Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES: To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. Patients Elderly patients with VTE were studied. METHODS: In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L(-1) ), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L(-1) , both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS: Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality. CONCLUSION: In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers.

The ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement.

OBJECTIVES: To compare the diagnostic performance between a vascular specialist and a rheumatologist not familiar with vascular ultrasound when applying the compression sign for the diagnosis of temporal arteritis. METHODS: Sixty consecutive patients with suspicion of giant cell arteritis were examined by both examiners. Compression of the temporal artery on both sides (stem and both branches) was performed to define whether signs of vasculitis, no vasculitis or an indefinite result were present. Each examiner was blinded to the result of the other. RESULTS: In 59/60 patients, the examiners found an identical result. The interobserver agreement (Krippendorf alpha) was 0.92. CONCLUSIONS: The new compression sign for the diagnosis of temporal arteritis is a simple and robust sonographic marker with an excellent interobserver agreement.

Bloodless lung transplantation in Jehovah's Witnesses: impact on perioperative parameters and outcome compared with a matched control group.

BACKGROUND: Jehovah's Witnesses (JW) refuse to receive blood products due to their religious beliefs. Bloodless transplantation programs have made the successful transplantation of solid organs like heart, liver, kidney, and pancreas in JW feasible. In this study we present the third and fourth case of a successful bloodless lung transplantation and analyze perioperative parameters and outcome with a strictly selected matched control group (CG). METHODS: Two JW patients suffering from idiopathic pulmonary fibrosis had single lung transplantation in the transfusion-free program. Ten of 113 patients (8.8%) undergoing lung transplantation fulfilled the matching criteria and served as CG. Perioperative parameters including blood loss and transfusions were collected from the charts. Regarding outcome parameters arterial blood gas, lung function testing, length of stay, and survival were analyzed. RESULTS: Concerning perioperative parameters no significant differences could be found between both groups except for the creatinine level, which was significantly lower in the JW group on postoperative day 0 (P = .037), and the hemoglobin and hematocrit levels, which were significantly higher in the JW group on postoperative day 3 (P = .032 and P = .041, respectively). The analysis of the outcome parameters revealed significantly higher postoperative lung functional testing values forced expiratory volume after 1 second (FEV1) and forced vital capacity (FVC) in the JW group compared with the CG (P = .037 and P = .036, respectively). CONCLUSION: Bloodless lung transplantation is feasible in carefully selected JW recipients. Comparing JW to CG, no statistically significant difference in the perioperative course and a trend towards a favorable postoperative lung function outcome were detected.

Temporal artery compression sign--a novel ultrasound finding for the diagnosis of giant cell arteritis.

PURPOSE: In patients with suspected giant cell arteritis (GCA), a search for the perivascular halo sign, a sophisticated color duplex ultrasound (CDU) finding, at experienced centers reliably identifies inflamed temporal arteries (TA). We tested whether TA compression in patients with GCA, a simple, largely operator-independent maneuver, elicits contrasting echogenicity between the diseased artery wall and the surrounding tissue (compression sign). MATERIALS AND METHODS: 80 individuals with suspected GCA were prospectively enrolled in this single-center study. In all study participants, bilateral ultrasound examination of the TA established the presence/absence of the halo and compression sign. A positive compression sign was defined as visibility of the TA upon transducer-imposed compression of the artery. Based on ACR criteria, a team of specialized physicians independently grouped patients as GCA versus non-GCA. RESULTS: 43/80 study participants were grouped as GCA. Both the halo sign and the compression sign were positive in 34/43 patients in the GCA group, and negative in all 37/37 of the non-GCA group, resulting in a sensitivity of 79 % and a specificity of 100 % for both the halo and the compression sign. CONCLUSION: In this cohort of individuals with suspected GCA, the halo sign and the compression sign were equal in their diagnostic performance. The simplicity of the compression sign suggests a level of reliability warranting further evaluation.

Prospective comparison of noninvasive, bedside ultrasound methods for assessing central venous pressure.

PURPOSE: To prospectively evaluate the accuracy of noninvasive central venous pressure (CVP) assessment by compression ultrasound of a forearm vein (CUS), inferior vena cava (IVC-C) and internal jugular vein collapsibility (IJV-C) compared to invasive CVP measurement (invCVP) as the gold standard. MATERIALS AND METHODS: CUS, IVC-C and IJV-C were performed in a random sequence in 81 consecutive intensive care patients with simultaneous invCVP monitoring. Examiners were blinded to invCVP and previous examinations. RESULTS: Median invCVP was 12.0 mmHg (range 1 - 23). CUS, IVC-C and IJV-C could be obtained in 89 %, 95 % and 100 % of cases, respectively, within a median time of 188 sec [IQR 125; 270], 133 sec [IQR 100; 211] and 60 sec [IQR 50; 109], respectively. The Spearman correlation coefficient between invCVP and CUS, IVC-C, and IJV-C was 0.485 95 %-CI [0.25; 0.65], -0.186 [-0.42; 0.07], and -0.408 [-0.59; -0.18], respectively. The median absolute difference between CUS and invCVP was 3 mmHg [IQR 2; 6.75]. CVP was categorized as low (< 7 mmHg; collapsibility > 0.6), normal (7 - 12 mmHg; collapsibility 0.6 - 0.2) and high (> 12 mmHg; collapsibility < 0.2) as prespecified. The proportions of identical CVP classifications compared to invCVP were 61.4% 95%-CI [49.3%; 72.4%] with CUS, 48.7% [37.4%; 60%] with IVC-C and 51.3% [40.3%; 62.3%] with IJV-C (p > 0.10 for all pair-wise comparisons). CONCLUSION: The overall ability of CUS, IVC-C and IJV-C to assess invCVP was only moderate. CUS seems to be the preferable method if absolute CVP values are needed. IJV-C seems to be the fastest and most easily acquirable method, and thus may be especially valuable in emergency rooms.

WE-G-217BCD-09: Calibration of a DRR Algorithm.

PURPOSE: To calibrate an algorithm for digitally reconstructed radiographs (DRRs) such that synthetic projections cast through an object in a fan-beam CT (FBCT) optimally match cone-beam CT projections of the same object. METHODS: Our DRR algorithm models the transmission of primary photons through an object with a ray-tracing algorithm that samples the CT at small steps along each source-detector pixel path. Sampled CT values are converted to linear attenuation coefficients (LACs), scaled by the step-size, and added to a running sum for each detector pixel. We made attenuation measurements of materials of known CT number to calibrate a CT to LAC conversion function for our FBCT and CBCT systems. DRRs are post- processed to reproduce the tube output, source fluence distribution, and detector response of the CBCT system. In addition, they are modified to account for scatter, beam hardening, and detector veiling glare. Finally, we determined CBCT geometry parameters using a specially designed phantom. RESULTS: We analyzed the quality of our DRR algorithm by directly comparing synthetic DRRs cast through the FBCT of a Catphan® phantom with actual CBCT projections of the phantom. Line plots comparing the intensity profiles of the DRRs and CBCT projections show that uncorrected DRRs do not align perfectly with the projections. However, when scatter, beam hardening, and veiling glare are modeled there is much closer agreement. Simulations with different geometry phantom shapes and sizes recommend a cylindrical phantom 150 mm in diameter. Computational times under one second per DRR are achieved using a GPU for a simulated 1024×768 pixel detector with a 512×512×281 mm CT volume and 0.5 mm ray step-size. CONCLUSIONS: Our DRR algorithm is able to closely reproduce actual CBCT projections taken through a test object. It is optimized specifically for the FBCT and CBCT systems in our department. Funded in part by NCI grants R01CA123299 and P01CA116602. The authors report no conflicts of interest.

Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats.

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse.

Gadofosveset enhanced MR phlebography for detecting pelvic and deep vein leg thrombosis.

BACKGROUND: Deep venous thrombosis is mainly diagnosed by ultrasound today. In some instances diagnosis is challenging and magnetic resonance angiography could be an attractive alternative. Gadofosveset is a blood pool contrast agent with some favourable properties for this purpose. PATIENTS AND METHODS: We investigated eight patients with proven deep venous thrombosis by Gadofosveset enhanced MR phlebography. We performed a 3D gradient-echo sequence with an overall measurement time of 9 minutes and 6 seconds. One minute after injection of Gadofosveset in a concentration of 0.12 ml/kg body weight images were acquired. Thrombi were visualised by their lack of luminal contrast filling. RESULTS: Thrombi were visualised in all patients. In one patient with extended thrombosis a previously undiagnosed ovarian adenocarcinoma was detected additionally. CONCLUSIONS: Deep venous thromboses in lower extremities can be visualised reliably by performing MR phlebography with blood pool contrast agent Gadofosveset. Visualisation of the complete venous system is feasible. This investigation method may be performed in patients difficult to investigate with ultrasound or may be used for planning interventional procedures.

Topographical distribution of corticotropin-releasing factor type 2 receptor-like immunoreactivity in the rat dorsal raphe nucleus: co-localization with tryptophan hydroxylase.

Corticotropin-releasing factor (CRF) and CRF-related neuropeptides are involved in the regulation of stress-related physiology and behavior. Members of the CRF family of neuropeptides bind to two known receptors, the CRF type 1 (CRF1) receptor, and the CRF type 2 (CRF2) receptor. Although the distribution of CRF2 receptor mRNA expression has been extensively studied, the distribution of CRF2 receptor protein has not been characterized. An area of the brain known to contain high levels of CRF2 receptor mRNA expression and CRF2 receptor binding is the dorsal raphe nucleus (DR). In the present study we investigated in detail the distribution of CRF2 receptor immunoreactivity throughout the rostrocaudal extent of the DR. CRF2 receptor-immunoreactive perikarya were observed throughout the DR, with the highest number and density in the mid-rostrocaudal DR. Dual immunofluorescence revealed that CRF2 receptor immunoreactivity was frequently co-localized with tryptophan hydroxylase, a marker of serotonergic neurons. This study provides evidence that CRF2 receptor protein is expressed in the DR, and that CRF2 receptors are expressed in topographically organized subpopulations of cells in the DR, including serotonergic neurons. Furthermore, these data are consistent with the hypothesis that CRF2 receptors play an important role in the regulation of stress-related physiology and behavior through actions on serotonergic and non-serotonergic neurons within the DR.

Current strategies and possible perspectives of ultrasonic risk stratification of ischemic stroke in internal carotid artery disease.

Atherosclerotic alterations of the internal carotid artery frequently result in ischemic stroke. However, it remains unclear which specific factor mainly causes an increased risk of stroke. Constant improvements of the diagnostic possibilities of ultrasonic examinations provide increasingly profound insight into plaque alterations. If "risk plaque" could be reliably identified, the therapeutic decision for either medical or surgical treatment could be made more rationally. In this review, we summarize current developments in the ultrasound imaging of atherosclerotic changes in carotid artery disease with special emphasis on technical aspects and the rationale of contrast imaging of plaque vascularization. Methodological limitations and possible future applications are discussed.

PROCAM-, FRAMINGHAM-, SCORE- and SMART-risk score for predicting cardiovascular morbidity and mortality in patients with overt atherosclerosis.

BACKGROUND: The predictive value of PROCAM, FRAMINGHAM, SCORE and SMART-score to estimate the cardiovascular risk in patients with overt atherosclerosis had never been assessed. PATIENTS AND METHODS: 96 consecutive patients with clinically evident atherosclerosis (coronary, cerebrovascular, peripheral artery and renovascular disease) were enrolled in this preliminary observational study. At baseline, medical history and blood chemistry were obtained. Sonographic measurement of the intima-media thickness (IMT) in the common carotid artery was performed and risk estimations according to the above listed risk scores were calculated. During a 6 year follow-up the occurrence of cardiovascular death, acute coronary syndrome and stroke was assessed. RESULTS: Mean (±SD) risk-scores were 10.9±2.5, range 6-17 (SMART); 18.9±18.2%; range 0.2-94.1% (PROCAM); 21.4±13.1%, range 4-56% (FRAMINGHAM); and 4.8±3.9%, range 0.4-15.3% (SCORE). Mean IMT was 0.84±0.14 mm, range 0.51-1.20 mm. All scores correlate significantly with each other (r>0.321; p<0.01), but only SMART-score correlated significantly with baseline IMT(r=0.372; p<0.001). Within the median follow-up of 73 months, a cardiovascular endpoint was observed in 36 (42%) patients. The AUC (95% confidence interval) for SMART-risk-score predicting a cardiovascular event was 0.67 (0.54-0.77; p<0.02); for PROCAM 0.60 (0.47-0.73; p=n.s.); for FRAMINGHAM 0.56 (0.43-0.69; p=n.s.); and for SCORE 0.60 (0.46-0.73; p=n.s.). Cox regression analysis showed a relative risk for a cardiovascular event per additional SMART score point of 1.15 (95% CI 1.01-1.30 p=0.03). CONCLUSIONS: PROCAM-, FRAMINGHAM- and SCORE-risk score seem to be barely useful in a secondary prevention setting. In patients with overt atherosclerosis, the cardiovascular risk seems to be better assessed by means of the SMART score.

Use of B-type natriuretic peptide to predict blood pressure improvement after percutaneous revascularisation for renal artery stenosis.

OBJECTIVES: The purpose of this study was to evaluate the utility of B-type natriuretic peptide (BNP) to predict blood pressure (BP) response in patients with renal artery stenosis (RAS) after renal angioplasty and stenting (PTRA). METHODS: In 120 patients with RAS and hypertension referred for PTRA, 24-h ambulatory BP recordings were obtained before and 6 months after intervention. BNP was measured before, 1 day and 6 months after PTRA. RESULTS: BP improved in 54% of patients. Median BNP levels pre-intervention were 97 pg ml(-1) (interquartile range (IQR) 35-250) and decreased significantly within 1 day of PTRA to 62 pg ml(-1) (IQR 24-182) (p < 0.001), remaining at 75 pg ml(-1) (IQR 31-190) at 6 months. The area under the receiver operating curve for pre-intervention BNP to predict BP improvement was 0.57 (95% confidence interval (CI) 0.46-0.67). Pre-intervention BNP >50 pg ml(-1) was seen in 79% of patients with BP improvement compared with 56% in patients without improvement (p = 0.01). In a multivariate logistic regression analysis, BNP >50 pg ml(-1) was significantly associated with BP improvement (odds ratio (OR) 4.0, 95% CI 1.2-13.2). CONCLUSIONS: BNP levels are elevated in patients with RAS and decrease after revascularisation. Although BNP does not seem useful as a continuous variable, pre-interventional BNP >50 pg ml(-1) may be helpful to identify patients in whom PTRA will improve BP.