Recreational use of aminorex and pulmonary hypertension.

Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice"), is a "designer" drug with central stimulant activity. This drug was discovered on the property of three individuals with diagnoses of pulmonary hypertension. The association between "recreational" aminorex manufacture and ingestion and the development of pulmonary hypertension is described.

Thoracoabdominal aorta in Marfan syndrome: MR imaging findings of progression of vasculopathy after surgical repair.

PURPOSE: To determine the natural history of vasculopathy of the thoracoabdominal aorta in patients with Marfan syndrome after composite graft repair of the aortic root. MATERIALS AND METHODS: A total 224 magnetic resonance (MR) images obtained in 48 patients with Marfan syndrome over a period of 2.3-9.4 years (mean, 5.0 years) were retrospectively reviewed. On each image, the diameter of the thoracoabdominal aorta was measured and the presence of dissection or major peripheral artery aneurysms was determined. RESULTS: In 31 (65%) of the 48 patients, no statistically significant change (3 mm or less increase in diameter) in the diameter of the aorta occurred during the study (group 1); in the remaining 17 (35%) patients, a significant change occurred (greater than 3 mm increase) (group 2). The mean initial diameter of the native aorta was slightly larger in group 2 (mean, 27 mm +/- 8 [standard deviation]) than in group 1 (mean, 23 mm +/- 6). In group 1, the mean rate of dilation was 0.07 mm/y +/- 0.2; in group 2, the rate was 2.3 mm/y +/- 3.3. Two patients with aortic dissection were in group 1, whereas 14 such patients were in group 2 (P < .001). Aneurysms that involved major peripheral arteries were present in four (13%) of the 31 group 1 patients and in 12 (71%) of the 17 group 2 patients (P < .001). Surgical intervention was necessary in two group 1 patients and in 14 group 2 patients (P < .001). CONCLUSION: A subset of patients with Marfan syndrome manifested multiple forms of vasculopathy, including progressive aortic dilation, dissection, and peripheral artery aneurysm after composite aortic graft repair of the ascending aorta. Patients with these characteristics merit more frequent MR follow-up since further surgery was often necessary in these individuals.

Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome.

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

Stimulus-evoked sinus arrest in severe Guillain-Barré syndrome: a case report.

Guillain-Barré syndrome, or acute inflammatory demyelinating polyradiculoneuropathy, is frequently accompanied by cardiac and autonomic dysfunction. We report a patient in whom minor autonomic stimulation by upgaze, tongue protrusion, opening the mouth against resistance, eyeball pressure, and carotid sinus massage produced asystole. The frequency of potentially lethal dysrhythmias in Guillain-Barré syndrome, coupled with the relative ease of cardiac pacing, makes recognition of these phenomena of utmost importance in affected patients.

The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome)

BACKGROUND: The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies. METHODS: Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members. RESULTS: A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2). CONCLUSIONS: Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

Neonatal lupus erythematosus syndrome: late detection of isolated heart block.

Heart block in neonatal lupus erythematosus is typically complete and detected in utero or in the neonatal period. We describe a child diagnosed with incomplete heart block at 9 years of age whose mother was diagnosed with Sjögren's syndrome and anti-Ro(SSA) 2 years after diagnosis of heart block in her child. This is the first case of late detection of incomplete heart block in a child felt to be causally related to the presence of anti-Ro(SSA) in the mother.

Surgical treatment of postinfarction ventricular septal defect with aortic stenosis.

A 69-year-old man with an acute postinfarction ventricular septal defect was also found to have aortic stenosis. Successful management required closure of the postinfarction ventricular septal defect and replacement of the stenotic aortic valve. The contribution of aortic stenosis to the cause of the infarction and the postinfarction ventricular septal defect, as well as the implications for surgical management, are discussed.

Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.

BACKGROUND: The clinical diagnosis of familial hypertrophic cardiomyopathy is usually made on the basis of the physical examination, electrocardiogram, and echocardiogram. Making an accurate diagnosis can be particularly difficult in children, who may not have cardiac hypertrophy until adulthood. Recently, we demonstrated that mutations in the cardiac myosin heavy-chain genes cause familial hypertrophic cardiomyopathy in some families. We report a diagnostic test for familial hypertrophic cardiomyopathy that relies on the detection of mutations in the beta myosin heavy-chain gene in circulating lymphocytes that we used to evaluate three generations of a family, including the children. METHODS AND RESULTS: Using the polymerase chain reaction, we found that normal and mutant beta cardiac myosin heavy-chain genes are transcribed in circulating lymphocytes. This allowed us to examine beta cardiac myosin heavy-chain messenger RNA from blood lymphocytes, even though ordinary expression of the gene is virtually restricted to the heart. Base sequences amplified from this messenger RNA were analyzed with a ribonuclease protection assay to identify small deletions, abnormal splicing, or missense mutations. Using this technique we identified a novel missense mutation in a patient with familial hypertrophic cardiomyopathy. We evaluated 15 of the patient's adult relatives and found perfect agreement with the clinical diagnosis (8 affected and 7 not affected). Clinical analysis of 14 of the children (age, 1 to 20 years) of these affected family members revealed 1 child with echocardiographic findings diagnostic of familial hypertrophic cardiomyopathy. However, genetic analyses showed that six other children had also inherited the missense mutation and might later manifest the disease. CONCLUSIONS: Transcripts of beta cardiac myosin heavy-chain gene can be detected in blood lymphocytes and used to screen for mutations that cause familial hypertrophic cardiomyopathy. This approach makes practical the identification of mutations responsible for this disorder and may be applicable to other diseases in which direct analysis is difficult because the mutated gene is expressed only in certain tissues. Preclinical or prenatal screening in an affected family will make it possible to study the disease longitudinally and to develop preventive interventions.

Persistent pulmonary hypertension after heterotopic heart transplantation: a case report.

Right-sided failure occurring in the donor heart immediately after transplantation is primarily caused by increased recipient pulmonary artery pressure and resistance and represents one of the leading causes of perioperative mortality associated with orthotopic heart transplantation. After transplantation pulmonary hypertension gradually declines, returning to near normal levels within 30 days of transplantation. This article describes a case report of the persistence of pulmonary hypertension after heterotopic heart transplantation. The heterotopic position was utilized because of marked elevation of the pulmonary artery resistance (18 Wood units) calculated at the time of operation. Cardiac catheterization data-obtained during the subsequent 6 months of follow-up showed persistent elevation of pulmonary artery pressure and pulmonary vascular resistance. The patient, however, clinically continues to feel well and remains asymptomatic without signs of right-sided heart failure. Indications, suggested advantages, and demonstrated disadvantages of heterotopic heart transplantation are discussed.

Unique aspects of heart and lung transplantation exhibited in the 'domino-donor' operation.

During the past 2 decades various refinements in heart and lung transplantation procedures have taken place. Improved preservation methods, new immunosuppressive medications, and advances in technical capabilities have allowed innovative procedures to be performed. In May 1987 the first "domino-donor" operation was performed in the United States. A 28-year-old man with cystic fibrosis and end-stage lung disease received the heart and lungs of an anonymous donor after he donated his heart to a 38-year-old man with end-stage ischemic cardiomyopathy. The technical and logistical aspects of this transplantation procedure are described herein. Other unusual features of this case that are discussed include heart-lung transplantation for a patient with cystic fibrosis, the use of cardiopulmonary bypass to allow lung procurement and transplantation across long distances, and the current role of heterotopic cardiac transplantation.

Diagnosis of lung allograft rejection by bronchial intraepithelial Leu-7 positive T lymphocytes.

Currently there is no reliable technique for the diagnosis of lung allograft rejection. The presence of intraepithelial lymphocytes expressing the Leu-7 antigen is a specific marker of renal rejection. We examined whether immunoperoxidase techniques that detect Leu-7 positive lymphocytes could be used to diagnose lung rejection in heart-lung transplant recipients. In lungs from two autopsied patients with lung allograft rejection, numerous Leu-7 positive lymphocytes were present in the donor bronchial mucosa (32 and 65 cells/section), submucosa (23 and 80 cells/section), and submucosal glands (7 and 19 cells/section). These Leu-7 positive lymphocytes were associated with proximal airway injury, including squamous metaplasia, destruction of submucosal glands, and ulceration. In one case, there was bronchiectasis. Both cases also had distal airway bronchiolitis obliterans. In contrast, Leu-7 positive lymphocytes were not identified in the epithelium of the native trachea of these two patients; nor were they found in the bronchial epithelium of two sets of transplanted lungs without evidence of rejection. Only rare Leu-7 positive lymphocytes were evident in the epithelium (0 to 2 cells/section) and submucosal glands (0 to 1 cell/section) of 20 lungs from autopsied patients who had not received a transplant. Application of this technique to epithelial biopsy specimens obtained at bronchoscopic examinations demonstrated that it could be applied to the diagnosis of rejection in living heart-lung transplant recipients.

Pharmacodynamics and tolerance of oral sustained release ritodrine.

A new oral sustained release formulation of ritodrine was tested for patient tolerance in this open study. The doses tested were 120 mg/day, 240 mg/day, and 360 mg/day. No objective toxicity was seen at any level. Doses of 120 mg/day and 240 mg/day were well-tolerated. Of the subjects who received the 360 mg/day dose, most tolerated it well.

Depletion of bronchus-associated lymphoid tissue associated with lung allograft rejection.

Pulmonary infections remain one of the major complications of lung transplantation. The bronchus-associated lymphoid tissue (BALT) forms a local immune system that normally protects the lung from infection. The effects of lung transplantation and lung allograft rejection on the BALT were examined using immunoperoxidase techniques. The BALT was evaluated by quantifying the number of immunoglobulin-bearing plasma cells in the lamina propria of sections of trachea and mainstem bronchus. Sections of donor mainstem bronchus from 2 patients with allograft rejection were compared with sections of native trachea from these same patients, and with sections of mainstem bronchus from 2 transplanted lungs without rejection and 20 controls. Lung allografts from the 2 patients with rejection had a marked depletion of submucosal IgA-bearing and IgG-bearing plasma cells. Two sets of transplanted lungs without evidence of rejection showed only a mild reduction of the BALT. The depletion of BALT associated with allograft rejection may contribute to the increased incidence of pulmonary infections seen in these patients.

Abnormalities of dynamic ventricular shape change in patients with aortic and mitral valvular regurgitation: assessment by Fourier shape analysis and global geometric indexes.

The normal cardiac cycle is associated with dynamic changes in left ventricular shape, which can be disturbed in disease states. To assess the influences of diastolic volume, percent ejected volume, and abnormalities of acute or chronic systolic loading on general and detailed chamber geometry, we studied dynamic shape change recorded by x-ray contrast ventriculography in both normal patients and those with aortic (AR) or mitral (MR) valve regurgitation. While both lesions increased diastolic volume, the character of load throughout ejection differed markedly. Detailed cavity geometry was assessed by a Fourier analysis technique and general shape by eccentricity and circularity indexes. Normal hearts, showed increased systolic elongation by all indexes. AR patients displayed a similar rise in eccentricity during ejection; however, the extent of shape change when measured by Fourier and circular indexes was reduced. In contrast, MR patients displayed enhanced systolic shape change, particularly in chamber elongation. Neither simple eccentricity of circular indexes adequately differentiated these shape abnormalities, whereas detailed Fourier geometric analysis precisely characterized the abnormalities of shape change in these two diseases. Relations between the extent of shape change and ejected volume for each patient group revealed significantly more systolic deformation with a different shape versus volume relation for the MR hearts as compared with AR and controls. Thus, while dynamic left ventricular shape is certainly influenced by the extent of volume change, it also varies independently from volume related to the specific nature of loading during ejection.

Arteriolar vasculitis on endomyocardial biopsy: a histologic predictor of poor outcome in cyclosporine-treated heart transplant recipients.

The histologic pattern of severe, potentially lethal cardiac rejection in transplant recipients who are treated with cyclosporine may be difficult to distinguish from mild or moderate rejection. The purpose of this study was to determine whether specific histologic abnormalities seen on endomyocardial biopsy could identify which histologic patterns of rejection are associated with progression to graft dysfunction or graft failure. We performed a blinded, retrospective analysis of endomyocardial biopsies from our initial 19 transplant recipients. Group 1 was composed of five patients who developed graft failure or dysfunction after transplantation. Group 2 was composed of the remaining 14 patients with normal hemodynamics and function at heart catheterization 1 year after transplantation. Seventeen histologic parameters were semiquantitatively graded, and comparisons between the two groups were made with the Student's t test. Of the 17 parameters, only arteriolar vasculitis was significantly increased in group 1 versus group 2 biopsies (p = 0.002). Arteriolar vasculitis was identified in four of five patients in group 1 and was unique to group 1. Of 53 group 1 biopsies, eight patients had foci of arteriolar vasculitis and were seen up to 88 days before graft failure. Therefore the finding of arteriolar vasculitis on endomyocardial biopsy may identify high risk rejection episodes in transplant recipients who are treated with cyclosporine.

Histologic predictors of acute cardiac rejection in human endomyocardial biopsies: a multivariate analysis.

To identify specific histologic abnormalities that could predict early cardiac rejection before the development of myocyte necrosis, 167 consecutive endomyocardial biopsy samples from 18 cardiac transplant recipients were retrospectively analyzed and 17 histologic variables were semiquantitatively graded from 0 to 3. Forty-five biopsy samples contained foci of myocyte necrosis and were labeled Rejectors. The two samples immediately preceding Rejector biopsies were labeled Predictors (n = 44). All remaining samples were labeled Others (n = 78). Endocardial and interstitial infiltrates, interstitial mononuclear cells, pyroninophilic mononuclear cells, polymorphonuclear leukocytes and other cells (eosinophils and plasma cells) were significantly increased in graded severity in Rejector biopsy samples as compared with Predictors or Others (p less than 0.001, ANOVA testing). These variables cannot distinguish Predictor biopsy specimens from Others. On the other hand, interstitial edema, perivascular karyorrhexis and perivascular infiltrate with intermyocyte extension are histologic abnormalities that can distinguish Predictor biopsy samples from Others (p less than 0.001, ANOVA testing). Multiple logistic regression analysis indicates that the relative risk of developing myocyte necrosis when a biopsy sample contains interstitial edema is 8.1. With perivascular infiltrate with intermyocyte extension in addition, the relative risk is 41.4. In summary, three histologic abnormalities have been identified that help predict the future development of myocyte necrosis within the next two endomyocardial biopsies. Biopsy specimens with these abnormalities probably represent early cardiac rejection before the development of myocyte necrosis.