Biomedical subjects

B M McManus

Publications and source records attributed to B M McManus.

At least 73 records · Page 4Linked to original sources

PubMed1997

Enhanced lymphocyte longevity and absence of proliferation and lymphocyte apoptosis in Quilty effects of human heart allografts.

"Quilty effect" (QE) is a common and problematic observation in endomyocardial biopsy specimens from patients after cardiac transplantation. The origin, fate, and significance of QE cellular elements are unknown. Twenty-six paraffin-embedded endomyocardial biopsy specimens with QE (five QE As and twenty-one QE Bs) from twenty-two cardiac allografts were studied by immunohistochemistry for expression of Bcl-2, Fas antigen, proliferating cell nuclear antigen (PCNA), perforin, T cells (UCHL-1), macrophages (CD68), and apoptosis by in situ terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nick end labeling (TUNEL). Approximately 50% of the lymphocytes present, mainly in the deeper region of 20 of 21 QE Bs and all 5 QE As, expressed Bcl-2 in a pseudo-nodular pattern surrounding high endothelial venules. Fas expression was detected in lymphocytes in 20 of 21 QE Bs and 5 QE As in a similar pattern to Bcl-2. However, endothelial cells and macrophages were Bcl-2 negative, whereas both cell types were Fas positive. Perforin was negative in nearly all lymphocytes. TUNEL staining revealed that lymphocytes in QEs did not undergo apoptosis; however, TUNEL positivity was observed in approximately 70% of endothelial cells and macrophages and certain adjacent cardiac myocytes in 20 of 21 QE Bs and 5 QE As. One large QE B with a germinal center was noted. Germinal center cells expressed PCNA intensely but were negative for Bcl-2, Fas, and TUNEL. Cells surrounding the germinal center expressed abundant Bcl-2. The following conclusions were drawn. 1) Apoptosis does not occur in lymphocytes in QE where enhanced Bcl-2 (apoptosis inhibitor) and Fas antigen (apoptosis inducer) are expressed. 2) PCNA negativity indicates that QE lymphocytes may not proliferate, and perforin negativity indicates that they may not exhibit perforin-based cytotoxicity. We propose that there may be a relationship between the longevity of lymphocytes in QE and the absence of apoptosis.

Adult↗

PubMed1997

Diet-induced atherosclerosis in the domestic cat.

The domestic cat has not been used in studies of atherosclerosis, with the exception of a single study published in 1970. We have further evaluated the susceptibility of the domestic cat to diet-induced atherosclerosis, the ultimate intent being to discern the atherogenic risk due to lipoprotein lipase deficiency in an affected feline kindred with a phenotype very similar to that of the human form of this condition. We subjected a group of normal domestic cats to a moderately high-fat, cholesterol-enriched diet (30% fat and 3% cholesterol) for a period of 2 to 8 months. Plasma lipid levels were monitored monthly. At the time of killing, all organs and the entire vascular tree were removed, sectioned, processed, and stained with hematoxylin and eosin. The entire vascular tree was also stained with Movat's pentachrome and oil red O (ORO) and assessed semiquantitatively (0 to 5+/5+) and quantitatively (mean intimal area and ORO positivity, mm2). Both blood lipid measurements (total cholesterol, high-density lipoprotein-cholesterol, triglycerides, and low-density lipoprotein-cholesterol) and vessel wall lesion assessment (intimal area, mm2) were statistically elevated (p < 0.05) in the cholesterol-fed cats as compared to those on a normal diet. The highest correlations obtained between blood lipid components and vessel wall measures were the percent increase in triglyceride from base line versus the ORO measurement or foam cell grade (r = 0.86), and percent increase in triglycerides versus the intimal area in the lower abdominal aorta (r = 0.91). Similar relationships were found when the intimal area in the brachiocephalic/subclavian vessels was correlated with the absolute triglyceride values (r = 0.85) or with the percent increase in triglycerides (r = 0.83). Thus, we produced atherosclerotic lesions in the cat within 2 to 4 months on a cholesterol-enriched diet; blood lipid levels were highly correlated with lesional measurements in the vessel wall. This study will provide the basis for evaluation of the susceptibility of New Zealand lipoprotein lipase-deficient cats to diet-induced atherosclerosis.

Animal Feed↗

PubMed1996

Allograft inflammatory factory-1. A cytokine-responsive macrophage molecule expressed in transplanted human hearts.

Allograft inflammatory factor-1 (AIF-1), a cytokine-responsive macrophage molecule, was originally identified and cloned from rat cardiac allografts with chronic cardiac rejection. We performed the present study to determine whether AIF-1 was also involved in the inflammatory response associated with human cardiac transplant rejection. AIF-1 gene transcripts were identified by the reverse-transcriptase polymerase chain reaction in endomyocardial biopsy specimens from human heart transplants and in macrophage cell lines. In the 441-base pair coding region of the human and rat cDNAs, the nucleotide sequences were 86% identical and the deduced amino acid sequences were 90% identical. Consistent with our studies in the rat. AIF-1 was selectively expressed in human macrophage-like cell lines, and immunostaining in human heart allografts localized the AIF-1 gene product to a subset of CD68+ macrophages in the interstitial and perivascular spaces. The parallels between rat and human AIF-1 expression suggest that AIF-1 may have a common effect on the function of activated macrophages in cardiac allografts.

Animals↗

PubMed1996

Serum from patients with chronic renal insufficiency alters growth characteristics and ANP mRNA expression of adult rat cardiac myocytes.

Left ventricular hypertrophy is very prevalent among patients with renal insufficiency. Known hypertrophic factors, such as systemic hypertension, do not adequately account for the prevalence of left ventricular hypertrophy in these patients. Circulating growth factors may stimulate cardiomyocyte growth and contribute to the development of left ventricular hypertrophy. The effects of sera from patients with (n = 30) and without (n = 5) chronic renal insufficiency on the growth of cultured adult cardiomyocytes were compared. An adult rat cardiomyocyte primary culture system was established with a high purity of cardiomyocyte population as confirmed by immunocytochemical staining of cardiac contractile proteins. Myocytes responded with increased [3H]thymidine incorporation when treated with angiotensin II, epidermal growth factor, hydrocortisone and insulin, and with increased [3H]phenylalanine incorporation when treated with parathormone, isoproterenol, phenylephrine and insulin. Renal insufficiency serum stimulated [3H]thymidine incorporation was 1.5 times that of the control (P < 0.02) and also tended to increase incorporation of [3H]phenylalanine compared to the control (P = N.S.). Increased [3H]thymidine incorporation by renal insufficiency serum did not correlate with serum insulin, parathormone or glucose in the renal insufficiency patients. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) method was used to measure renal insufficiency serum-induced atrial natriuretic peptide mRNA expression in cultured cardiomyocytes. Atrial natriuretic peptide (ANP) mRNA was increased 1-3-fold in cardiomyocytes treated with renal insufficiency sera in comparison to control sera. These data suggest that circulating growth factor(s) may contribute to the development of cardiac hypertrophy in patients with renal insufficiency.

Animals↗

PubMed1996

Interleukin-6 secreted from human myxoma reduces murine viral myocarditis.

The effect of interleukin-6 (IL-6) secreted by a human atrial myxoma in vitro was investigated in C3H female mice with acute viral myocarditis. A culture medium containing IL-6 (100 ng/ml) and IL-8 (250 ng/ml), was prepared; viral myocarditis was induced by exposure to the encephalomyocarditis virus. Mice were assigned to four groups: 1) intraperitoneal (i.p.) injection of supernatant with IL-6 and IL-8 (0.2 ml/mice) given simultaneously with virus, 500 pfu for 4 days (Group 1); 2) i.p. injection of supernatant with IL-6 starting on Day 4 for 4 days in the same manner (Group 2); 3) i.p. injection of culture medium simultaneously with the virus (Group 3); and 4) i.p. injection of PBS in the same manner (Group 4). Uninfected control mice were administered medium only (Group 5) or supernatant with IL-6 and IL-8 (Group 6) for 4 days without virus. The survival rate on Day 14 in Group 1 was 90% significantly (p < 0.01) prolonged. The ratio of heart weight-to-day weight in the Group 1 was significantly (p < 0.01) lower. Histopathological examination revealed that cardiac necrosis and cellular infiltration in Group 1 was reduced compared with Group 3. Moreover, the radio of spleen weight/body weight in Group 1 was significantly (p < 0.01) higher than that of Group 3 and of Group 4. To confirm the effect of IL-6 or IL-8, mice were treated with recombinant IL-6 to IL-8 simultaneously with virus for 4 days. IL-6 treated mice survived significantly compared with IL-8 treated mice and untreated mice. The viral titer on day 4 of IL-6 treated mice was significantly lower than IL-8 treated or untreated mice. Thus, IL-6 derived from human myxoma improved the survival of murime viral myocarditis and reduced myocardial necrosis when the myxoma-derived IL-6 was administered simultaneously with the virus, due to eliciting cellular immunity in the spleen.

Animals↗

PubMed1996

The pathogenesis of cardiac allograft vasculopathy.

There has been an intensive effort in the past year to identify immunologic and nonimmunologic factors in the pathogenesis of cardiac allograft vasculopathy. Significant progress has been made regarding cell proliferation and cell death, with particular focus on cell growth factors, cell death factors, and their receptors. Endothelial cell injury and endothelin expression and production have been implicated in the development of cardiac allograft vasculopathy. A significant clinical association between dyslipidemia and cardiac allograft vasculopathy has been detected by intracoronary ultrasonography. Furthermore, proteoglycans are postulated to play an important role through lipoprotein-proteoglycan interactions. The role of cytomegalovirus infection remains controversial. Immunosuppressive agents such as rapamycin and FK506 may contribute to a reduction of vasculopathy.

Animals↗

PubMed1996

Pathogenesis of murine enterovirus myocarditis: virus dissemination and immune cell targets.

In order to identify organ and cellular targets of persistent enterovirus infection in vivo, immunocompetent mice (SWR/J, H-2q) were inoculated intraperitoneally with coxsackievirus B3 (CVB3). By use of in situ hybridization for the detection of enteroviral RNA, we show that CVB3 is capable of inducing a multiorgan disease. During acute infection, viral RNA was visualized at high levels in the heart muscle, pancreas, spleen, and lymph nodes and at comparably low levels in the central nervous system, thymus, lung, and liver. At later stages of the disease, the presence of enteroviral RNA was found to be restricted to the myocardium, spleen, and lymph nodes. To characterize infected lymphoid cells during the course of the disease, enteroviral RNA and cell-specific surface antigens were visualized simultaneously in situ in spleen tissue sections. In acute infection, the majority of infected spleen cells, which are located primarily at the periphery of lymph follicles, were found to express the CD45R/B220+ phenotype of pre-B and B cells. Whereas viral RNA was also detected in certain CD4+ helper T cells and Mac-1+ macrophages, no enteroviral genomes were identified in CD8+ cytotoxic/suppressor T cells. Later in disease, the localization of enteroviral RNA revealed a persistent type of infection of B cells within the germinal centers of secondary follicles. In addition, detection of the replicative viral minus-strand RNA intermediate provided evidence for virus replication in lymphoid cells of the spleen during the course of the disease. These data indicate that immune cells are important targets of CVB3 infection, providing a noncardiac reservoir for viral RNA during acute and persistent myocardial enterovirus infection.

Acute Disease↗

PubMed1996

Direct interactions of coxsackievirus B3 with immune cells in the splenic compartment of mice susceptible or resistant to myocarditis.

In vitro replication of coxsackievirus B3 (CVB3) in cells of the immune system derived from uninfected adolescent A/J and C57BL/6J mice and replication of CVB3 in and association with immune cells from spleens of infected animals in vivo were assessed. Nonstimulated or mitogen-stimulated spleen cells were minimally permissive for viral replication during an 8-h period. Three days postinfection (p.i.), CVB3 RNA was localized in vivo to B cells and follicular dendritic cells of germinal centers in both A/J and C57BL/6J mice; however, extrafollicular localization was greater in C57BL/6J mice (P = 0.0054). Although the pattern of CVB3 RNA localization was different, the total load of infections virus (PFU per milligram of tissue) was not different. Splenic CVB3 titers (PFU per milligram of tissue) in both strains were maximal at day 3 or 4 p.i. and were back to baseline by day 7 p.i., with most infectious virus being non-cell associated. CVB3 titers (PFU per milligram of tissue) correlated directly with in situ hybridization positivity in splenic follicles and extrafollicular regions in both murine strains; however, follicular hybridization intensity was greater in A/J mice at day 5 p.i. (P = 0.021). Flow cytometric analysis demonstrated that 50.4% of total spleen cells positive for CVB3 antigen were B cells and 69.6% of positive splenic lymphocytes were B cells. Myocardial virus load in C57BL/6J mice was significantly lower than that in A/J mice at days 4 and 5 p.i. These data indicate that CVB3 replicates in murine splenocytes in vitro and in B cells and extrafollicular cells in vivo.

Animals↗

PubMed1996

Modification of viral myocarditis in mice by interleukin-6.

Inflammatory cytokines play a key role in the myocardial injury produced by viral myocarditis. Although interleukin-6 (IL-6) reportedly possesses antiviral properties, its effect in viral myocarditis is unclear. To investigate the role of IL-6 in viral myocarditis induced by encephalomyocarditis virus (EMCV) in mice, we evaluated (1) the survival rate following IL-6 administration, (2) the viral titer in the heart, (3) viral replication in the heart by in situ hybridization, (4) histopathological changes using immunohistochemical staining, (5) neutralizing antibody against EMCV, (6) circulating interferon and tumor necrosis factor-alpha (TNF-alpha), (7) viral suppression in vitro by IL-6, and (8) natural killer (NK)-cell activity. Eight-week-old C3H/HeJ mice were injected intraperitoneally with EMCV (day 0) and were also injected subcutaneously twice daily for 4 consecutive days with 10 micrograms/0.1 mL of human IL-6 on day -4 (group A), day 0 (group B), or day +4 (group D) for 4 days. As a control, 0.1 mL PBS instead of IL-6 was injected on day 0 for 4 days (group C). Certain mice were killed on day 4. The myocardial virus titers, viral replication in situ, and NK-cell activity in the spleen were determined. Decreased viral titer and viral replication in the heart reduced the titer of circulating TNF-alpha, and lower NK-cell activity was observed in group B versus group C (control group). The titer of neutralizing antibodies against EMCV was significantly (P < .05) increased in group B compared with group C. The remaining mice were killed on days 10 and 30 after infection. The ratio of heart weight (HW) to body weight (BW) and myocardial injury in group B were reduced versus group C on days 10 and 30. The HW of group B on day 30 did not differ from the normal control group. The ratio of splenic weight to BW and the ratio of thymic weight to BW of group B increased on day 10, with expanded follicles observed in the spleen and enlargement of the medulla observed in the thymus. Immunohistochemical study revealed an increased percentage of macrophages in the heart and spleen of group B. In summary, IL-6 reduces myocardial damage in mice with viral myocarditis. Modification of immune responses together with reduction in viral replication appears to be the mechanism of the IL-6 effect. Although IL-6 is likely important in the process of viral antigen presentation, early activation of immune responses and attenuation of viral replication appear most significant, as reflected in the limited time window during which IL-6 is effective in myocarditis.

Animals↗

PubMed1996

Human transplant coronary artery disease: pathological evidence for Fas-mediated apoptotic cytotoxicity in allograft arteriopathy.

Cytotoxicity mediated by cytolytic T cells occurs exclusively through Fas- and perforin-based pathways. Such mechanisms may be important in transplant coronary artery disease (TxCAD). We studied Fas and perforin expression and apoptosis using immunohistochemical methods, in situ terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL), and morphologic analysis of vessels with TxCAD taken from 12 transplant patients, which we compared with vessels of 10 patients with native coronary artery disease (CAD) and vessels from 14 patients with normal coronary arteries. Fas was detected in all TxCAD specimens. Fas-positive cells were mainly endothelial cells (EC); 100% of EC and approximately one-third of T cells and macrophages were positive for Fas. Almost all TUNEL-positive cells were Fas-expressing cells. Of the T cells and macrophages that expressed Fas, 18% appeared apoptotic in the mild and moderate-to-severe TxCAD group as compared with 78% in severe TxCAD patients (p = 0.0124). By contrast, EC damage was less evident in the vessels with greater intimal disease severity: 10% in severe TxCAD versus 75% in the mild and moderate-to-severe TxCAD group (p = 0.0122). Perforin was positive in 5% of the total intimal T cells in 3 of 12 arteriopathy specimens. Fas and perforin were virtually negative in vessels taken from CAD patients. TUNEL was diffusely positive in CD68-positive foam cells in the lipid-rich core, but Fas was negative in all CAD specimens. In normal arteries, 8 of 14 specimens contained a few TUNEL-positive and Fas-positive EC and T cells. Perforin was negative. We conclude that EC damage in TxCAD seems to be brought about through a Fas-based apoptotic pathway and that CD4-positive cytolytic T cells may be the major lytic cells involved in TxCAD.

Adolescent↗

PubMed1996

Consistencies and controversies in the application of the International Society for Heart and Lung Transplantation working formulation for heart transplant biopsy specimens. Rapamycin Cardiac Rejection Treatment Trial Pathologists.

BACKGROUND: The International Society for Heart and Lung Transplantation (ISHLT) working formulation was proposed in 1990 to promote standardization in the interpretation of endomyocardial biopsy specimens obtained after heart transplantation, especially in the setting of multicenter clinical trials and for publication purposes. METHODS: To assess uniformity in interpretation, 16 pathologists experienced in posttransplant endomyocardial biopsy specimen interpretation each read independently, in randomized order, an identical series of 23 biopsy specimens representing all ISHLT grades of rejection (n = 12) and other posttransplant biopsy findings (n = 11). The pathologists represented heart transplantation centers participating in the Rapamycin Treatment Trial for Grades 2 and 3A Rejection. The index diagnosis in each case was determined by two pathology consultants who had concurred blindly on 22 of 23 (96%) biopsy specimen evaluations on their first independent reading. Discrepancies that would not affect clinical response (for example grades 0 versus 1A, 1A versus 1B, 3A versus 3B, 3B versus 4) were considered minor; those that could alter therapy were considered major. RESULTS: The 16 trial pathologists were in exact agreement with the index diagnosis in 17 (mean) +/- 3 biopsy specimens (range 10 to 22) and 20 (mean) +/- 2 biopsy specimens (range 16 to 22) if minor discrepancies were excluded. Of 368 diagnoses rendered, 265 agreed exactly with the index diagnosis and 103 differed, of which 50 were minor discrepancies. The 53 major discrepancies included grades 1A/B versus 2, 22 discrepancies; 2 versus 3A, 11; Quilty B versus 2/3A, 10; biopsy site versus 3A, 2; ischemic injury versus 3A/B, 2; Toxoplasma versus 3A, 2; posttransplantation lymphoproliferative disorder versus 3B/4, 3; and Quilty B versus posttransplantation lymphoproliferative disorder, 1. Interobserver agreement assessed by weighted kappa values was 0.67. CONCLUSIONS: First, there was agreement among the trial pathologists and the index diagnosis (excluding minor discrepancies) in 85% of biopsy specimen interpretations. Second, of 53 major discrepancies, 43 (81%) involved grades 1A/B versus 2, 2 versus 3A, and Quilty B versus 2/3A. Third, in 54% of instances in which biopsy findings other than rejection were misdiagnosed as rejection grades, the grade was sufficiently high to have adverse treatment implications. Fourth, the ISHLT working formulation provides for a high degree of diagnostic consistency among experienced observers, and concordance could be further enhanced by clarification of criteria for grade 2 rejection and Quilty B lesions.

Biopsy↗

PubMed1996

The autopsy. Simple thoughts about the public needs and how to address them.

Dialogue regarding the autopsy has been sustained largely by medical students and professionals, and by families of deceased patients. Exclusion of the general public may represent a significant reason for the inexorable decline of autopsy rates and politicoeconomic support. Sensitivity to public concerns regarding the autopsy process carries far-reaching moral and educational significance. A better understanding of the social value of the autopsy will help to ensure its survival in a climate of ever-tightening health-care budgets. Emphasis must be placed on integrating the autopsy process, from the initial request, performance and post-autopsy follow-up with families, to the diagnostic, pathobiologic and epidemiologic interpretation of the results obtained. Opportunities for investigating cause of death currently lie primarily in animal models or in forensic postmortem material where the cause of death is frequently known. Public awareness of the autopsy's special role in the setting of natural and unexplained death is essential if the autopsy is to be retained as a key tool in understanding human disease.

Autopsy↗

PubMed1996

Prominence of apolipoproteins B, (a), and E in the intimae of coronary arteries in transplanted human hearts: geographic relationship to vessel wall proteoglycans.

BACKGROUND: Transplant arteriopathy (TA) is characterized by vessel wall thickening with prominent glycosaminoglycan and lipid deposits. In this light, we have recently demonstrated the distribution of proteoglycans in allograft coronary arteries. The aim of this study is to examine the distribution of apolipoproteins within allograft coronary arteries and to investigate their localization in relation to proteoglycans. METHOD: Particular transverse sections of left and right epicardial coronary arteries from 46 human cardiac allografts, 11 normal hearts, and 11 hearts with native atherosclerosis were stained immunohistochemically for apolipoprotein B, apolipoprotein (a) (apo[a]), apolipoprotein E (apoE), biglycan, decorin, and versican by use of an automated immunostainer. RESULTS: Apo(a) and apoE immunopositivity in TA was much more intense than that in native atherosclerosis, whereas the reverse was true for apoB. Prominent apoE deposits were evident circumferentially in endothelia and extracellularly in superficial intima of mildly diseased TA, as well as in deeper intima of severely diseased TA. Apo(a) had a staining pattern very similar to apoE except for a patchy deposition also seen in TA media. The intimal areas staining prominently with apoE or apo(a) in TA arteries corresponded very closely to the areas with proteoglycan deposits, especially versican. CONCLUSION: The distinctive patterns of apolipoprotein accumulation in TA and native atherosclefosis appear to reflect different pathogenetic processes in the two conditions. The colocalization of proteoglycans and apolipoproteins in TA intima supports the hypothesis that interactions between proteoglycans and apolipoproteins influence lipid retention and overload in allograft coronary arteries.

Apolipoproteins↗

PubMed1996

Biglycan, decorin, and versican protein expression patterns in coronary arteriopathy of human cardiac allograft: distinctness as compared to native atherosclerosis.

BACKGROUND: Histochemical staining has demonstrated previously dramatic deposits of glycosaminoglycans associated with prominent lipid accumulations in thickened vessel walls of allograft coronary arteries. In this study, we characterized the amount, distribution, and types of proteoglycan in the walls of coronary arteries from human cardiac allografts and from native atherosclerotic (NA) controls as part of a strategy to understand the pathogenesis of transplant arteriopathy (TA). METHOD: We used polyclonal rabbit antibodies against human biglycan, decorin, and versican localize the proteoglycan molecules in standardized transverse sections of the proximal left anterior descending and right coronary arteries. Slides were scored in a blinded fashion for intensity of proteoglycan staining (0 to 6+) and for localization in the vessel walls. RESULTS: Unique patterns of proteoglycan distribution were present in TA and NA. Biglycan was particularly prominent in intima and evolving atheromata in severely diseased TA coronary arteries, but not in NA. Decorin was present mainly in adventitia of all vessels and in the intima of NA. Prominent versican accumulation occurred in intima and media of TA coronaries, associated with smooth muscle cells and foam cells. There was a reciprocal pattern of biglycan and decorin staining. Versican colocalized with biglycan. Intimal biglycan and versican deposits were positively correlated to the extent of luminal narrowing in TA. CONCLUSION: The distinctive staining patterns for biglycan, decorin and versican in both native and allograft disease indicate that the synthesis and distribution of these proteoglycans are regulated by different local mechanisms in different atheromatous diseases.

Biglycan↗

PubMed1996

Pathology of sudden death in the young.

Sudden death is a relative concept, but generally refers to death occurring soon after symptom onset. In this review, cardiac causes of sudden death, designated coronary and noncoronary, are addressed. In the coronary category, coronary artery anomalies and altered coronary tone are discussed, while myocardial causes, valvular causes, aortic dissection and conduction system are outlined as part of noncoronary causes of sudden death. Sudden death in athletes and exercising youth also receives special comment.

Adult↗

PubMed1995

A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.

BACKGROUND: Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis and to examine measures of the immune response as predictors of the severity and outcome of disease. METHODS: We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. RESULTS: In the group as a whole, the mean (+/- SE) left ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P < 0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03 to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at base line, and a shorter duration of disease, but not the treatment assignment, were positive independent predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56 percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less severe initial disease. CONCLUSIONS: Our results do not support routine treatment of myocarditis with immunosuppressive drugs. Ventricular function improved regardless of whether patients received immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory response had less severe disease.

Adult↗

PubMed1995

Localization of aortic disease is associated with intrinsic differences in aortic structure.

PURPOSE: While localization of atherosclerosis and aneurysms to the infrarenal aorta has been attributed, in part, to hemodynamic factors, anatomic differences between the proximal and the distal aorta may also be important. Our purpose was to determine the changes in content and organization of major structural proteins (elastin and collagen) throughout the normal human aorta. METHODS: Biochemical analysis for desmosine-isodesmosine (elastin) and hydroxyproline (collagen) content was done by HPLC on complete 1-cm transverse rings removed from the ascending and descending thoracic aorta and abdominal supraceliac, suprarenal, and midinfrarenal aorta. Elastin and collagen content was normalized to lumenal surface area and compared by ANOVA: Light microscopy and optical micrometry were used to determine changes in intimal, medial, and adventitial thickness and number of elastin lamellae at each level. RESULTS: Both collagen/cm2 and elastin/cm2 decrease from the proximal to distal aorta. Collagen content did not differ among the three abdominal segments, but there was a 58% decrease in elastin between the suprarenal and the infrarenal aorta. The proportion of elastin and collagen does not differ throughout the aorta except in the infrarenal aorta where there is decreased elastin relative to collagen. CONCLUSION: Collagen and elastin in the distal aorta bear an increased load as compared to the proximal aorta. The infrarenal aorta differs biochemically and histologically from the remainder of the aorta. A decrease in infrarenal elastin without a corresponding decrease in collagen may effect the compliance and integrity of the distal aorta. These anatomic differences may be important in predisposing the infrarenal aorta to atherosclerosis and aneurysm formation.

Adult↗

PubMed1995

The Myocarditis Treatment Trial: design, methods and patients enrollment.

The Myocarditis Treatment Trial was a multicentre clinical trial conducted to determine the efficacy of immunosuppressive therapy for treatment of biopsy-documented myocarditis, and to improve understanding of the immunological mechanisms in the development of myocarditis. Thirty-one centres screened 2305 patients with unexplained heart failure, and 2233 patients underwent an endomyocardial biopsy which provided adequate tissue for diagnosis. Those with a positive biopsy and a left ventricular ejection fraction (LVEF) less than 45% were randomly assigned to receive immunosuppressive therapy plus conventional drug therapy for congestive heart failure (66 patients) or conventional therapy only (45 patients) for 24 weeks. For 28 additional weeks all patients received conventional therapy only. In addition to diagnostic and clinical data, serum and myocardial tissue for immunological marker analysis and histopathologic evaluation were collected at baseline and at 12, 28 and 52 weeks after randomization. The primary analysis of efficacy was designed as a comparison of the mean increase in LVEF at week 28 between treatment limbs. Secondary objectives were to evaluate survival differences, and changes in the histopathology of the disease and immunological markers. Randomized patients were relatively young (mean age, 42.0 years +/- 13.8 standard deviation (sd) and entered the Trial with a mean LVEF percent of 24.3 +/- 10.1 sd) and mean exercise treadmill duration of 9.4 (+/- 5.3 sd) minutes. The incidence of biopsy-documented myocarditis was low (9.6%). The analyses of outcome and immunological data are reported elsewhere.

Adolescent↗