Idiopathic atrial fibrillation patients rapidly outgrow their low thromboembolic risk: a 10-year follow-up study.

BACKGROUND: Healthy atrial fibrillation (AF) patients will eventually outgrow their low thromboembolic risk. The purpose of this study is to compare the development of cardiovascular disease in healthy AF patients as compared to healthy sinus rhythm patients and to assess appropriate anticoagulation treatment. METHODS: Forty-one idiopathic paroxysmal AF patients (56 ± 10 years, 66% male) were compared with 45 healthy sinus rhythm patients. Patients were free of hypertension, antihypertensive and antiarrhythmic drugs, diabetes, congestive heart failure, coronary artery or peripheral vascular disease, previous stroke, thyroid, pulmonary and renal disease, and structural abnormalities on echocardiography. RESULTS: Baseline characteristics and echocardiographic parameters were the same in both groups. During 10.7 ± 1.6 years, cardiovascular disease and all-cause death developed significantly more often in AF patients as compared to controls (63% vs 31%, log rank p < 0.001). Even after the initial 5 years of follow-up, survival curves show divergent patterns (log rank p = 0.006). Mean duration to reach a CHA2DS2-VASc score > 1 among AF patients was 5.1 ± 3.0 years. Five of 24 (21%) patients with CHA2DS2-VASc > 1 did not receive oral anticoagulation therapy at follow-up. Mean duration of over- or undertreatment with oral anticoagulation in patients with CHA2DS2-VASc > 1 was 5 ± 3.0 years. CONCLUSION: The majority of recently diagnosed healthy AF patients develop cardiovascular diseases with a consequent change in thromboembolic risk profile within a short time frame. A comprehensive follow-up of this patient category is necessary to avoid over- and undertreatment with anticoagulants.

Visualisation of coronary venous anatomy by computed tomography angiography prior to cardiac resynchronisation therapy implantation.

BACKGROUND: The purpose of this study was to illustrate the additive value of computed tomography angiography (CTA) for visualisation of the coronary venous anatomy prior to cardiac resynchronisation therapy (CRT) implantation. METHODS: Eighteen patients planned for CRT implantation were prospectively included. A specific CTA protocol designed for visualisation of the coronary veins was carried out on a third-generation dual-source CT platform. Coronary veins were semi-automatically segmented to construct a 3D model. CTA-derived coronary venous anatomy was compared with intra-procedural fluoroscopic angiography (FA) in right and left anterior oblique views. RESULTS: Coronary venous CTA was successfully performed in all 18 patients. CRT implantation and FA were performed in 15 patients. A total of 62 veins were visualised; the number of veins per patient was 3.8 (range: 2-5). Eighty-five per cent (53/62) of the veins were visualised on both CTA and FA, while 10% (6/62) were visualised on CTA only, and 5% (3/62) on FA only. Twenty-two veins were present on the lateral or inferolateral wall; of these, 95% (21/22) were visualised by CTA. A left-sided implantation was performed in 13 patients, while a right-sided implantation was performed in the remaining 2 patients because of a persistent left-sided superior vena cava with no left innominate vein on CTA. CONCLUSION: Imaging of the coronary veins by CTA using a designated protocol is technically feasible and facilitates the CRT implantation approach, potentially improving the outcome.

The occurrence of cardiovascular disease during 5-year follow-up in patients with idiopathic atrial fibrillation.

AIMS: Idiopathic atrial fibrillation (AF) may be an expression of as yet undetected underlying heart disease. We found it useful for clinical practice to study the long-term development of cardiovascular disease (CVD) in patients diagnosed with idiopathic AF. METHODS AND RESULTS: Forty-one consecutive idiopathic AF patients (56 ± 10 years, 66% male) were compared with 45 healthy control patients in permanent sinus rhythm. Patients were free of hypertension, antihypertensive and antiarrhythmic drugs, diabetes, congestive heart failure, coronary artery or peripheral vascular disease, previous stroke, thyroid, pulmonary and renal disease, and structural abnormalities on echocardiography. Baseline characteristics and echocardiographic parameters were equal in AF cases and controls. During a mean follow-up of 66 ± 11 months, CVD occurred significantly more often in idiopathic AF patients compared with controls (49 vs. 20%, P= 0.006). Patients with idiopathic AF were significantly younger at the time of their first CV event compared with controls (59 ± 9 vs. 64 ± 5 years, P= 0.027), and had more severe disease. Multivariable Cox regression analysis revealed that age, a history of AF, and echocardiographic left ventricular wall width were significant predictors of CVD development. CONCLUSION: Patients originally diagnosed with idiopathic AF develop CVD more often, at younger age, and with a more severe disease profile compared with healthy sinus rhythm control patients. The detection and treatment of CVD in an early stage could improve the prognosis of these patients. At present it seems prudent to regularly check idiopathic AF patients for the insidious development of CVD.

[Diagnostic image (393). A boy with a white rim around a birth mark]. / Diagnose in beeld (393). Een jongen met een witte rand rond een moedervlek.

Diagnostic image (393). A boy with a white rim around a birth mark.- A 6-year-old boy presented with a congenital halo naevus naevocellularis.

Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations.

In breast cancer, loss of heterozygosity (LOH) on 17p is a frequent event and a likely target is the p53 gene on 17p13.1. However, several LOH mapping studies have indicated that, in some breast tumors, LOH affects only the most distal 17p markers, suggestive of a second tumor suppressor locus in 17p13.3. In order to distinguish which gene has most probably served as the target for LOH on 17p, we have screened 141 breast tumors for somatic mutations in the p53 gene in conjunction with detailed LOH mapping on the short arm of chromosome 17. A total of 32 mutations were detected in 31 tumors, 15 of which have never been reported in breast cancer before. The majority are point mutations leading to an amino acid change in the protein. In addition, we have stained a subset of 87 tumors for the p53 protein by immunohistochemistry. In 21 of these tumors (24%), nuclear staining was detected in over 25% of the tumor cells with the anti-p53 antibody DO7. A positive correlation was found between p53-positive staining and p53 mutation (P < 0.001). A strong association was observed between p53 mutation and LOH at the TP53 locus but not between p53 expression and LOH on 17p. In breast tumors without a detectable p53 mutation but with LOH on 17p, the 17p13.3 region is always involved and, in some cases, even exclusively involved. These results suggest that a second tumor suppressor gene, located distal to TP53, is targeted by LOH on 17p in some breast tumors and that a substantial number of breast tumors stabilize p53 through mechanisms other than mutation.

Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation.

BACKGROUND: The total atrial conduction time (TACT) is an independent predictor of atrial fibrillation (AF). A new transthoracic echocardiographic tool to determine TACT by tissue Doppler imaging (PA-TDI (the time from the initiation of the P wave on the ECG (lead II) to the A' wave on the lateral left atrial tissue Doppler tracing)) has been developed recently. OBJECTIVE: To test the hypothesis that measurement of PA-TDI enables prediction of new-onset AF. METHODS: 249 Patients without a history of AF were studied. All patients underwent an echocardiogram and the PA-TDI interval was measured. Patient characteristics and rhythm at follow-up were recorded. RESULTS: During a mean (SD) follow-up of 680 (290) days, 15 patients (6%) developed new-onset AF. These patients had a longer PA-TDI interval than patients who remained in sinus rhythm (172 (25) ms vs 150 (20) ms, p = 0.001). Furthermore, the patients developing AF were older, more often had a history of heart failure or chronic obstructive pulmonary disease, more often used alpha blockers, had enlarged left atria and more frequently mitral incompetence on the echocardiogram. After adjusting for potential confounders, Cox regression showed that PA-TDI was independently associated with new-onset AF (OR = 1.375; 95% CI 1.037 to 1.823; p = 0.027). The 2-year incidence of AF was 33% in patients with a PA-TDI interval >190 ms versus 0% in patients with a PA-TDI interval <130 ms (p = 0.002). CONCLUSIONS: A prolonged PA-TDI interval may predict the development of new-onset AF. This measure may be used to identify patients at risk in future strategies to prevent the development or complications of AF.

Eight year's experience with automated anesthesia record keeping: lessons learned--new directions taken.

For the past eight years, an automated anesthesia record keeping system, COMANDAS (COMputerized ANesthesia Data Acquisition System) has been used in the cardiovascular operating rooms at Mayo Clinic. The automated anesthesia record is designed to match the traditional hand-written record and becomes part of the official medical record. COMANDAS is interfaced with the physiologic monitor and mass spectrometer in each OR, and a number of other computers within the Mayo Medical Center. Since the introduction of COMANDAS over 24,000 surgical procedures have been charted. The anesthesia record is more complete, consistent in organization, and legible when compared to a hand-written record. Recently, it was determined that the computers and peripherals that make up COMANDAS were wearing out and that the vendors would no longer support or replace the equipment. A process to find a replacement for COMANDAS was then begun. Although the cardiovascular anesthesia group was satisfied with the automated anesthesia record, there were a number of areas in which improvement was desired. A systematic evaluation of the system was begun with a survey of the users. The majority of those surveyed felt that COMANDAS was a useful system which made parts of their job easier. The user interface, method of manual data entry, time to produce the record and difficulty learning the system were the source of the greatest dissatisfaction. Artifacts, networking, interfacing with other devices and computers were also issues for the replacement system. Most commercial systems were found wanting in one or more areas of significance. The most practical solution appeared to be the modification of a currently available intensive care unit patient data management system.

Cyclin D1 gene amplification and overexpression are present in ductal carcinoma in situ of the breast.

Cyclin D1 (CCND1) amplification is found in 10-15 per cent of invasive breast carcinomas, but it is not well established whether this gene alteration also occurs in the precursor of invasive breast carcinoma, ductal carcinoma in situ (DCIS). By Southern blot analysis, cyclin D1 gene amplification was detected in 10 per cent (3/32) of DCIS cases. In addition, 15 cases of DCIS were analysed using bright field in situ hybridization (BRISH), of which 11 had already been analysed by Southern blotting. One additional case with gene amplification was found by BRISH. The use of BRISH for the detection of gene amplification is shown to be a novel and reliable in situ method on paraffin-embedded tissue sections. By immunohistochemistry, 147 cases of DCIS were analysed for the expression of cyclin D1. Cyclin D1 overexpression was found in 9 per cent of well-differentiated, 29 per cent of intermediately differentiated, and 19 per cent of poorly differentiated DCIS. No statistically significant association was found between cyclin D1 overexpression and the differentiation grade of DCIS, although 90 per cent of the cases that show overexpression are classified as intermediately and poorly differentiated. An association was found between cyclin D1 overexpression and oestrogen receptor positivity. Cyclin D1 overexpression was found in all four cases with cyclin D1 gene amplification, but was also found in 30 per cent (8/27) of cases without detectable gene amplification. It is concluded that cyclin D1 gene amplification is an early event in the development of breast carcinoma and occurs in poorly differentiated DCIS. Cyclin D1 protein overexpression is also present in tumours without cyclin D1 gene amplification and is seen predominantly in DCIS of intermediately and poorly differentiated histological type and oestrogen receptor positivity.

Comparative genomic hybridization with lissamine- and fluorescein-labeled nucleotides.

Biotin deoxyuridine 5'-triphosphate (dUTP) and digoxigenin dUTP are the labels most commonly used in comparative genomic hybridization (CGH). The relative infrequent use of direct fluorochrome-labeled nucleotides in CGH is related to the lower sensitivity they provide. Here we report the evaluation of two fluorochrome-conjugated nucleotides that have not been previously used in CGH (lissamine-5-dUTP and fluorescein-N6dATP) and show that this direct label combination performs at least as well as the indirect biotin/digoxigenin pair.

Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type.

We analysed the involvement of known and putative tumour suppressor- and oncogene loci in ductal carcinoma in situ (DCIS) by microsatellite analysis (LOH), Southern blotting and comparative genomic hybridization (CGH). A total of 78 pure DCIS cases, classified histologically as well, intermediately and poorly differentiated, were examined for LOH with 76 markers dispersed along all chromosome arms. LOH on chromosome 17 was more frequent in poorly differentiated DCIS (70%) Compared to well-differentiated DCIS (17%), whereas loss on chromosome 16 was associated with well- and intermediately differentiated DCIS (66%). For a subset we have done Southern blot-and CGH analysis. C-erbB2/neu was amplified in 30% of poorly differentiated DCIS. No amplification was found of c-myc, mdm2, bek, flg and the epidermal growth factor (EGF)-receptor. By CGH, most frequent alterations in poorly differentiated DCIS were gains on 8q and 17q22-24 and deletion on 17p, whereas in well-differentiated DCIS amplification on chromosome 1q and deletion on 16q were found. In conclusion, our data indicates that inactivation of a yet unknown tumour suppressor gene on chromosome 16q is implicated in the development of most well and intermediately differentiated DCIS whereas amplification and inactivation of various genes on chromosome 17 are implicated in the development of poorly differentiated DCIS. Furthermore these data show that there is a genetic basis for the classification of DCIS in a well and poorly differentiated type and support the evidence of different genetic routes to develop a specific type of carcinoma in situ of the breast.

E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis.

In breast cancer, inactivating point mutations in the E-cadherin gene are frequently found in invasive lobular carcinoma (ILC) but never in invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) adjacent to ILC has previously been shown to lack E-cadherin expression, but whether LCIS without adjacent invasive carcinoma also lacks E-cadherin expression and whether the gene mutations present in ILC are already present in LCIS is not known. We report here that E-cadherin expression is absent in six cases of LCIS and present in 150 cases of ductal carcinoma in situ (DCIS), both without an adjacent invasive component. Furthermore, using mutation analysis, we could demonstrate the presence of the same truncating mutations and loss of heterozygosity (LOH) of the wild-type E-cadherin in the LCIS component and in the adjacent ILC. Our results indicate that E-cadherin is a very early target gene in lobular breast carcinogenesis and plays a tumour-suppressive role, additional to the previously suggested invasion-suppressive role.

Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ.

Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and gamma-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and alpha- and beta-catenin expression was found; in 50 per cent of these cases, additional loss of gamma-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma.