Cronic non-rheumatic valvular heart disease. An autopsy study.

The frequency of chronic non-rheumatic valvular heart disease in Iceland was investigated via autoposies performed from November 1965 through December 1974. During this period, about 12.400 Icelanders died at the age of 16 years and older and 28.8 per cent of these were included in the study. At autopsy, males outnumbered females by 2:1. The frequency of calcific aortic stenosis was found to be 3.63 per cent and the prevalence was calculated to be 3.17 per cent among males and 4.50 per cent among females. Calcific aortic stenosis in tricuspid valves was more frequent in females and calcific aortic stenosis in bicuspid valves was more frequent in males. Among the hearts with calcific aortic stenosis, 70.8 per cent were found to have normally tricuspid valves, 25.4 per cent bicuspid valves and 3.8 per cent tricuspid valves with an unicommissural fusion. In 0.59 per cent of the hearts the aortic valve was either bicuspid or had an uncommissural fusion without the features of calcific stenosis. However, a functional stenosis was suggested by the increased weight of most of these hearts. The frequency of bicuspid aortic valves was 1.2 per cent with a prevalence in males of 1.54 per cent and in females 0.50 per cent. A calcified mitral annulus was found in 1.98 per cent of the hearts and in most, it was either associated with calcific aortic stenosis in a tricuspid valve, or it was a single valvular disease. Rheumatic valvular disease was found in 1.08 per cent of the heart examined.     

Is focal chronic autoimmune thyroiditis an age-related disease? Differences in incidence and severity between Japanese and British

The incidence of chronic lymphocytic thyroiditis in autopsy material from Japanese and British subjects was evaluated. Lymphocytic infiltration in representative thyroid sections from 1826 Japanese cases collected from four different institutions was analysed. The overall incidence of lymphocytic infiltration was significantly higher in females (22.2 per cent) than in males (13.9 per cent). In females, the incidence reached 23.2 per cent in the fourth decade and showed no increase with age thereafter. The overall incidence of lymphocytic infiltration in thyroid sections from 810 British cases was 42.5 per cent in females and 19.4 per cent in males; an increase in the incidence of thyroiditis from the sixth decade onwards was noted in British females, the figure reaching 50.0 per cent in those aged over 70 years. These findings suggest possible racial differences in susceptibility to chronic thyroiditis. The disorder is not necessarily related to age, increasing severity of disease with age being found only in British females.     

Overexpression of transforming growth factor-beta 1 in the valvular fibrosis of chronic rheumatic heart disease

For the purpose of determining the pathogenic role of transforming growth factor-beta1 (TGF-beta 1) in the mechanism of chronic rheumatic heart disease, we evaluated the expression of TGF-beta 1, proliferation of myofibroblasts, and changes in extracellular matrix components including collagen and proteoglycan in 30 rheumatic mitral valves and in 15 control valves. High TGF-beta 1 expression was identified in 21 cases (70%) of rheumatic mitral valves, whereas only 3 cases (20%) of the control group showed high TGF-beta 1 expression (p<0.001). Additionally, increased proliferation of myofibroblasts was observed in the rheumatic valves. High TGF-beta1 expression positively correlated with the proliferation of myofibroblasts (p=0.004), valvular fibrosis (p<0.001), inflammatory cell infiltration (p=0.004), neovascularization (p=0.007), and calcification (p<0.001) in the valvular leaflets. The ratio of proteoglycan to collagen deposition inversely correlated with TGF-beta 1 expression in mitral valves (p=0.040). In conclusion, an ongoing inflammatory process, the expression of TGF-beta 1, and proliferation of myofibroblasts within the valves have a potential role in the valvular fibrosis, calcification, and changes in the extracellular matrix that lead to the scarring sequelae of rheumatic heart disease.     

Postinflammatory scarring of cardiac valves of rheumatic and nonrheumatic etiology

In rheumatic heart disease, cardiac valves often display only a nonspecific postinflammatory scarring, without specific features, such as the rheumatic granuloma. Fifty-five native valves excised from 47 patients, exhibiting postinflammatory scarring, were studied. Patients were subdivided into three groups according to their case histories: patients with both streptococcal infection and rheumatic fever (group I), with streptococdal infection without noncardiac major manifestations of rheumatic fever (group II), and without either of these features (group III). Pathological examination alone was unable to differentiate among the three groups, all the valves showing the same general pathological features. Differences in terms of sex, age, and valvular involvement were detected among group III and the others, whereas patients belonging to the first two groups did not differ significantly. These results suggest that diagnostic criteria for rheumatic fever are too restrictive and that a postinflammatory valvular scarring of nonrheumatic etiology does exist.     

Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.

Association of group A streptococci with acute rheumatic fever and valvular heart disease is well established; however the basis of valve injury remains unclear. In this study, anti-streptococcal monoclonal antibodies (MAbs) cross-reactive with myocardium were reacted with sections from 22 rheumatic valves, nine normal, five endocarditic, one 'floppy,' and one Marfan valve. In immunohistochemical studies, MAb reactivity was observed with cardiac myocytes, smooth muscle cells, cell surface and cytoplasm of endothelial cells lining valves, and valvular interstitial cells. Endothelial basement membrane and elastin fibrils reacted with the MAbs, whereas collagen was unreactive. Similar reactivity was seen with sera from acute rheumatic fever patients. The anti-streptococcal MAbs reacted with intravalvular myosin and vimentin in Western blots, and purified elastin competitively inhibited the binding of the anti-streptococcal MAbs to whole group A streptococci. The data show that human heart valves have numerous sites of immunoreactivity with anti-streptococcal MAbs and acute rheumatic fever sera of potential importance in the pathogenesis of rheumatic valvular injury.     

Incidental in vivo detection of an epithelioid hemangioendothelioma of the mitral valve

Valvular epithelioid hemangioendotheliomas (EHE) are exceptional. To the authors' knowledge only four cases have been reported. Herein is described an EHE incidentally detected in the mitral valve of a 69-year-old woman with chronic rheumatic valvular heart disease. The 0.4 cm lesion was situated in the anterior leaflet and was discovered in the pathological study after mitral valve replacement. The patient was alive and well 6 months after operation. Review of the literature including the present report, revealed that the mean age was 60.2 years (range, 49-69 years). Symptomatic patients had clinical features of valvular disease or embolism. Each of the four cardiac valves can be affected. Mean tumor size was 2.4 cm (range, 0.4-8 cm). In 40% of cases the EHE was an incidental finding at autopsy or in a removed valve. In two cases the involved cusp was affected by chronic rheumatic disease. In conclusion, EHE is a rare lesion that can be an incidental finding and it should be considered in the differential diagnosis of valve tumors. Although EHE can present a histologically benign appearance, the correct pathological diagnosis is clinically important because the lesion can be potentially malignant. Regular follow up is suggested due to this potential.     

Thrombotic endocarditis and lupus anticoagulant. A pathogenetic possibility for idiopathic 'rheumatic type' valvular heart disease

Lupus anticoagulant and anti-phospholipid antibodies are well recognized as being associated with thromboembolic disorders in patients both with and without systemic lupus erythematosus (SLE). There have been recent reports of the association of lupus anticoagulant and antiphospholipid antibodies with severe valvular heart disease in patients with SLE and it has been suggested that organizing thrombus on the surface of the valve may be a cause of distortion and subsequent dysfunction. We describe two patients who did not have SLE, but who did have both lupus anticoagulant and antiphospholipid antibodies. Both had severe valvular heart disease, the pathology of which demonstrates valve distortion by layers of organizing thrombus identical to that of previously described patients with SLE. The gross appearance of these valves is similar to that of the valves in "rheumatic" heart disease. We suggest that in some patients with "rheumatic" heart disease, but without a history of rheumatic fever, the prothrombotic tendency associated with lupus anticoagulant and phospholipid antibodies may either contribute to, or be responsible for, the pathogenesis of "rheumatic" type valve deformities.     

Adenocarcinoma of the vermiform appendix. A population study.

We report seven cases of adenocarcinoma of the vermiform appendix occurring in Iceland during 1974-1989. The patients ranged in age from 25-83 years, mean age 55.1 years. There were five males and two females. Five had mucinous adenocarcinoma, two had adenocarcinoma. Four patients presented with symptoms and signs of acute appendicitis and all had surgically resectable disease. Three of these patients were alive with no evidence of disease four months, two years and 15 years after presentation; one death of disease occurred seven years after ileocecal resection. In three cases, the clinical presentation was that of metastatic adenocarcinoma of unknown origin. Of these patients two were diagnosed at autopsy and one after appendectomy for perforated appendicitis. Survival in this group was six weeks, three months and twelve months, respectively. In none of our patients was the diagnosis made preoperatively and no tumors were found in appendices removed incidental to other intra-abdominal operations. The incidence of adenocarcinoma of the vermiform appendix in Iceland during 1974-1989 was approximately 0.2 cases/100.000/year.     

Etiology of acquired valvular heart disease in adults. A survey of 18,132 autopsies and 100 consecutive valve-replacement operations

The cardiac valve pathology in 18,132 autopsies was analyzed. A total of 1,136 patients (6.3%) had acquired valvular disease. The most commonly diseased cardiac valve was the mitral valve (49%), followed by the aortic valve (42%) and the tricuspid (9%) and pulmonary valves (0.3%). Rheumatic fever accounted for 99.7% of cases of mitral stenosis and 68.4% of mitral incompetence. The autopsy incidence of mitral stenosis remained constant over 30 years (1950 to 1979). Only 44.4% of the cases of acquired aortic stenosis were due to rheumatic fever. Review of 100 consecutive, surgically excised native valves revealed that if the pathologist is given adequate information regarding the macroscopic appearance of the intact valve prior to excision, an accurate etiopathologic diagnosis can be made in 81% of cases compared with only 35% of cases without such information.     

Isolated valvular amyloid

Two cases are described of grossly evident amyloid infiltration of the cardiac valves, while only minor deposits were found in other locations. The right-sided valves were more heavily involved than the left. No pre-existing disease of the valves was found, and the lesions appeared to have no adverse effect upon the subjects. Only one other similar case was found in the literature. The only consistently associated condition among the recognized cases was advancing age. The name proposed for the condition is isolated valvular amyloid.     

Pathology and pathogenesis of rheumatic heart disease

Cardiovascular disease is on the rise. In India and other developing countries, rheumatic heart disease (RHD) continues to be a major public health problem and contributes to significant cardiac morbidity and mortality. RHD in the juvenile age group namely juvenile mitral stenosis is a variant which is unique to the Indian subcontinent. Severe valve deformities lead to high morbidity and mortality. Despite various measures no appreciable decline in prevalence of RHD has been documented. At autopsy, mitral valve was most commonly affected either alone or in combination with aortic and tricuspid valves. Both functional and organic involvement of tricuspid valve was documented. It has been convincingly demonstrated that molecular mimicry between Streptococcus pyogenes antigen and human proteins lead to autoimmune reactions both humoral and cell mediated causing RF/RHD. Heart tissues namely the valves, left atrial appendage (LAA) and myocardium reveal variable amounts of infiltration by lymphocytes. Significant endocarditis and valvulitis is observed in these cases. CD4+ T cells are most likely the ultimate effectors of chronic valve lesions in RHD. They can recognize Streptococcal M5 protein peptides and produce various inflammatory cytokines such as TNF-alpha, IFN-gamma, IL-10, IL-4 which could be responsible for progressive fibrotic valvular lesions. Cardiac myosin has been defined as a putative autoantigen recognized by autoantibodies of RF patients. Cross reactivity between cardiac myosin and group A beta hemolytic Streptococcal M protein has been adequately demonstrated. Cardiac myosin has been shown to produce myocarditis in rats and mice. Valvulitis/ endocarditis has been observed in excised LAA, cardiac valves and in hearts at autopsy from cases of RHD. The disease predominantly affects the valvular endocardium culminating in crippling valve deformities. Endocardial infiltrate and their migration into the valve substance has been elegantly demonstrated in rats and mice. Immune responses against cardiac myosin lead to valvular heart disease and infiltration of the heart by Streptococcal M protein reactive T lymphocytes. Mitral valves showed various degrees of calcification. An interesting observation is the nature of calcification in diseased/distorted valves in RHD. Recent studies indicate that calcification is not merely an inactive, "dystrophic" process but involves a regulated inflammatory process associated with expression of osteoblast markers and neoangiogenesis. Increased plasma osteopontin levels correlated with severity of mitral valve calcification. Further evidence of inflammation is supported by high levels of advanced oxidation protein products and high sensitive C-reactive protein in plasma detected in patients with RHD. Presence of inflammatory cells and increased expression of several cytokines in cases of "end stage" RHD reflects a possible subclinical, ongoing insult/injury to some unrecognized antigenic stimulus by beta hemolytic Streptococcal antigens that have sensitized/primed the various target tissues and which further culminate in permanent valve deformities.     

Heart valve involvement in familial amyloidosis with polyneuropathy

Involvement of the heart is common in the various types of amyloidosis. Little attention has, however, been paid to the presence and significance of amyloid in cardiac valves. We examined the heart valves of twelve autopsy cases with familial amyloidosis with polyneuropathy. All leaflets showed more or less abundant amyloid infiltration with significant valvular aortic stenosis due to degenerative calcification in two cases. In familial amyloidosis with polyneuropathy, amyloid deposits are thus invariably present in the valves, but the valvular function is often preserved. Amyloid may, however, produce hemodynamically significant valvular lesions, and the importance of valvular involvement in the various types of amyloidosis may still be underestimated.     

Causes of Isolated Aortic Insufficiency in an Urban Population in the 1990s: A Review of 56 Surgical Pathology Cases

Until recently, the cause of isolated aortic insufficiency (AI) was usually thought to be inflammatory or rheumatic in most cases. However, at our institution we have noted a high prevalence of myxomatous degeneration (MD) in aortic valves removed for AI. In this study we report anatomic observations on valves from 56 consecutive patients with isolated AI undergoing aortic valve replacement surgery. Fifty-six consecutive aortic valves removed at our institution from 1994 to 1996 for isolated AI and/or aortic aneurysm were reviewed. Anatomic features were compared with clinical history and echocardiographic data. The anatomic results were also compared to 22 age-matched control aortic valves obtained at autopsy. In 13/56 cases (23%), a specific valvular cause of AI was determined (infectious endocarditis, seven cases; chronic rheumatic disease, four cases; congenital bicuspid valve, two cases). Of the remaining (idiopathic) 43 cases, 18 (42%) had severe isolated MD defined as >50% expansion of the spongiosa and disruption of the fibrosa by the deposition of acid mucopolysaccharides in the absence of severe calcification, fibrosis, or other pathologic findings. Only 1/22 aortic valves from the autopsy controls had severe MD. Eighteen of the 56 patients also had a clinical history of aortic dilatation/aneurysm of which 12 were confirmed to be dilated by echocardiographic criteria. Of these 12, five (42%) had MD of the aortic valve only, three (25%) had both MD and cystic medial degeneration (CMD) of the aorta, two (17%) had CMD of the aorta only, and two (17%) had no specific diagnosis. Isolated MD of the aortic valve is the most common cause of isolated AI in our patient population. Furthermore, in a subset of non-Marfan’s patients with both AI and dilatation of the aortic root/aortic aneurysm the incidence of MD is even higher (67%). These results suggest that there is overlap between MD and CMD in non-Marfan’s patients and that both entities may be part of a spectrum of a generalized connective tissue disorder.     

Epstein-Barr virus (EBV) and Hodgkin's disease in children: incidence of EBV latent membrane protein in malignant cells.

Previous studies have detected EBV DNA by Southern blotting or in situ hybridization in biopsy material from up to 30 per cent of adult cases of Hodgkin's disease. Here we have used monoclonal antibodies specific for the EBV latent membrane protein LMP1 to examine archival material from children with Hodgkin's disease. Material from 74 cases (54 males and 20 females) was examined and 37 (30 males and 7 females) were classified as LMP1-positive in the malignant cells. LMP1 positivity was present in 4/13 (31 per cent) of lymphocyte predominant, 14/36 (39 per cent) of nodular sclerosis, 17/20 (85 per cent) of mixed cellularity, 1/2 (50 per cent) of lymphocyte depletion, and 1/3 (33 per cent) of unclassified subtypes. The positive cases by clinical stage were I 9/22 (41 per cent), II 9/20 (45 per cent), III 11/24 (46 per cent), and IV 8/8 (100 per cent). LMP1 positivity was present in 2/5 (40 per cent) children aged less than 5 years, 12/27 (44 per cent) aged 5-10 years, and 23/42 (48 per cent) aged between 10 and 15 years. The association between EBV and Hodgkin's disease in children thus appeared to be more frequent in patients with mixed cellularity and advanced disease, but examples of EBV-positive tumours were found in all histological subtypes, stages, and ages. Stepwise discriminant function analysis showed that clinical stage IV and mixed cellularity histology are independently associated with LMP1 positivity. These observations indicate that Hodgkin's disease in children is at least as strongly linked to EBV as is the disease in adults.     

Biopsy of the heart valves. 872 cases

In this study, 872 heart valves surgically excised from 810 patients during a period of 5 years (1994 through 1998) were examined pathologically. There was a predominance of aortic (506 patients) versus mitral valves (246 pts.). While aortic valves came more often from men (364) than from women (142), in mitral valves the M:F ratio is 82/164. Isolated calcific aortic stenosis appeared as the most frequent valvular disease (418 pts.), with predominance of its sclerotic-senile type (238 pts.). Mitral stenosis (185 pts.) remains the classical post-rheumatic disease. The relative frequency of a subvalvular stenosing mitral lesion is stressed. The "pure" incompetence of both aortic (70 pts.) and mitral (56 pts.) valve was usually based on valvular myxoid degeneration. An aorto-mitral disease requiring replacement of both valves (51 pts.) presented typically as a post-rheumatic lesion, however, a combination of a post-rheumatic mitral with a degenerative-sclerotic aortic valve disease may be possible. In 30 patients, the valvular replacement was performed for infective endocarditis or a post-IE lesion, mostly of the aortic valve. With the almost non-existence of acute rheumatic fever and with the increasing average age of population in this country, we may expect a long-term decline in mitral valve disease and an increase in aortic valve disease, particularly in the sclerotic type of aortic stenosis.     

Mitral and aortic valve disease associated with ergotamine therapy for migraine. Report of two cases and review of literature

Ergotamine has been associated with numerous vascular complications but only rarely with fibrosing disorders or valvular heart disease. Two patients are described in whom severe valvular dysfunction developed during ergotamine therapy for migraine headache. The surgically excised mitral and aortic valves were involved by a proliferative process that was strikingly similar to lesions described in patients with carcinoid heart disease and methysergide-associated valvular disease.     

Correlation of clinical diagnoses with autopsy findings: A retrospective study of 2,145 consecutive autopsies

The protocols of 2,145 autopsies were retrospectively reviewed and the findings compared with the clinical diagnoses. A sudden decline in the autopsy rate that occurred during the period studied was followed by a highly statistically significant difference in clinical accuracy (P less than 0.01), in favor of the predecline period. The overall rate of major discrepancies was 29 per cent. The most frequently missed diagnoses were infections, which were found in 26 per cent of all autopsies and had not been diagnosed clinically in 63 per cent of these cases. Malignancies occupied second place among overlooked diagnoses in the selected disease categories; in 99 per cent of the cases the malignancy was the principal diagnosis, and it had been misdiagnosed clinically in 42 per cent of these cases. Cerebrovascular disorders were correctly diagnosed in most cases (87 per cent of the patients in this group). Among autopsy diagnoses labeled as the immediate causes of death, the most frequently overlooked were pulmonary embolism and gastrointestinal hemorrhage, which were not recognized in 84 and 78 per cent, respectively. In cases in which clinicians were not entirely confident in their impressions, their diagnoses were usually confirmed at autopsy. In these cases 15 per cent of the patients died soon after admission to the hospital, with accurate diagnoses in 71 per cent. The discrepancies disclosed should be regarded as sufficiently large to mandate continued emphasis on autopsy evaluation as the basis for the control of the quality of patient care.     

Acquired coronary arterial aneurysms: an autopsy study of 52 patients

In the past decade most studies of coronary arterial aneurysms have been clinical; few have focused on morphology and etiopathogenesis. The subjects of the present autopsy study were 52 patients, 5 months to 80 years of age, with coronary arterial aneurysms. Patients were divided into two groups: 38 with atherosclerotic coronary aneurysms and 14 with aneurysms secondary to inflammation. Of the 38 patients with atherosclerotic aneurysms, 20 (53 per cent) had histories of ischemic heart disease; the aneurysms were in the right coronary artery in 18 (47 per cent), the left coronary artery in 13 (35 per cent), and in the right and left coronary arteries in seven (18 per cent). Of the four major coronary arteries, the average number of severely narrowed arteries (reduction of more than 75 per cent) in cross-sectional luminal area) was 1.8/patient; aortic aneurysms were present in eight of these patients (24 per cent). Of the 14 patients with coronary aneurysms secondary to inflammation, four had histories of ischemic heart disease; 10 had histories of an influenza-like syndrome. Isolated left coronary arterial aneurysms were seen in six of these patients (43 per cent), while eight (51 per cent) had multiple right and left coronary arterial aneurysms. The average number of severely narrowed coronary arteries in this group was 1.5/patient, and only one patient had an aortic aneurysm. Therefore, patients with atherosclerotic aneurysms are more often symptomatic; they have increased heart weights and equal numbers of coronary arterial aneurysms in the right and left vessels, and the majority (89 per cent) have single aneurysms with thrombi in the lumen. Patients with coronary arterial aneurysms secondary to inflammation are younger; the majority of these patients have a prodromal influenza-like syndrome, a low incidence of ischemic heart disease, and multiple coronary arterial aneurysms.     

Comparative study of calcified changes in aortic valvular diseases.

Calcification of the aortic valve leads to stenosis or regurgitation or both. To clarify the mechanism of heart valve calcification, comparative studies using histological and ultrastructural examinations were performed of calcified aortic valves. These valves were obtained at valve replacement surgery from 11 patients with rheumatic aortic valvular disease (RAVD), 10 patients with degenerative aortic valve disease (DAVD), and 10 patients with congenitally bicuspid aortic valves (CBAV). For electron microscopic study, 5 cases were selected from each group. In RAVD, histological examination revealed calcification in a degenerated amorphous area at the center of fibrous thickened regions and in laminar fibrous thickened areas near the valve surface. In DAVD, calcification was observed mainly in the fibrosa near the valve ring. In CBAV, basic pathological changes were similar to those in DAVD; however, additional severe calcification of the raphe was observed, if the raphe was present. Ultrastructural examinations showed deposition of electron-dense materials in two patterns in all three groups; one pattern was observed in the interfibrillar spaces of collagen fibrils, and the other pattern was widespread macular deposition unrelated to the preexisting structure. In RAVD, microfibril-like fibrillar structures were found in the areas of deposition of electron-dense materials. These findings suggest that newly formed connective tissue degraded and became necrotic because of nutritional deprivation, especially in the thickened central area, causing calcium deposition. In DAVD and CBAV, numerous lipid vacuoles were found in the electron-dense deposition areas similar to lipid deposition in aortic atherosclerosis. Localized calcium deposition in the fibrosa suggests that the stress of valvular motion and pressure load induces sclerotic changes with the degeneration of collagen fibers, providing a core for calcification. In CBAV, the raphe was the main location of calcification, wherein spiraled collagen fibrils were observed. Increasing the hemodynamic load with abnormal structure might influence calcification. The ultrastructural pattern of calcification of the valve is common; however, additional findings suggest that the cause and mechanism are different in each type of heart valve disease.