Dierk Werner

Incidence and characteristics of segmental postsystolic longitudinal shortening in normal, acutely ischemic, and scarred myocardium

OBJECTIVE Myocardial longitudinal shortening after aortic valve closure (postsystolic shortening [PSS]) is considered a marker of pathology with diagnostic potential. However, PSS can also occur in healthy subjects. We, therefore, investigated the occurrence and characteristics of PSS in control subjects and patients, and how to distinguish normality from disease. METHODS In 20 young control subjects, 10 older control subjects, 30 patients with acute myocardial infarction (acute ischemia), and 10 patients with postischemic myocardial scar, longitudinal myocardial deformation was measured with Doppler tissue strain rate (SR) imaging. Segmental SR and strain were visually and quantitatively analyzed and compared. RESULTS In young control subjects, PSS was found in 98 of 313 segments (31%) and showed gaussian distribution (median 1.3%). During ejection time, median peak SR was -1.4 s(-1) and median strain -16.6%. In older control subjects, parameters differed only slightly. In acutely ischemic and scarred myocardium, both systolic strain and SR were significantly reduced or inverted. In disease, PSS occurred significantly more often (78% and 79%, respectively), was significantly higher in magnitude, and its peak occurred later than in young and older control subjects. CONCLUSION PSS is a normal finding in healthy subjects occurring in approximately one-third of myocardial segments and, thus, is not always a marker of disease. Our data indicate that pathologic PSS can be detected by coexisting reduction in systolic strain and, second, by exceeding a postsystolic strain magnitude cutoff.

Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest

BACKGROUND Mild therapeutic hypothermia (MTH) achieved by endovascular cooling has emerged as a new treatment strategy to reduce hypoxic brain injury after cardiac arrest (CA). It remains to be established how the time interval between CA and MTH impacts the neurologic outcome. We hypothesized that a more rapid achievement of MTH (time to target temperature [TTT], time to coldest temperature [TCT]) improves the outcome after CA. METHODS Forty-nine consecutive patients successfully resuscitated from CA were enrolled. MTH with a body core temperature between 32.0 and 34.0 degrees C (target temperature: 33.0 degrees C) over 24 h was achieved using a closed-loop endovascular system. Based on the neurologic outcome at discharge, the patient group was dichotomized into good (no/mild cerebral disability) and poor (severe disability, coma/vegetative state, brain death) outcomes. Serum neurone specific enolase (NSE) as biochemical marker of brain damage was sampled at 24, 48, and 72 h after CA. RESULTS Twenty-eight patients were discharged with a good outcome. Multivariate stepwise regression showed TTT (odds ratio for every h TTT: 0.69 [95% confidence interval: 0.51-0.98]) or, if entered into the model, TCT (odds ratio for every h TCT: 0.72 [95% confidence interval: 0.56-0.94]) to be independent predictors for good outcome. Further independent determinants were age, BMI, asystole as presenting rhythm, and thrombolysis during resuscitation. However, TCT was the only variable to correlate with maximum NSE values after CA (r=0.32, P<0.05). CONCLUSIONS Early achievement of MTH by endovascular cooling appears to reduce hypoxic brain injury and to favour a good neurologic outcome after CA.

Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol‐associated adverse effects

The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance. Cytochrome P450 2D6 (CYP2D6) poor metabolizers exhibit 3‐ to 10‐fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. However, the impact of the CYP2D6 genotype on the occurrence of adverse effects of metoprolol remains controversial. This study addressed whether the incidence of poor metabolizers was higher in patients with metoprolol‐associated adverse effects than in the German population at large.

Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans

In vitro data have shown that celecoxib inhibits the metabolism of cytochrome P450 (CYP) 2D6 substrates. However, very limited data are available on the influence of cyclooxygenase 2 inhibitors on the disposition of CYP2D6 substrates in humans. Therefore the objective of this study was to examine the effect of celecoxib and rofecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol.

Pneumatic external counterpulsation: a new noninvasive method to improve organ perfusion.

Pneumatic external counterpulsation, which is operated by applying electrocardiographic-triggered diastolic pressure via air-filled cuffs to the vascular limbs of lower limbs, is a relatively new therapeutic option for patients with angina pectoris and cerebrovascular diseases like transient ischemic attacks or sudden deafness. In this study, an augmentation in flow volume in the carotid, renal, and hepatic arteries from 20% to 25% and in the coronary arteries from 20% to 40%, as well as an increase in stroke volume by 12% was demonstrated; this shows the therapeutic results in patients with diseases caused by disturbed organ perfusion.

Determinants of Steady-State Torasemide Pharmacokinetics Impact of Pharmacogenetic Factors, Gender and Angiotensin II Receptor Blockers

AbstractBackground: Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide. Patients and methods: Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69 ± 8 years) or losartan 100 mg (two female and ten male patients aged 61 ± 8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients’ long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n = 15]; *1/*2 [n = 4]; *1/*3 [n = 5]) as well as for SLCO1B1 (c.521TT [n = 13]; c.521TC [n = 11]). Results: Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC24,ss/D]: *1/*1 375.5 ± 151.4 μg · h/L/mg vs *1/*3 548.5 ± 271.6 μg · h/L/mg, p = 0.001), the SLCO1B1 genotype (AUC24,ss/D: TT 352.3 ± 114 μg · h/L/mg vs TC 487.6 ± 218.4 μg · h/L/mg, p < 0.05) and gender (AUC24,ss/D: males 359.5 ± 72.2 μg · h/L/mg vs females 547.3 ± 284 μg · h/L/mg, p < 0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC24,ss/D of torasemide (p = 0.002), whereas losartan had no effect. Conclusion: This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life.

Single-dose nimodipine normalizes impaired retinal circulation in normal tension glaucoma.

Purpose:Several studies indicate that calcium channel blockers improve the clinical course of normal tension glaucoma (NTG), whereas the underlying mechanism is not fully investigated. Hemodynamic improvement and neuroprotective effects are discussed. In this study, we measured the hemodynamic effects of nimodipine on retinal circulation. Patients and Methods:Sixteen patients with NTG and clinical signs of vasospastic hyperreactivity, such as suffering from extremely cold hands and feet, were consecutively selected out of the local glaucoma registry. Ten healthy age-matched volunteers were included as controls. Retinal capillary blood flow was measured by Scanning Laser Doppler Flowmetry in both eyes before and 90 ± 10 minutes after a single oral dose of 30 mg nimodipine. Results:Before administration of nimodipine, retinal capillary blood flow was significantly reduced in NTG patients compared with controls (262 ± 80 vs. 487 ± 164 AU, P < 0.001). Nimodipine increased retinal capillary blood flow in NTG patients by 91 ± 73% (P < 0.001) to values of healthy controls (440 ± 113 vs. 439 ± 123 AU, P = 0.635). In controls, nimodipine did not show significant effects. Conclusions:In NTG patients with additional vasospastic symptoms, retinal capillary blood is significantly reduced in comparison with healthy controls. Single-dose nimodipine yields to a normalization of retinal circulation in NTG patients up to values of healthy controls 90 minutes after drug administration.

Selective and rapid liquid chromatography-mass spectrometry method for the quantification of rofecoxib in pharmacokinetic studies with humans.

An easy, rapid and selective method for the determination of rofecoxib in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography coupled to atmospheric pressure chemical ionisation mass spectrometry (Finnigan Mat LCQ ion trap). The retention time of rofecoxib was 1.2 min. The method has been validated over a linear range from 1 to 500 microg/l using celecoxib as internal standard. After validation, the method was used to study the pharmacokinetic profile of rofecoxib in 12 healthy volunteers after administration of a single oral dose (12.5 mg). The presented method was sufficient to cover more than 95% of the area under the curve. The pharmacokinetic characteristics (mean+/-SD) were tmax: 2.4+/-1.0 h, Cmax: 147+/-34 microg/l, AUCinfinity: 2038+/-581 microg h/l and t 1/2: 11.3+/-2.1 h.

Percutaneous occlusion of femoral artery pseudoaneurysm by para-aneurysmal saline injection

The increasing number of coronary interventions and more aggressive anticoagulation is associated with a larger number of iatrogenic femoral pseudoaneurysms (PAs). The majority of PAs clot spontaneously or can be repaired by ultrasound‐guided compression or ultrasound‐guided thrombin injection. The therapeutic armamentarium for the remaining PAs ranges from different interventional procedures to surgical occlusion. In a small case series, we describe our initial experiences with a new, less invasive approach after unsuccessful compression therapy. Ultrasound‐guided injection of 52 ± 33 ml saline beneath the communication tract of the PA yields to rapid occlusion in six consecutive patients. During 4 weeks of follow‐up, the PAs remained occluded in all patients and surgical intervention could be avoided. Cathet Cardiovasc Intervent 2003;58:500–504.

Accelerated reperfusion of poorly perfused retinal areas in central retinal artery occlusion and branch retinal artery occlusion after a short treatment with enhanced external counterpulsation.

Background: To date, no satisfactory therapy has become available for patients with acute central retinal artery occlusion (CRAO) or branch retinal artery occlusion (BRAO). Enhanced external counterpulsation (EECP) is a new noninvasive procedure that increases perfusion of inner organs. In the current study, the authors measured the impact of EECP on reperfusion in ischemic retinal tissue. Methods: In a prospective, randomized study, 20 patients with CRAO or BRAO were included. Ten patients were given hemodilution therapy and 2 hours of EECP, and 10 patients were given regular hemodilution therapy only. Quantification of changes in retinal perfusion was carried out by means of scanning laser Doppler flowmetry (in arbitrary units). Results: Enhanced external counterpulsation caused no observable adverse events. A significant increase in perfusion occurred immediately after EECP in the ischemic retinal areas (57 ± 19 arbitrary units versus 99 ± 14 arbitrary units). In contrast, no change was measured in the group not treated with EECP (83 ± 19 arbitrary units versus 89 ± 44 arbitrary units). Forty-eight hours later, a significant increase in perfusion could be shown in the ischemic retina of both groups, and no significant difference of perfusion was found between the two groups any longer. Conclusion: The current study suggests that EECP could be a clinically useful and safe procedure in patients with CRAO or BRAO to accelerate recovery of perfusion in ischemic retinal areas.