Biomedical subjects
William D Edwards
Publications and source records attributed to William D Edwards.
Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
Mutations in the cardiac-specific insert of vinculin, metavinculin, rarely cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Subsequently, a missense mutation in the ubiquitously expressed vinculin was discovered in a patient with obstructive HCM. Microscopic examination of both myectomy specimens from patients bearing genetic defects in metavinculin and vinculin showed a marked reduction of vinculin/metavinculin expression in the intercalated disc, but normal expression in the Z-disc. Given that distinct functional domains were altered by the metavinculin and vinculin mutations, we hypothesized that the intercalated disc-specific reduction of vinculin may stem from left ventricular tract obstruction in general rather than rarely observed perturbations in VCL-encoded vinculin. To test this hypothesis, we examined the localization of vinculin/metavinculin in hypertrophied human heart tissue from patients with cardiovascular conditions associated with obstruction and hemodynamic overload using an immunohistochemistry approach. Tissue specimens derived from patients with obstructive HCM and aortic stenosis (AS) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z-disc, whereas tissue specimens derived from patients with either DCM, hypertensive heart disease (HTN), or pulmonary hypertension (PHTN) exhibited normal expression of vinculin/metavinculin in both the Z- and the intercalated disc despite being associated with hypertrophy. Results of this study suggest that cardiac hypertrophy may be associated with different expression of the marker vinculin/metavinculin depending on the underlying pathophysiology; hemodynamic overload may not affect the localization whereas obstructive disease substantially reduces the expression of vinculin preferentially in the intercalated disc.
Giant coronary artery aneurysm causing superior vena cava syndrome and congestive heart failure.
Coronary artery aneurysms are defined as localized coronary artery dilations >1.5 times the diameter of the adjacent segments. In adults, they are commonly of atherosclerotic origin and are usually asymptomatic. This is the first case report of a coronary artery aneurysm causing superior vena cava syndrome and heart failure. Chest x-ray showed cardiomegaly, and transthoracic echocardiography showed a mass that was confirmed by transesophageal echocardiography, computed tomography, and coronary angiography. In conclusion, giant coronary artery aneurysms can cause superior vena cava syndrome.
A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
The R975W mutation, in the alternatively spliced exon 19 of vinculin (VCL) which yields the isoform metavinculin, was associated previously with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and shown to alter in vivo organization of intercalated discs. We tested the hypothesis that alterations in the ubiquitously expressed, VCL-encoded protein, vinculin, may provide a pathogenic substrate for HCM. Comprehensive mutational analysis of VCL's 22 translated exons was performed in a cohort of 228 unrelated patients with genotype negative HCM, having no identifiable mutations in 12 HCM-associated myofilament/Z-disc-encoding genes. A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy. This mutation was not detected in 400 reference alleles. Immunohistochemical analysis of the proband's myectomy specimen demonstrated markedly reduced vinculin levels in the intercalated discs. We provide the first report of a cardiomyopathy associated mutation in vinculin. Despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype.
Endothelial and smooth muscle cell populations in a decellularized cryopreserved aortic homograft (SynerGraft) 2 years after implantation.
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Giant-cell temporal arteritis in a 17-year-old male.
Temporal arteritis, particularly in its classic form, is exceedingly rare in individuals <50 years old. We report the youngest case of biopsy-proven giant cell temporal arteritis. A 17-year-old male presented with a progressively expanding and pulsatile but otherwise asymptomatic mass in his forehead. The patient's medical history was significant for uveitis since the age of 3, and severe allergic rhinitis, mild asthma, and juvenile rheumatoid arthritis as a young adolescent. Admission laboratory values included a mildly elevated erythrocyte sedimentation rate and C-reactive protein level. A computed tomography evaluation demonstrated aneurysmal degeneration of the frontal branch of the right superficial temporal artery and confirmed no other cerebrovascular changes. Histologically, the aneurysmal arterial segment demonstrated subacute temporal arteritis. The arterial wall had a primarily lymphoplasmacytic infiltrate with rare giant cells and focally marked medial destruction. Additionally, severely obstructive intimal hyperplasia with chronic adventitial and periadvential dense fibrosis was noted. The diagnosis of classic giant cell temporal arteritis was established from the biopsy result. Postoperatively, the patient was treated with prednisone for 3 months. Three years after surgery, the patient remains well and reports no recurrence of temporal artery disease.
Death during coronary angiography in a woman with cardiac amyloidosis.
Amyloidosis is a well-recognized systemic disease entity. Patients with cardiac amyloidosis have a poor prognosis; the median survival time after development of congestive heart failure is 4 months. We describe a 72-year-old woman with unsuspected cardiac amyloidosis who died during diagnostic coronary angiography. To our knowledge, this is the first report of this complication.
Surgical pathology of the ascending aorta: a clinicopathologic study of 513 cases.
Only 2 comprehensive surgical series, published in 1977 and 1983, have evaluated clinicopathologic features of the ascending aorta. Retrospective review of medical records and microscopic slides was performed on 513 consecutive patients with surgical resection of ascending aortic tissue (1985 to 1999). Patients were 2 to 89 years old (mean 59 y), and 303 (59%) were men. Aneurysm or dissection was the indication for surgery in 479. Aortic valves were also excised in 360. Systemic hypertension was present in 279, inherited connective tissue disease (ICTD) in 67, arteritis in 33, and acquired connective tissue disease in 16. Microscopy showed cystic medial degeneration (CMD) in 209, aortic dissection (AD) in 109 (with CMD in 56), normal media in 90, aortitis in 57 (with CMD in 14), and other findings in 48. The most significant, independent risk factor of CMD and AD was ICTD (confidence interval=7.61 and 2.26, respectively). Systemic hypertension was more common in patients with AD than without (P=0.0202). Normal media was the most common histologic finding associated with bicuspid aortic valve (P<0.0001). Among 57 patients with aortitis (giant cell in 39), ages ranged from 16 to 85 years (mean 64 y), and 42 (74%) were women; only 8 had Takayasu arteritis, and 11 had temporal or systemic arteritis. In surgically resected ascending aorta, the 3 most common histologic findings were CMD, AD, and normal media. ICTD, systemic hypertension, and bicuspid aortic valve were common comorbid findings. Giant cell aortitis occured predominantly in women, usually without systemic disease.
Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant.
BACKGROUND: Aortitis is emerging as an important cause of ascending aortic aneurysm in the elderly. Its features have not been described in a surgical population. DESIGN: Retrospective clinicopathologic review of 45 cases of active noninfectious aortitis among 513 consecutive ascending aortic resections (1985 to 1999). METHODS: Clinical data were collected from medical records. Histopathologic features were recorded during review of slides stained with hematoxylin-eosin and Verhoeff-van Gieson. Cases were categorized by predefined clinical criteria. Clinicopathologic features were compared among groups, with emphasis on unsuspected aortitis without systemic arteritis. RESULTS: The 2 largest groups were isolated aortitis (47%) and giant cell arteritis (31%). Other aortitis groups included Takayasu (14%), rheumatoid (4%), and unclassified (4%). Patients with isolated aortitis and giant cell arteritis were generally women (80%; mean age 73 y). All 6 with Takayasu arteritis were women (mean age 26). Although giant cell arteritis and isolated aortitis were histologically indistinguishable, their clinical courses differed substantially. Among 21 patients with isolated aortitis (2 treated with corticosteroids), only 10% later developed aortic aneurysms. In contrast, of 14 patients with giant cell arteritis (11 treated with corticosteroids), 21% subsequently developed aneurysms (P=0.09). CONCLUSIONS: Aortitis primarily affected women. Patients with isolated aortitis and giant cell arteritis were generally older than 50 years and, by definition, those with Takayasu arteritis were younger. In patients with isolated aortitis, outcomes were generally good, despite the absence of anti-inflammatory therapy. Accordingly, a conservative approach may be warranted for managing this subset of patients with aortitis.
Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
We tested the hypothesis that perturbations in metavinculin may provide a pathogenic substrate for hypertrophic cardiomyopathy (HCM). HCM and dilated cardiomyopathy (DCM) are partially allelic disorders whereby identical genes have been implicated in the pathogenesis of both diseases. Mutations in metavinculin, a muscle-specific isoform of vinculin, were identified previously in DCM and shown to alter in vitro organization of actin filaments. Using denaturing high performance liquid chromatography and direct DNA sequencing, mutational analysis of the metavinculin-specific exon of vinculin (VCL, exon 19) was performed in a cohort of 389 unrelated patients with clinical HCM, previously genotyped for the 8 most common HCM-associated myofilament-encoding genes. Overall, 3 non-synonymous single nucleotide polymorphisms (A934V, P943A, and R975W) were detected in 4 patients. One patient with severely obstructive, mid-ventricular and apical hypertrophy harbored the previously published DCM-associated mutation, R975W. R975 is a highly conserved residue and R975W was absent in over 1400 reference alleles. Immunohistochemical analysis of the proband's myectomy specimen revealed a paucity of vinculin/metavinculin in the intercalated discs. Metavinculin mutations are pathogenic substrates for both HCM and DCM, further highlighting the allelic nature of these cardiomyopathies. Mutations in functionally distinct regions of certain cardiomyopathy-associated genes may have a dominant effect in determining a remodeling pathway of either maladaptive hypertrophy or dilation. However, this study demonstrates that the same fundamental mutation in humans can yield either cardiomyopathic phenotype, underscoring a critical role for modifier genes and/or environmental stressors in cardiac remodeling.
Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation.
BACKGROUND: Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis. METHODS AND RESULTS: To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, alpha-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves. CONCLUSIONS: These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis.
Obstructive intramural coronary amyloidosis and myocardial ischemia are common in primary amyloidosis.
PURPOSE: The purpose of this study was to determine the prevalence of clinical syndromes and pathologic changes of myocardial ischemia due to obstructive intramural coronary amyloidosis among patients with primary amyloidosis and cardiac involvement. SUBJECTS AND METHODS: Medical records and pathologic specimens were reviewed from 96 patients with primary amyloidosis and cardiac involvement at autopsy or after cardiac transplantation during a 20-year period. Medical records were reviewed for patient demographic and clinical characteristics, including evidence for syndromes of myocardial ischemia. Pathologic specimens were examined for obstructive intramural coronary amyloidosis and microscopic changes of myocardial ischemia. RESULTS: Obstructive intramural coronary amyloidosis was present in 63 of 96 patients (66%). Microscopic changes of myocardial ischemia were more common in patients with obstructive intramural coronary amyloidosis (86%) than in those without (52%) (P <.001). In the 76 patients without coexistent severe epicardial coronary atherosclerosis, changes of myocardial ischemia were more common in those with obstructive intramural coronary amyloidosis (83%) than in those without (45%) (P <.001). In patients who had tissue available for review, none had obstruction of epicardial coronary arteries from amyloid. Syndromes of myocardial ischemia affected 16 patients (25%) with obstructive intramural coronary amyloidosis but only 2 patients (6%) without (P=.027). For 11% of the patients with obstructive intramural coronary amyloidosis, a syndrome of myocardial ischemia consisting of acute myocardial infarction or angina pectoris was the first manifestation of primary amyloidosis. CONCLUSION: Most patients with primary systemic amyloidosis and cardiac involvement have obstructive intramural coronary amyloidosis and associated microscopic changes of myocardial ischemia. Syndromes of myocardial ischemia may occur in these patients.
Surgical treatment of cardiac papillary fibroelastoma: a single center experience with eighty-eight patients.
BACKGROUND: Cardiac papillary fibroelastoma is a rare benign tumor that can cause thromboembolism. We have found no large surgical series describing its treatment and outcome. METHODS: A retrospective review of all patients treated surgically for this tumor from 1985 to 2002. RESULTS: There were 88 patients with a mean age of 62 +/- 16 years. Sixty-two (71%) were male. Cardiac papillary fibroelastoma was a primary indication for surgery in 47 (group 1, 53%) and an incidental finding in 41 (group 2, 47%). The common clinical symptoms were neurologic (group 1) and cardiac (group 2). Cardiac valves were predominantly involved (77%); the aortic valve was the most affected (52%). Other common sites were the left ventricular outflow tract (18%) and anterior mitral leaflet (11%). All heart valves were involved in one patient. Seventy-three patients (83%) had shave excision and 8 (9%) excision with valve repair. Of 5 (6%) valve replacements, 2 were for concurrent degenerative valve disease. Concomitant procedures included repair or replacement of another valve (32%), CABG (28%), and septal myectomy (19%). Surgical mortality occurred in 1 patient (2.1%) in group 1 who had concomitant lung resection for bronchiolitis obliterans. There was no tumor recurrence, and no tumor-related late morbidity or mortality at a mean follow-up of 3 years. CONCLUSIONS: Cardiac papillary fibroelastoma has a propensity to affect the anatomically contiguous structures of the aortic valve, left ventricular outflow tract, and anterior mitral leaflet. Surgical treatment by simple shave excision is low risk and can achieve good results.
Calcified right ventricular mass and pulmonary embolism in a previously healthy young woman.
A 20-year-old woman with a recent episode of pulmonary embolism was found by echocardiographic examination to have a calcified apical right ventricular intracavitary mass. She had a history of cigarette smoking and had been taking oral contraceptive pills. At age 17 years, she had sustained substantial blunt chest injury during a motor vehicle accident. The intracardiac mass was resected and represented an old calcified mural thrombus. It is postulated that its development was related to cardiac trauma. These intracavitary masses have been referred to as cardiac calcified amorphous tumors and generally represent old organized and focally calcified mural thrombus. They should be distinguished from calcified benign or malignant neoplasms of the heart.
Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction.
A 39-year-old woman with a history of systemic lupus erythematosus developed chest pain and conduction abnormalities. An echocardiographic examination revealed systolic dysfunction and ventricular thickening. Because of the unclear nature of her cardiac disease, right ventricular endomyocardial biopsy was performed. Light microscopy showed diffuse myocyte vacuolization without myocarditis, and transmission electron microscopy demonstrated sarcoplasmic myelinoid and curvilinear bodies, diagnostic of hydroxychloroquine toxicity. Among patients with autoimmune connective disorders, cardiac dysfunction may be a result of the disease or occasionally of its treatment. Although the nature of the cardiac disease (myocardial, valvular, or pericardial) can generally be evaluated echocardiographically, endomyocardial biopsy may be indicated to rule out diseases with a specific microscopic appearance, such as myocarditis or hydroxychloroquine cardiotoxicity.
A cautionary note regarding long-term sequelae of biologic glue.
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Atypical presentation of eosinophilic endomyocardial disease.
Idiopathic hypereosinophllic syndrome is classically defined as prolonged, unexplained peripheral eosinophilia in a patient presenting with evidence of end-organ damage. The heart is frequently Involved, resulting In eosinophilic endomyocardial disease and eventually restrictive cardlomyopathy. The mortality rate is high because of progressive heart failure or ventricular arrhythmias. We describe a patient who presented with a left ventricular apical thrombus without notable peripheral eosinophilia. Findings from clinical evaluation and extensive diagnostic testing, including right ventricular biopsy, were Inconclusive. Resection of the thrombus and subjacent endomyocardium revealed eosinophilic Infiltration of the endomyocardium, which led to the diagnosis of eosinophilic endomyocardial disease. Clinicians should be aware of the variable presentation of patients with eosinophil-associated endomyocardial disease so that affected patients may benefit from early diagnosis and treatment.
Molecular autopsy vs postmortem genetic testing.
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