Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias

Amiodarone, a drug that has electrophysiologic actions resembling those of hypothyroidism, increases serum levels of T4 and reverse T3 (rT3) and decreases T3. The drug's long-term effects on thyroid function are poorly defined. Serial thyroid hormone indexes in 76 patients given amiodarone for 6 to 32 months (mean +/- standard deviation 16 +/- 7) for arrhythmias were determined serially. Over this period, 68 patients (89%) remained euthyroid; hypothyroidism developed in 6 (8%) and hyperthyroidism developed in 2 (3%). In patients who remained euthyroid, thyroid hormone alterations attained steady-state values at 3 months: T4 increased 42% (p less than 0.01), rT3 increased 172% (p less than 0.01) and T3 decreased 16% (p less than 0.05), without significant effect on thyroid stimulating hormone. For the euthyroid patients, the 90% tolerance limits (95% confidence) over the follow-up period for T4 was 5 to 19 micrograms/dl (normal 4 to 12), for T3 36 to 163 ng/dl (normal 60 to 160), for rT3 22 to 131 ng/dl (normal 15 to 50) and for thyroid stimulating hormone 0 to 14 microU/ml (normal 1 to 6). The changes in hormone indexes in hyperthyroid or hypothyroid patients were unrelated to the cumulative dose or duration of drug therapy. The most reliable diagnostic indexes for amiodarone-induced altered thyroid state were: thyroid stimulating hormone level over 20 microU for hypothyroidism and T4 over 20 ng/dl or high T3 over 200 ng/dl for hyperthyroidism. All levels were within the 90% tolerance limits derived for these hormones from patients remaining euthyroid on amiodarone long-term.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.     

Amiodarone and thyroid function

Amiodarone blocks the action of thyroid hormone by the inhibition of 5′-deiodinase which reduces production of T₃ in peripheral tissues and possibly by blocking nuclear binding of T₃. Since the drug inhibits peripheral conversion of T₄ to T₃, many patients taking amiodarone have abnormal thyroid function studies (increased T₄ and rT₃; decreased T₃) despite being euthyroid. Treatment of patients with amiodarone generates an iodine excess, which contributes greatly to the significant incidence of altered thyroid status in this population. The diagnosis of hyperthyroidism and hypothyroidism can be difficult. However, using the overall clinical picture and the tolerance limits of hormone levels determined for patients remaining euthyroid on amiodarone therapy, the accurate diagnosis of clinically significant thyroid dysfunction can almost always be made. To screen for thyroid disease, thyroid function should be assessed before initiating therapy, semiannually during therapy or whenever clinical features of thyroid dysfunction occur. Subclinical hypothyroidism as denoted by modest increases in TSH levels do not require treatment or the discontinuation of amiodarone therapy. An appreciation of the mechanism of the interaction between amiodarone and thyroid hormone metabolism allows the clinician to recognize thyroid dysfunction at an early stage and initiate appropriate therapy, thereby minimizing the morbidity associated with forms of amiodarone toxicity.     

A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate

OBJECTIVES: We sought to test the hypothesis that complex fractionated electrograms (CFAEs) recorded during atrial fibrillation (AF) could be used as target sites for catheter ablation of AF. BACKGROUND: Mapping of AF in humans has shown that areas of CFAEs correlate with areas of slowed conduction and pivot points of reentrant wavelets. We hypothesized that such areas of CFAEs could be identified in patients with AF and might serve as target sites for catheter ablation to maintain sinus rhythm. METHODS: The study population included 121 patients (29 females; mean age, 63 years) with refractory AF (57 paroxysmal, 64 chronic). All patients underwent nonfluoroscopic electroanatomic mapping (CARTO) during AF. Using CARTO, the biatrial replica, displayed in a three-dimensional color-coded voltage map, was created during AF, and areas associated with CFAEs were identified. Radiofrequency ablation of the area with CFAEs was performed, aiming to eliminate CFAE and/or convert to sinus rhythm. RESULTS: Complex fractionated atrial electrograms were found in seven of nine regions of both atria, but were mainly confined to the interatrial septum, pulmonary veins, roof of left atrium, and left posteroseptal mitral annulus and coronary sinus ostium. Ablations of the areas associated with CFAEs resulted in termination of AF without external cardioversion in 115 of the 121 patients (95%); 32 (28%) required concomitant ibutilide treatment. At the one-year follow-up, 110 (91%) patients were free of arrhythmia and symptoms, 92 after one ablation and 18 after two. CONCLUSIONS: Areas with CFAEs represent a defined electrophysiologic substrate and are ideal target sites for ablations to eliminate AF and maintain normal sinus rhythm.     

High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors

Eight-five consecutive patients with relapsed or refractory Hodgkin's disease (HD) underwent high-dose chemotherapy or chemo/radiotherapy followed by autologous bone marrow (ABMT) and/or peripheral blood stem cell (PBSC) transplantation. Two preparative regimens were used. Twenty- two patients (26%) without prior radiation received fractionated total body irradiation (FTBI) 1,200 Gy in combination with high-dose etoposide (VP-16) 60 mg/kg and cyclophosphamide (CTX) 100 mg/kg. Sixty- three patients (74%) with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. The median age was 32 years (range, 16 to 56). The median number of prior chemotherapy regimens was three (range, 1 to 7). Forty-three patients (51%) received transplants in first relapse or second complete remission (CR), whereas 33 (39%) received transplants after second or subsequent relapse. All relapsed patients, except one, received conventional salvage chemotherapy and/or radiotherapy in an attempt to reduce tumor bulk before transplant. At the time of analysis in April 1994, fifty-seven patients (67%) are alive, including 44 (52%) in continuous CR, with a median follow-up for the surviving patients of 28 months (range, 7 to 66). Thirty patients (35%) relapsed at a median of 9 months (range, 1 to 43). Eleven patients (13%) died of transplant-related complications including veno- occlusive disease of the liver (VOD) in five, acute and late interstitial pneumonitis in three, graft failure in one, cerebral hemorrhage in one, and therapy-induced myelodysplasia (MDS)/acute leukemia in one patient. At a median follow-up of 25 months (range, 0.6 to 66), the cumulative probability of 2-year overall and disease-free survival (DFS) of all 85 patients is 75% (95% confidence interval [CI] 64% to 84%) and 58% (95% CI 47% to 69%), respectively. Three independent prognostic variables were identified by univariate analysis: number of prior chemotherapy regimens, prior radiotherapy, and extranodal disease at ABMT. Multivariate stepwise Cox regression identified the number of prior chemotherapy regimens as the only significant prognostic factor predicting for both relapse and DFS. There were no significant differences in the outcome of the treatment between the two preparative regimens. Our results confirm that high- dose therapy and ABMT is an effective therapy for patients with relapsed or refractory HD. Earlier transplantation is recommended before the development of drug resistance and end organ damage that results from repeated attempts of salvage therapy.     

Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study

We assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk [RR] = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio [OR] = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.     

Myelodysplasia and acute myeloid leukemia occurring after autologous bone marrow transplantation for lymphoma

Secondary hematopoietic disease manifesting as acute myeloid leukemia, myelodysplastic syndrome or clonal karyotypic abnormalities, has been recently recognized as a relatively frequent and potentially serious complication of autologous bone marrow transplantation for both Hodgkin's disease and non-Hodgkin's lymphoma. The available evidence suggests the disease results primarily from repeated exposure of the host stem cells to therapeutic agents before the time of transplant, but a conspiratory role for the transplantation procedure itself cannot be entirely excluded. Strategies to decrease the incidence of secondary hematopoietic disease include earlier stem cell harvest and/or transplantation, and the performance of screening karyotypic studies on the bone marrow prior to autologous grafting.     

Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides.

PURPOSE: Sezary syndrome (SS) and tumor-stage mycosis fungoides (MF) are generally incurable with currently available treatments. We conducted a retrospective study to evaluate the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) in this patient population. PATIENT AND METHODS: From August 1996 through October 2002, eight patients with advanced MF/SS underwent allogeneic HSCT at our institution. All patients were heavily pretreated, having failed a median number of seven prior therapies (range, five to 12). Clonal T-cell populations in peripheral blood or bone marrow were detectable by polymerase chain reaction analyses of T-cell receptor gamma-chain gene rearrangements in six patients and cytogenetics in three patients. The conditioning regimen included total-body irradiation and cyclophosphamide (n = 3), busulfan and cyclophosphamide (n = 1), and the reduced-intensity regimen of fludarabine and melphalan (n = 4). Allogeneic hematopoietic stem cells were obtained from HLA-matched siblings (n = 4) and unrelated donors (n = 4). RESULTS: All patients achieved complete clinical remission and resolution of molecular and cytogenetic markers of disease within 30 to 60 days after HSCT. Two patients died from transplantation-related complications; graft-versus-host disease (GVHD; n = 1) and respiratory syncytial virus pneumonia (n = 1). With a median follow-up of 56 months, six patients remain alive and without evidence of lymphoma. CONCLUSION: Our results suggest that allogeneic HSCT from both HLA-matched sibling and unrelated donors can induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma that is refractory to standard therapies.     

Novel mutations in domain I of SCN5A cause Brugada syndrome

Brugada syndrome, an autosomal dominantly inherited form of ventricular fibrillation characterized by ST-segment elevation in leads V1-V3 and right bundle-branch block on surface electrocardiogram, is caused by mutations in the cardiac sodium channel gene SCN5A. Patients with Brugada syndrome were studied using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing of SCN5A. Mutations were identified in SCN5A in two families and one sporadic case. In one family, a missense mutation leading to a glycine to valine substitution (G351V) in the pore region between the DIS5 and DIS6 transmembrane segments was detected. Biophysical analysis demonstrated that this mutation caused significant current reduction. In the other family, a 20-bp deletion of the exon 5 splice acceptor site was identified; as exon 5 encodes part of the intracellular loop between DIS2 and DIS3, this portion of the channel is disrupted. In the sporadic patient, a missense mutation resulting in the substitution of lysine by glutamic acid (K126E) in the intracellular loop at the boundary with DIS1 was identified. These three new SCN5A mutations in Brugada syndrome patients are all located within domain I of SCN5A, a region not previously considered important in the development of ventricular arrhythmias.     

Severity of silent myocardial ischemia on ambulatory electrocardiographic monitoring in patients with stable angina pectoris: relation to prognostic determinants during exercise stress testing and coronary angiography

The relation of silent ischemia in patients with stable angina to known predictors of severity of coronary disease on exercise stress testing and coronary angiography is poorly defined. This issue was therefore examined with use of Holter electrocardiographic (ECG) recordings, treadmill exercise tests and angiographic indexes in 102 patients (not taking antianginal therapy) and the results were compared with Holter and treadmill findings in 42 volunteers. A total of 159 ischemic episodes (90% silent) were identified during 2,503 h on Holter recording in 97 patients (mean duration per episode 22.7 +/- 147 min; range 1 to 234). Holter recordings had a 92% specificity and an 80% positive predictive value, but a sensitivity of only 37% and a negative predictive value of 27% for coronary disease. Sixty-three patients (Group I) had no ischemia on Holter recording, 22 (Group II) had a cumulative duration of 1 to 60 min/24 h and in 12 (Group III) ischemia exceeded 60 min/24 h. There was no significant correlation between cumulative ischemia duration on Holter recording and exercise duration or time to ST segment depression on treadmill exercise. In general, the greater the number of coronary vessels involved and the higher the proximal coronary artery stenosis score, the greater the likelihood of ischemia and the longer the cumulative ischemia duration on Holter recording. Irrespective of the severity of coronary disease, in about 25% of Holter recordings in each angiographic category there were no ischemic episodes.(ABSTRACT TRUNCATED AT 250 WORDS)