Toxicant-disease-environment interactions associated with suppression of immune system, growth, and reproduction.

The effects of marginal malnourishment , infections, and environmental chemicals on growth and reproductive success in Swiss-Webster white mice and wild deer mice were studied with fractional factorial designs. Interaction effects were discovered. For example, malnourished mice were more sensitive to virus exposure and environmental chemicals (a plant growth regulator or polychlorinated biphenyls). Since several commercial plant growth regulators also appear to suppress the immune system, these results cast doubt on the adequacy of current toxicity testing procedures in which factors are studied individually and not in combination.

Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic assessment of 14 hearts from autopsy.

In each heart taken from autopsies of 14 men with idiopathic hemochromatosis, the conduction system, atria and 10 sites in the ventricles were histologically graded for stainable iron. Stainable iron was exclusively sarcoplasmic; none was observed in the interstitium. The histologic grade for the same anatomic site varied among hearts and among different anatomic sites in the same heart. Ten hearts had stainable iron in all ventricular sites; one of the three hearts from patients who had undergone therapeutic phlebotomy had no iron at any site. Seven hearts had iron in the atria but at a lesser grade than that found in the ventricles; six hearts had mild focal iron deposition in the atrioventricular conduction system. None of the 14 hearts had stainable iron in the sinus node. Elemental iron was quantitated by atomic absorption spectroscopy in ventricular specimens contiguous to those studied histologically and also in age-matched control hearts. Elemental iron content was markedly increased in hearts with idiopathic hemochromatosis compared with control hearts (p less than 0.01). The quantity of elemental iron varied greatly, similar to stainable iron, but was highest subepicardially. Among the hearts from the 11 patients without prior phlebotomy, three had no stainable iron in the right ventricular septal subendocardium, suggesting that sampling error may be a problem in the evaluation of hemochromatosis by endomyocardial biopsy. The sarcoplasmic location of the iron indicates that cardiac involvement in idiopathic hemochromatosis represents a storage disease and not an infiltrative process; this finding is consistent with the normal ventricular wall thicknesses observed.

Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases.

Clinical and pathologic features of cardiac hemochromatosis diagnosed by endomyocardial biopsy in six men, aged 32 to 75 years (mean 52), are described. Echocardiography demonstrated left ventricular enlargement and marked global systolic dysfunction in five. Cardiac catheterization demonstrated normal coronary arteries, increased left ventricular end-diastolic pressure and decreased left ventricular systolic function in all five so studied. Stainable iron was present in all endomyocardial biopsy specimens from the five patients with decreased left ventricular systolic function. Histologically, iron was detected only within the sarcoplasm, and its extent varied inversely with ventricular function. Thus, cardiac hemochromatosis represents a storage rather than an infiltrative disease. These results indicate that stainable iron is consistently observed in endomyocardial biopsy specimens from patients with impaired left ventricular systolic function. Iron staining is recommended for endomyocardial biopsy specimens from patients with idiopathic cardiac dysfunction.

Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation.

Effects of a novel soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the alpha 1 and beta 1 subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn2+ or Mn(2+)-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 mumol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 mumol/L) and nitroglycerin (0.01 to 300 mumol/L). ODQ (10 mumol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimakalim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.

The premortem recognition of systemic senile amyloidosis with cardiac involvement.

PURPOSE: To recognize systemic senile amyloidosis involving the heart and to determine outcome. PATIENTS AND METHODS: All patients with the diagnosis of amyloidosis at the Mayo Clinic from January 1, 1984 through May 1, 1992, were reviewed. Amyloid was confirmed histologically by sulfated alcian blue and alkaline Congo red staining. The labeled streptavidin-biotin immunoperoxidase method was used with antisera against A kappa, A lambda, AA, transthyretin, and beta 2-microglobulin. Anti-P-component and antisera to albumin were used as controls. Chest radiographs, electrocardiograms, transthoracic echocardiograms, and cardiac catheterization data of all patients were reviewed. Serum and urine were examined with immunoelectrophoresis and immunofixation for the presence of a monoclonal protein. Lymphocyte DNA was examined for transthyretin mutations associated with familial amyloidosis. RESULTS: We identified 18 patients with myocardial tissue that stained positive for amyloid with sulfated alcian blue and Congo red and with transthyretin antisera. Congestive heart failure was present at diagnosis in 17 of the 18 patients. Atrial fibrillation was found in 11 patients. No monoclonal protein was found in the serum or urine. The echocardiographic findings were consistent with infiltrative cardiomyopathy due to amyloidosis in 16 patients. Right heart pressures were elevated in all 7 patients who had right-side heart catheterization. No transthyretin mutations were found in the leukocyte DNA from 12 patients. The actuarial median survival was 5 years; in contrast, the median survival was 5.4 months in 147 patients with primary amyloidosis (AL) who presented with congestive heart failure. CONCLUSION: Patients with cardiac amyloid and no monoclonal protein in the serum or urine must have immunohistochemical staining for kappa and lambda light chains and transthyretin to distinguish between systemic senile amyloidosis, familial amyloidosis, and AL. Patients with systemic senile amyloidosis should not be treated with alkylating agents. Their survival is much longer than that of patients with AL (60 versus 5.4 months).

Right ventricular assessment in patients presenting for lung transplantation.

Chronic pulmonary disease is associated with varying degrees of cardiac dysfunction. Because of the potentially predominant effect of severe lung disease on right ventricular (RV) size and function, a reliable method to assess RV mechanics before and after lung transplantation may provide information of long-term significance and/or prognosis. Conventional invasive and non-invasive imaging methods have a number of limitations in evaluating RV function. Ultrafast computed tomographic (ultrafast CT) scanning has been shown to provide quantitative assessment of RV and left ventricular (LV) function in individuals with and without cardiac disease. Twenty-two patients presenting during evaluation for possible lung transplantation with end-stage pulmonary disease formed the basis of this study. There were 14 patients with chronic obstructive pulmonary disease and 8 with pulmonary fibrosis. Conventional transthoracic echocardiography and ultrafast CT were used for the assessment of RV and LV function. All patients had invasive assessment of right-sided hemodynamics and pulmonary function studies performed within 7-10 days of cardiac imaging. A qualitative assessment of RV size or function was possible in all but two patients by echocardiogram, but in 45%, the echocardiographic examination was described as suboptimal. In contrast, a quantitative assessment of ventricular volumes and systolic function was obtained in all patients by ultrafast CT. Pulmonary function parameters or hemodynamic measurements obtained during cardiac catheterization did not correlate with any assessment of RV function. We concluded that (1) ultrafast CT provides measurement of the RV and LV cavity dimension and systolic function; (2) invasive right-sided hemodynamics or pulmonary function studies do not predict RV function; and (3) echocardiography does not uniformly provide assessment of RV function in patients with chronic pulmonary disease.

Effects of pentoxifylline on renal function and blood pressure in cardiac transplant recipients: a randomized trial.

BACKGROUND: The current success of cardiac transplantation is in part attributable to the development of effective immunosuppressive agents such as cyclosporine. However, concern remains regarding the potential for cyclosporine-induced nephrotoxicity. Animal studies and early reports of renal protective effects of pentoxifylline in bone marrow transplant recipients prompted a randomized trial in cardiac transplant recipients. METHODS: Twenty-nine patients were randomized to receive pentoxifylline 400 mg p.o. t.i.d. or matching placebo for 1 year after cardiac transplantation. Renal function was assessed preoperatively and at 1, 6, and 12 months postoperatively. Glomerular filtration rate and renal plasma flow were measured with iothalamate and para-aminohippurate, respectively. Serum creatinine was also measured. Ambulatory blood pressure monitoring after withdrawal of antihypertensives for 3 days was performed 12 months postoperatively. RESULTS: Twenty-seven patients completed the study. Glomerular filtration rate rose between 1 and 6 months after transplantation, presumably due to the reduction in goal cyclosporine level in that period, and then fell modestly between 6 and 12 months, presumably due to ongoing nephrotoxic effects of cyclosporine. No difference in glomerular filtration rate or creatinine was seen between pentoxifylline and placebo groups at any interval. Renal plasma flow increased modestly between baseline and 6 months in the pentoxifylline group, but not in the placebo group, and then fell between 6 and 12 months. Serum creatinine increased between baseline and 6 months in both groups, apparently due to increased body weight. Results of 18-hr ambulatory blood pressure monitoring obtained 1 year after transplantation was not different between groups. CONCLUSIONS: Renal function declines only modestly in the first year after cardiac transplantation. Pentoxifylline did not attenuate this process and had no effect on blood pressure. The modest decline in renal function may be related to current immunosuppressive strategies.

Echocardiographic features of idiopathic hemochromatosis.

To characterize cardiac involvement in idiopathic hemochromatosis, clinical records and 2-dimensional (2-D) echocardiograms of 24 patients with idiopathic hemochromatosis were reviewed. The 17 men and 7 women were 24 to 80 years old (mean 48). Of 19 patients without valvular, ischemic, hypertensive or other known heart disease, 7 (37%) had structural and functional echocardiographic abnormalities attributed to idiopathic hemochromatosis (group 1) and 12 had normal echocardiographic findings (group 2). Age, gender and laboratory markers of iron overload did not differentiate patients with cardiac dysfunction (group 1) from those without cardiac dysfunction (group 2). In group 1, echocardiographic abnormalities included chamber dilatation and global systolic dysfunction. Increased wall thickness was not a feature of idiopathic hemochromatosis. All group 1 patients had abnormal electrocardiographic findings and cardiomegaly on radiography. Despite therapeutic phlebotomy, 4 patients in this group died, between 0.5 and 30 months after echocardiography, because of congestive heart failure. In conclusion, there is a spectrum of cardiac dysfunction in idiopathic hemochromatosis. In patients with idiopathic hemochromatosis and left ventricular dysfunction, absolute wall thickness is normal. Survival is poor in patients with idiopathic hemochromatosis and severe left ventricular dysfunction.

Symptomatic conduction system disease in cardiac amyloidosis.

Symptomatic conduction system disease in cardiac amyloidosis and its management has been reported infrequently. We report our experience of patients with amyloidosis having symptomatic conduction system disease requiring permanent pacemaker implantation.

Management of patients after cardiac transplantation.

During the past decade, the morbidity and mortality associated with cardiac transplantation have decreased dramatically. The current survival for patients who undergo orthotopic cardiac transplantation is 80 to 90% at 1 year and 70 to 80% at 5 years; these results are attributed chiefly to improved immunosuppression and the consequent decrease in infectious illnesses and rejection. Because surgical mortality and technique have not changed appreciably during the past 20 years, improved survival can be ascribed to advances in the medical management of recipients of cardiac transplants. Medical problems frequently encountered in such patients include allograft rejection, allograft vasculopathy, hypertension, renal dysfunction, hyperlipidemia, hyperglycemia, malignant disorders, general surgical disease, and osteopenic bone disease. Hence, the expertise needed for management of patients who undergo cardiac transplantation is not confined to a particular specialty--optimal care necessitates the integrated efforts of a team, including transplant physicians and personnel to provide broad subspecialty and laboratory support. Meticulous management with proactive intervention and minimal effective immunosuppression will prevent or ameliorate many problems and contribute to increased survivorship and improved quality of life. For additional substantive improvement in long-term survival and quality of life for recipients of cardiac allografts, multicenter, prospective, and placebo-controlled clinical investigations will be necessary.

Surgical pathology of combined aortic stenosis and insufficiency: a study of 213 cases.

The gross surgical pathologic features of the aortic valve were reviewed in 213 patients who had had clinically combined aortic stenosis and insufficiency and aortic valve replacement at our institution during the years 1965, 1970, 1975, and 1980. The three most common causes were postinflammatory disease (69%) and calcification of congenitally bicuspid (19%) and unicommissural (6%) aortic valves. Other causes included infective endocarditis (2%) and congenitally quadricuspid or malformed tricuspid aortic valves (1% each); the cause was indeterminate in 1%. In the postinflammatory and bicuspid states, calcification tended to be more extensive in men than in women. The relative incidence of postinflammatory disease in our study did not change appreciably from 1965 to 1980, despite the steadily decreasing incidence of acute rheumatic fever reported in western countries.

Surgical pathology of pure aortic stenosis: a study of 374 cases.

The gross surgical pathologic features of the aortic valve were reviewed in 374 patients who had had clinically pure aortic stenosis and aortic valve replacement at our institution during the years 1965, 1970, 1975, and 1980. The most common cause of aortic stenosis, accounting for 46% of our cases, was calcification of a congenitally bicuspid valve. In the remainder, stenosis was produced by postinflammatory fibrocalcific disease (including rheumatic disease) in 35%, by degenerative calcification of an aging valve in 10%, and by calcification of a congenitally unicommissural valve in 6%. The cause of aortic stenosis was indeterminate in 4%. Valvular lesions included various degrees of dystrophic calcification, commissural fusion, and cuspid fibrosis. Calcification tended to occur more extensively and at a younger age in men than in women. Furthermore, it tended to produce stenosis and to necessitate valve replacement earliest in patients with unicommissural valves (mean age, 48 years), later in those with bicuspid or postinflammatory valves (mean age, 59 and 60 years, respectively), and latest in those with degenerative stenosis (mean age, 72 years). In our study, the relative incidence of postinflammatory aortic stenosis remained unchanged from 1965 to 1980, despite the steadily decreasing incidence of acute rheumatic fever reported in western countries. Our data suggest that (1) the incidence of chronic rheumatic heart disease has not yet begun to decrease appreciably, (2) many episodes of acute rheumatic fever may be subclinical, or (3) some forms of nonrheumatic aortic valve disease may produce gross alterations indistinguishable from those of classic chronic rheumatic valvulitis.

Surgical pathology of pure aortic insufficiency: a study of 225 cases.

The gross surgical pathologic features of the aortic valve were reviewed in 225 patients who had had clinically pure aortic insufficiency and aortic valve replacement at our institution during the years 1965, 1970, 1975, and 1980. The four most common causes of aortic regurgitation were postinflammatory disease (46%), aortic root dilatation (21%), incomplete closure of a congenitally bicuspid aortic valve (20%), and infective endocarditis (9%). Other causes of aortic incompetence in our study included ventricular septal defects (2%) and quadricuspid aortic valves (1%); the cause was indeterminate in 1%. The mean age of patients at valve replacement was approximately 50 years for all etiologic factors except a ventricular septal defect. All forms of aortic insufficiency were much more common in male than in female patients, except the postinflammatory and indeterminate types, which occurred approximately equally in both sexes. Moreover, the incidences of postinflammatory disease and aortic root dilatation changed appreciably with time. Before 1980, their incidences were 51% and 17%, respectively, but during 1980, they were 29% and 37%, respectively. Accordingly, aortic root dilatation is now the most common cause of pure aortic regurgitation in our surgical population. The decrease in the incidence of postinflammatory disease may be a result of the decreasing incidence of acute rheumatic fever reported in western countries.

Cardiac involvement in Lyme disease: manifestations and management.

Cardiac involvement in Lyme disease may manifest as atrioventricular block, myopericarditis, and left ventricular dysfunction. Diagnosis depends on recognition of the systemic nature of Lyme disease, including cardiac involvement, and its natural history. Serologic tests that are both sensitive and specific may aid in diagnosis. Although current recommendations for the treatment of Lyme disease with carditis include antibiotics and salicylates or corticosteroids, these types of therapy have not been unequivocally demonstrated to alter the natural history of cardiac involvement. Supportive therapy may necessitate temporary transvenous cardiac pacing in symptomatic patients.

Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years.

The gross surgical pathologic features of the mitral valve were reviewed in 712 patients who had undergone mitral valve replacement at our institution during 1965, 1970, 1975, 1980, and 1985. Among the 452 cases of mitral stenosis, either with or without mitral insufficiency, 99% were attributable to postinflammatory disease and 1% were related to congenital mitral stenosis. Among the 260 cases of pure mitral regurgitation, the two most common causes were a floppy valve (38%) and postinflammatory disease (31%). Moreover, a floppy valve was observed in 73% of the 59 examples of chordal rupture and in 38% of the 16 cases of infective endocarditis. Women accounted for 73% of the 452 cases of mitral stenosis and for 72% of the 530 cases of postinflammatory disease. In contrast, men accounted for 58% of the 260 cases of pure mitral regurgitation, including 76% of the floppy valves and 69% of the infected valves. During the 21 years spanned by the study, the relative frequency of postinflammatory mitral insufficiency progressively decreased, whereas that of floppy mitral valves increased. It is unclear whether aging, heredity, environmental factors, changes in the frequency of acute rheumatic fever, or changes in patient referral practices may account for this observation.

Surgical pathology of the pulmonary valve: a study of 116 cases spanning 15 years.

The gross surgical pathologic features of the pulmonary valve were reviewed in 116 patients (63 male and 53 female) who had undergone a cardiac operation with pulmonary valve excision at our institution during the period 1973 through 1987. Although the mean age was 12 years, subjects ranged in age from 3 months to 73 years, and 25 patients, including 19 with congenital heart disease, were older than 20 years of age. Among 105 patients who had pure pulmonary stenosis, 61 (58%) had tetralogy of Fallot, 18 had isolated pulmonary stenosis, 23 had other congenital cardiac anomalies, and 3 had carcinoid heart disease. Five patients had pure pulmonary regurgitation (four with tetralogy and one with infective endocarditis), and four had combined pulmonary stenosis and regurgitation (two with congenital cardiac anomalies and two with carcinoid heart disease). In two patients, the valve was neither stenotic nor regurgitant. Thus, congenital heart disease accounted for 110 of the 116 cases (95%), and tetralogy of Fallot was the most commonly observed form (65 cases). Bicuspid pulmonary valve was the most common anomaly and was present in 58% of patients with tetralogy but in only 17% of those with isolated pulmonary stenosis.

Hemorrhagic cardiac tamponade: a clinicopathologic correlation.

Staphylococcus aureus pericarditis and recurrent episodes of hemorrhagic cardiac tamponade developed in a 31-year-old man. He later died of exsanguination and at autopsy was found to have a ruptured infective pseudoaneurysm of the aortic arch. When hemorrhagic pericardial effusions of undetermined cause are encountered, the heart and great vessels should be evaluated as potential sources of the hemorrhage.

Combined immunosuppression for the treatment of idiopathic giant cell myocarditis.

Giant cell myocarditis (GCM) is a rare and frequently fatal disorder with no proven treatment. Case reports and data from a rat model of GCM suggest that immunosuppressive therapy directed against T lymphocytes may have clinical benefit. We describe a 47-year-old man with severe acute heart failure due to GCM in whom the left ventricular ejection fraction normalized and the myocardial inflammatory infiltrate resolved rapidly after treatment with muromonab-CD3, cyclosporine, azathioprine, and corticosteroids. Three previously published cases with less impressive responses to treatment including muromonab-CD3 and a critical review of the published data on immunosuppressive therapy are included in this report. The response to immunosuppressive therapy is highly variable, and direct comparisons between immunosuppressive regimens do not exist. Therefore, despite individual reports of dramatic improvement after immunosuppressive treatment, firm conclusions cannot be made about the benefit of immunosuppression for GCM. The benefits of immunosuppressive therapy must be confirmed in a prospective, randomized trial.

Increase in total plasma homocysteine concentration after cardiac transplantation.

OBJECTIVE: To determine whether plasma homocysteine concentrations are increased in patients after cardiac transplantation. DESIGN: Total plasma homocysteine concentration was measured in 44 consecutive patients before and at 3, 6, and 12 months after orthotopic heart transplantation between June 1, 1988, and Oct. 15, 1992, and the data were analyzed statistically. RESULTS: Mean homocysteine concentrations (normal range, 4 to 17 mumol/L) increased 70% from 12.5 mumol/L before cardiac transplantation to 21.2 mumol/L (P < 0.002) 3 months after transplantation, at which time the concentrations were above normal in 14 of 26 patients (54%). Homocysteine concentrations remained elevated 6 and 12 months after transplantation (20.4 and 22.6 mumol/L, respectively) but did not increase further. Mean concentrations of plasma folic acid and vitamin B12, cofactors in homocysteine metabolism, decreased 20% and 49%, respectively, within 3 months after transplantation (11.6 to 9.3 micrograms/L [P = 0.04] and 584 to 295 ng/L [P = 0.01]). The mean glomerular filtration rate decreased 25% during this same interval (81 to 61 mL/min; P = 0.0001). Linear regression analysis revealed an association between the increase in homocysteine concentration and the folic acid concentration that approached statistical significance (P = 0.07); we found no statistically significant correlates of the increase in homocysteine concentration. CONCLUSION: The homocysteine concentration increases in most patients within 3 months after cardiac transplantation to levels previously associated with premature atherosclerotic coronary artery disease, and it remains increased for at least 1 year. Further investigation into the mechanism for the increase in homocysteine concentration and the relationship between homocysteine and coronary artery disease after transplantation is warranted.

Aortic valve stenosis: etiology, pathophysiology, evaluation, and management.

More patients with valvular aortic stenosis are being recognized, especially elderly patients with degenerative disease of the aortic valve. For nearly all patients with aortic valvular stenosis, 2-D and Doppler echocardiography have been found to be reliable for both the diagnosis and the establishment of severity (by gradient and valve area) of stenosis as well as for assessment of left ventricular function. Therefore, we project a lesser role for cardiac catheterization in the future, limited to definition of the coronary anatomy. Aortic valve replacement remains the proven therapy for patients with symptomatic aortic stenosis, although the decalcification/lithotripsy and balloon valvuloplasty techniques appear to be promising options in selected patients.