SUMMARY Sixteen healthy subjects, ages 18-35 years, were studied in the supine position by means of systolic time intervals and echocardiography before and after smoking a high-nicotine cigarette (2.5 mg nicotine) and a tobacco cigarette of very low nicotine content (< 0.02 mg nicotine) to assess and compare the immediate effects upon left ventricular function.Smokers (n = 12) and nonsmokers (n = 4) behaved alike. High-and low-nicotine cigarettes both caused significant increases in heart rate, systolic and diastolic blood pressure and the triple product (systolic blood pressure X left ventricular ejection (LVET) X heart rate), prolonged LVETc and decreased the preejection period (PEP) and PEP/LVET. In addition, smoking a nicotine reference cigarette increased the echocardiographically derived LV end-diastolic volume by 7.5%, augmented ejection fraction by 4%, while significantly enhancing mean normalized circumferential fiber shortening by 12.5% and mean normalized posterior wall velocity by 9%. Smoking a tobacco cigarette of ultra-low nicotine content resulted in comparable increases in ejection fraction and mean circumferential fiber shortening, albeit on the basis of a significant decrease in end-systolic volume without alteration in end-diastolic volume.These data suggest that in the supine position smoking a high-nicotine cigarette acutely increases venous return and augments the principal determinants of myocardial oxygen consumption heart rate, contractility, preload and afterload and that cigarette smoke may contain inotropic and chronotropic substances other than nicotine.CIGARETTE SMOKING has been linked epidemiologically as a risk factor in the development of myocardial infarction and has been associated with an increase in sudden death among chronic cigarette consumers.', I The cause of this increased morbidity and mortality has not been established; among the factors under consideration are hypoxemia,3 enhanced cor-

The role of cell membrane permeability to sodium in cell volume regulation during inhibition of the sodium-potassium exchange pump with ouabain and during total metabolic blockade was evaluated in sections of guinea pig renal cortex, ventricle, and atrium incubated in Krebs-Henseleit solution. In all tissues, 2 and 3 h of ouabain and metabolic blockade resulted in similar marked losses of potassium and parallel continuous reductions in resting membrane potentials. Only metabolic blockade of renal cortex increased cell water, chloride, and total monovalent cations (potassium plus sodium) significantly. Compared to ouabain, metabolic blockade markedly increased the rate of cellular washout of 24Na+ from renal cortex (t 1/2 reduced by 47%), which was significantly greater than reductions in t 1/2 from ventricle (16%) and atrium (15%). Thus, inhibition of sodium-potassium exchange pump activity was not sufficient to produce cell swelling unless associated with marked increases in cell membrane permeability to sodium, in which case sodium influx exceeded potassium loss and substantial increases in monovalent cations, chloride, and water occurred.

To test the therapeutic efficacy of immunosuppression with cyclophosphamide (CYP) on coxsackievirus B3 (CB3) myocarditis, 2-week-old DBA/2 mice were inoculated with 3X102 plaque-forming units of CB3 vlrus. CYP (100 mg/kg/day s.c.) was administered daily on days 0-8 (experiment 1; group 2), days 8-21 (experiment 2; group 4), and days [21][22][23][24][25][26][27][28][29][30][31][32][33][34] (experiment 3; group 6). Groups 1, 3, and 5 were infected control groups for each experiment. Spleen, thymus, and body weights were measured. In experiment 1, survival rate in group 2 on day 8 was low compared with group 1 (nine of 51 versus eight of 28; p=NS), and myocardial virus titers in group 2 on day 8 were higher (p<0.05) compared with group 1; however, cellular infiltration and myocardial necrosis in group 2 were less severe (p<0.05), and serum neutralizing antibody titers were decreased (p<0.01). In experiment 2, survival rate in group 4 on day 21 was significantly lower (six of 24 versus 12 of 16; p<0.01), but cellular infiltration, myocardial necrosis, and calcification in group 4 were significantly less severe, and serum neutralizing antibody titers were decreased (p<0.01). In experiment 3, survival rate, cardiac histopathology, and serum neutralizing antibody titers did not differ between groups 5 and 6. In experiments 1, 2, and 3, the treated groups were characterized by lower spleen-to-body-weight and thymus-to-body-weight ratios and by marked cellular depletion in spleen and thymus. A similar reduction of cardiac histopathology, associated with lymphoid organ atrophy in the treated group, was demonstrated in the early study (day 4) in experiment 1. Thus, the administration of CYP (100 mg/kg/day) induced immunosuppression in CB3 myocarditis in mice. Notwithstanding an associated higher mortality rate, the severity of cardiac pathology was reduced in the acute stage. However, no beneficial effects were seen in the later stage. It is concluded that immune mechanisms play a role in the early stage of development of CB3 myocarditis. (Circulation 1990;82:982-989)

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A B S T R A C T As part of an inquiry into possible antecedents of idiopathic cardiomyopathy, acute experimental coxsackie virus myocarditis was studied for late structural and functional sequelae. Myocarditis was induced in 12-and 22-day-old hamsters by inoculation with coxsackie virus B3. Early viremia occurred, followed by virus replication in heart muscle.Maximum peak developed tension (Tpd) of isometrically contracting isolated heart muscle was depressed 17 and 43% in the animals inoculated at 12 days, and studied 18 and 90 days later, respectively, as compared to their uninoculated controls. In both infected groups, less muscle stretch was required to reach the length at which Tpd was produced. Animals studied 180 days after inoculation did not differ from controls.The muscles from animals inoculated at 22 days of age and studied 18 days later showed a 15% depression of Tpd compared to their controls. Glycerinated muscles from this infected group developed 50% less tension than their controls. The muscles of hamsters inoculated with virus at 22 days and studied 90 and 180 days later showed no change in Tpd.The data suggest that contractility and compliance of heart muscle are decreased 18 days after inoculation, but recover by 90 days if the animals are inoculated at age 22 days. However, if the animals are inoculated at a younger age (12 days), depression of myocardial performance persists for at least an additional 90 days.It is concluded that the inflammatory stage of experimental acute coxsackie virus B3 myocarditis in the