To investigate the relationship between airflow limitation and airway inflammation in smokers, we examined paraffin-embedded bronchial biopsies obtained from 30 smokers: 10 with severe airflow limitation, eight with mild/moderate airflow limitation, and 12 control smokers with normal lung function. Histochemical and immunohistochemical methods were performed to assess the number of inflammatory cells in the subepithelium and the expression of CC chemokines macrophage inflammatory protein (MIP)-1alpha and -1beta in the bronchial mucosa. Compared with control smokers, smokers with severe airflow limitation had an increased number of neutrophils (p < 0.02), macrophages (p < 0.03), and NK lymphocytes (p < 0.03) in the subepithelium, and an increased number of MIP-1alpha+ epithelial cells (p < 0.02). When all smokers were considered together, the value of FEV1 was inversely correlated with the number of neutrophils (r = -0.59, p < 0.002), macrophages (r = -047, p < 0. 012), NK-lymphocytes (r = -0.51, p < 0.006) in the subepithelium, and with the number of MIP-1alpha+ epithelial cells (r = -0.61, p < 0.003). We conclude that in smokers the severity of airflow limitation is correlated with the severity of airway inflammation and that severe airflow limitation is associated with an increased number of neutrophils, macrophages, NK lymphocytes, and MIP-1alpha+ cells in the bronchial mucosa.

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Three novel 63 cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change. (J. Clin. Invest. 1994. 93:280-285.)

The consequences of transfusional iron overload on left ventricular diastolic filling have never been investigated systematically in patients with thalassemia major. In the present study, the pattern of left ventricular filling was assessed by Doppler echocardiography in 32 patients with thalassemia major (age, 17±5 years) who had not experienced symptoms of heart failure and had normal left ventricular systolic function. Data were compared with those obtained in 32 age-matched and sex-matched normal subjects. An abnormal Doppler pattern of left ventricular filling with increased flow velocity at mitral valve opening followed by an abrupt and premature decrease of flow velocity in early diastole was identified in the patients with thalassemia. Peak flow velocity in early diastole was increased in patients compared with controls (90±10 vs. 81+ 15 cm/sec; p<0.01), and rate of deceleration of flow velocity after the early diastolic peak and the ratio between the early and late (atrial) peaks of flow velocity were also increased (1,050±325 vs. 762±+193 cm/sec2 and 2.7±0.7 vs. 2.2+0.5, respectively;p<0.001) whereas flow velocity deceleration time was reduced (97±22 vs. 119±19 msec; p<0.001). This Doppler pattern of diastolic filling is usually described as "restrictive" and reflects a decrease in left ventricular chamber compliance. A restrictive pattern of left ventricular filling was also identified in the subgroup of 16 study patients who had undergone optimal iron chelation therapy with deferoxamine. Rate of deceleration of flow velocity after the early diastolic peak was increased, and flow velocity deceleration time was reduced in these 16 patients (1,080+±356 cm/sec2 and 94±19 msec) compared with controls (795±214 cm/sec2 and 118+19 msec, respectively; p<0.01). The results of this investigation demonstrate that left ventricular filling is altered in patients with thalassemia major and that diastolic abnormalities develop in an early phase of cardiac involvement, when symptoms of heart failure are absent and systolic function is normal. The findings of this study also suggest that chelation therapy with deferoxamine does not completely protect patients with thalassemia from myocardial danmage due to iron-related cardiac toxicity. (Circulation 1990;82:88-94) In patients with thalassemia major, long-terrn transfusion therapy, extravasal hemolysis, and increased intestinal absorption of iron result in systemic iron overload; the deposition of iron in the inyocardium causes left ventricular dysfunction.1-2 Although hemochromatosis of the heart is generally described as a dilated cardiomyopathy with increased left ventricular diastolic cavity dimension and depressed systolic function1-4 a restrictive cardiomyopathy with impaired left ventricular filling has also been reported in some patients with idiopathic hemochromatosis.5 7 Diastolic filling, however, has never been systematically investigated in patients with thalassemia major.Doppler echocardiography has been extensively used to assess left ventricular dias...

Hypertrophic cardiomyopathy has been investigated mainly at referral institutions. Thus, the clinical history of the disease that emerges from published studies could be influenced by a bias in patient selection. In the present study, we compared the clinical features of an outpatient population of 25 patients who had hypertrophic cardiomyopathy with those reported in 78 studies published during the past five years. In the 25 study patients, age, sex, and the extent of left ventricular hypertrophy, as well as the prevalence of diastolic filling abnormalities, subaortic obstruction, and ventricular arrhythmias, were similar to those in patients described in the literature. Cardiac symptoms, however, were much less severe in the study patients. Eighteen patients (72 percent) were asymptomatic, six (24 percent) had mild symptoms, and only one (4 percent) had moderate-to-severe symptoms. Of 24 patients followed for a mean period of 4.4 years (range, 2.9 to 5.7), none died or had clinical deterioration. Of 3404 patients described in the 78 studies we reviewed, 2483 (73 percent) came from only two referral institutions. Of the 1721 patients in whom severity of symptoms was reported, 757 (44 percent) had moderate-to-severe symptoms. However, 727 (96 percent) of these patients were studied at one of the same two referral institutions. We conclude that the natural history of hypertrophic cardiomyopathy may be more benign than can be inferred from published reports.