Severe pulmonary hypertension without pulmonary fibrosis occurred in 10 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), reputedly a benign variant of progressive systemic sclerosis. Time from the initial symptom, Raynaud's phenomenon, to the recognition of pulmonary hypertension was as long as 40 years. Pulmonary hypertension and increased pulmonary vascular resistance was shown in all patients. Autopsy examination in three of six deaths attributable to pulmonary hypertension showed intimal proliferation with myxomatous change in the small- and medium-sized pulmonary arteries similar to changes in the digital arteries of patients with scleroderma and Raynaud's phenomenon, and interlobular renal arteries of those with "scleroderma kidney." It is concluded that the CREST syndrome is not entirely benign but may be complicated, after a long clinical course, by progressive pulmonary vascular obliteration, pulmonary hypertension, and death in the absence of significant pulmonary fibrosis.

We demonstrate that familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder of heart muscle, is a genetically heterogeneous disease. The locus responsible for FHC in members of one large kindred was recently mapped to chromosome 14q11-12 (FHC-1). We have characterized three additional unrelated families in which the gene for FHC segregates as an autosomal dominant trait to determine if these disease loci also map to FHC-1. All family members were clinically studied by physical examination, electrocardiogram, and two-dimensional echocardiography. Genetic studies were performed using DNA probes which are derived from loci that are closely linked to FHC-1. In one family the genetic defect maps to the previously identified FHC-1 locus. However, the loci responsible for FHC in two other families were not linked to FHC-1. We conclude that FHC can be caused by defects in at least two loci and is a genetically heterogeneous disorder. (J. Clin. Invest. 1990. 86:993-999.)

A patient who developed severe iron overload cardiomyopathy is described. Venesection could not be performed because the patient had chronic anemia. Deferoxamine mesylate, a chelating agent, was administered daily for more than 2 years and produced significant improvement in ventricular function which was associated with a biopsy-proven decrease in myocardial iron stores. This is the first reported case in which a severe cardiomyopathy due to iron overload was reversed by chelation therapy alone.

Diastolic time intervals (DTIs) were calculated from simultaneous recordings of a phonocardiogram, apexcardiogram, and echocardiogram in 84 patients with hypertrophic cardiomyopathy and 35 patients with hypertrophy secondary to chronic pressure and volume loading and were compared with those in 31 normal subjects. The isovolumetric relaxation period (IRP) was measured as the interval from the aortic closure sound (A2, phonocardiography) to the opening of the mitral valve (MO, echocardiography) and the interval from A2 to the 0 point of the apexcardiogram was used as an index of total relaxation. Their difference, the MO-0 interval, was also calculated. In 12 patients with volume loading secondary to mitral regurgitation there was no significant difference in any of the DTIs compared with those in normal subjects. There was a wide range of IRPs (from 10 to 90 msec), and hemodynamic correlation in a representative patient with a short A2-MO interval revealed that this was due to premature MO secondary to a high V wave in the wedge pressure. In 12 patients with volume loading secondary to chronic aortic regurgitation there was an increase in the IRP (83 + 26 vs 62 + I I msec; p < .001) and a decrease in the MO-0 interval (48 + 27 vs 67 + 15 msec; p < .01), with no significant difference in their sum (the A2-0 interval). Hemodynamic data in one patient demonstrated that prolonged IRP was secondary to the large pressure drop from the A2 to the MO. In 11 patients with chronic pressure overload secondary to valvular aortic stenosis and in the 84 patients with hypertrophic cardiomyopathy there was no significant difference in the IRP as compared with that in normal subjects; in patients with these conditions the MO-0 interval was significantly increased, as was the A2-0 interval in the patients with hypertrophic cardiomyopathy. In four of the patients with aortic stenosis and in 15 patients with hypertrophic cardiomyopathy, the IRP was more than 2 SDs below the mean value in normal subjects. Hemodynamic correlation at cardiac catheterization in patients with both conditions demonstrated that a delayed A2 was primarily responsible for the abbreviated A2-MO interval and that this was secondary to a large left ventriculoaortic pressure gradient and/or the "hangout" phenomenon. In this situation A2 is an inappropriate marker of the onset of rapid left ventricular pressure decline and the A2-MO interval is not a valid reflection of diastolic relaxation. We conclude that the duration of DTIs is multifactorially determined and that none of these noninvasively measured intervals is a consistently valid gauge of left ventricular relaxation. In left ventricular hypertrophy, in which alterations in preload, afterload, and the timing of A2 are common, as are primary changes in the rate of left ventricular pressure decline, the duration of these intervals will represent the net effect of all of their determinants. Circulation 68, No. 1, 76-87, 1983

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