of changes in atrial volume and transmitral flow velocity.

To assess left atrial mechanical function in the elderly, 35 old (age > 70 years) and 18 sex-matched young (age < 50 years) healthy subjects were studied. Transmitral flow velocities were recorded with pulsed Doppler echocardiography. Left atrial volumes were measured echocardiographically at mitral valve opening (maximal) and closure (minimal) and at onset of atrial systole (P wave of the electrocardiogram) according to the biplane area-length method. Left atrial passive emptying was assessed with the passive emptying volume (maximal-volume at onset of atrial systole) and fraction (passive emptying volume/maximal). Left atrial active emptying was assessed with the active emptying volume (volume at onset of atrial systole-minimal) and fraction (active emptying volume/volume at onset of atrial systole) and with left atrial ejection force = 0.5.blood density.volume at onset of atrial systole.active emptying fraction.(A velocity)2/A integral. Left atrial volumes were greater in old compared with young subjects (maximal: 31 +/- 10 cm3/m2 vs 24 +/- 8 cm3/m2, p = 0.02; at onset of atrial systole: 23 +/- 8 cm3/m2 vs 15 +/- 5 cm3/m2, p = 0.0002; minimal: 13 +/- 5 cm3/m2 vs 9 +/- 4 cm3/m2, p = 0.001). Passive emptying volume and fraction were lower (7.8 +/- 1.7 cm3/m2 vs 9.2 +/- 3.2 cm3/m2 [p = 0.04] and 26.4% +/- 9.8% vs 37.9% +/- 11.2% [p = 0.003], respectively), whereas atrial ejection force and active emptying volume were greater in old compared with young subjects (6.8 +/- 3.3 kdynes/m2 vs 4.2 +/- 2.8 kdynes/m2 [p = 0.007] and 9.2 +/- 4.1 cm3/m2 vs 5.7 +/- 2.9 cm3/m2 [p = 0.002], respectively). The active emptying fraction was similar in the two groups (39.7% +/- 11% vs 38.4% +/- 13%; difference not significant). Thus advanced age is associated with depressed left atrial passive emptying function and increased left atrial volume. Left atrial dilation contributes to an increase in atrial ejection force and the amount of blood ejected during left atrial systole and may represent an important compensatory mechanism in this age population.

Effect of atrial fibrillation on exercise capacity in mitral stenosis.

To determine the preoperative and postoperative effect of atrial fibrillation (AF) on exercise capacity in mitral stenosis, 12 digitalized patients in AF (7 women and 5 men, age 52 +/- 6.1 years) and 10 in sinus rhythm (5 women and 5 men, age 46 +/- 5 years) underwent maximal cardiopulmonary exercise testing according to Weber's protocol and Doppler echocardiographic examination before and at 3 and 6 months after mitral valve replacement. The ratio of right ventricular acceleration to ejection time was used as an estimate of mean pulmonary artery pressure. Preoperative exercise duration (6.8 +/- 1 vs 8 +/- 2 minutes), peak oxygen consumption (9.7 +/- 3 vs 12.3 +/- 3 ml/kg/min), and right ventricular acceleration to ejection time ratio (0.34 +/- 0.07 vs 0.34 +/- 0.08) were not significantly different between patients with AF and those in sinus rhythm. Postoperative improvement in these parameters was lower in patients with AF than in those in sinus rhythm: exercise duration at 3 months, 7.5 +/- 2 vs 11.9 +/- 2 minutes (p < 0.001); at 6 months, 9 +/- 2 vs 12 +/- 2 minutes (p < 0.001); peak oxygen consumption at 3 months, 10.8 +/- 3 vs 17.5 +/- 3 ml/kg/min (p < 0.001); and at 6 months, 11.9 +/- 3 vs 17.8 +/- 3 ml/kg/min (p < 0.001); right ventricular acceleration to ejection time ratio at 3 months, 0.35 +/- 0.08 vs 0.42 +/- 0.05 (p < 0.05); and at 6 months, 0.38 +/- 0.05 vs 0.44 +/- 0.05 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of a thrombotic tendency in patients with acute myocardial infarction and angiographically normal coronary arteries.

The hematological profile of 12 patients with acute myocardial infarction and normal coronary arteriographic findings was compared to that of 8 patients with acute myocardial infarction associated with obstructive coronary artery disease, and of 12 patients with no evidence of myocardial infarction and normal coronary arteriographic and left ventriculographic findings who served as control. There were no significant differences in the hematological profile among the 3 groups, suggesting lack of a thrombotic tendency in patients with acute myocardial infarction and normal coronary arteriographic findings.

Relation of left atrial volume and systolic function to the hormonal response in idiopathic dilated cardiomyopathy.

We studied the relation of left atrial mechanical function to the hormonal response in 14 patients with idiopathic dilated cardiomyopathy. Left atrial volumes were echocardiographically measured at mitral valve opening (maximal), at onset of atrial systole (onset of the P wave of the electrocardiogram) and at mitral valve closure (minimal) from the apical 2- and 4-chamber views using the biplane area-length method. Left atrial systolic function was assessed with the left atrial active emptying fraction ([volume at onset of atrial systole-minimal]/[volume at onset of atrial systole]). Plasma renin activity, aldosterone and atrial natriuretic peptide plasma levels were determined using commercially available kits. Left atrial maximal volume was directly, and left atrial active emptying fraction was inversely related to plasma renin activity (r = 0.60, P = 0.02 and r = -0.59, P = 0.026, respectively), aldosterone (r = 0.61, P = 0.02 and r = -0.53, P = 0.048) and atrial natriuretic factor (r = 0.79, P = 0.0009 and r = -0.62, P = 0.01) plasma levels. Thus, increased left atrial size and depressed left atrial contractile performance are associated with increased hormonal response in idiopathic dilated cardiomyopathy.

Factors affecting the postoperative exercise capacity of patients with mitral stenosis and aortic regurgitation.

Factors affecting the exercise capacity of patients with mitral stenosis (MS) and aortic regurgitation (AR) are incompletely understood. Accordingly, exercise capacity was assessed in 13 patients with MS and in 13 with AR by means of cardiopulmonary exercise testing before as well as 3, 6 and 12 months after valve replacement. Left- and right-ventricular function were evaluated echocardiographically. Both in MS and in AR exercise capacity expressed by maximal oxygen consumption (VO2max) increased significantly after valve replacement and was directly related to right ventricular (RV) function assessed by the ratio of RV acceleration time to RV ejection time (r = 0.87, p < 0.001 and r = 0.74, p < 0.001, respectively) and inversely related to left atrial diameter (r = -0.72, p < 0.001 and r = -0.76, p < 0.001, respectively). No relation between VO2max and resting left-ventricular function was found. Thus, the postoperative improvement in the exercise capacity both in mitral stenosis and in aortic regurgitation is associated with an improvement in right-ventricular function and a decrease in left-atrial size.