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.

Physical activity and risk of bleeding in elderly patients taking anticoagulants.

BACKGROUND: Although the possibility of bleeding during anticoagulant treatment may limit patients from taking part in physical activity, the association between physical activity and anticoagulation-related bleeding is uncertain. OBJECTIVES: To determine whether physical activity is associated with bleeding in elderly patients taking anticoagulants. PATIENTS/METHODS: In a prospective multicenter cohort study of 988 patients aged ≥ 65 years receiving anticoagulants for venous thromboembolism, we assessed patients' self-reported physical activity level. The primary outcome was the time to a first major bleeding, defined as fatal bleeding, symptomatic bleeding in a critical site, or bleeding causing a fall in hemoglobin or leading to transfusions. The secondary outcome was the time to a first clinically relevant non-major bleeding. We examined the association between physical activity level and time to a first bleeding by using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS: During a mean follow-up of 22 months, patients with a low, moderate, and high physical activity level had an incidence of major bleeding of 11.6, 6.3, and 3.1 events per 100 patient-years and an incidence of clinically relevant non-major bleeding of 14.0, 10.3, and 7.7 events per 100 patient-years, respectively. A high physical activity level was significantly associated with a lower risk of major bleeding (adjusted sub-hazard ratio 0.40, 95% confidence interval 0.22-0.72). There was no association between physical activity and non-major bleeding. CONCLUSIONS: A high level of physical activity is associated with a decreased risk of major bleeding in elderly patients receiving anticoagulant therapy.

Risk of falls and bleeding in elderly patients with acute venous thromboembolism.

OBJECTIVE: Whether or not a high risk of falls increases the risk of bleeding in patients receiving anticoagulants remains a matter of debate. METHODS: We conducted a prospective cohort study involving 991 patients ≥ 65 years of age who received anticoagulants for acute venous thromboembolism (VTE) at nine Swiss hospitals between September 2009 and September 2012. The study outcomes were as follows: the time to a first major episode of bleeding; and clinically relevant nonmajor bleeding. We determined the associations between the risk of falls and the time to a first episode of bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS: Four hundred fifty-eight of 991 patients (46%) were at high risk of falls. The mean duration of follow-up was 16.7 months. Patients at high risk of falls had a higher incidence of major bleeding (9.6 vs. 6.6 events/100 patient-years; P = 0.05) and a significantly higher incidence of clinically relevant nonmajor bleeding (16.7 vs. 8.3 events/100 patient-years; P < 0.001) than patients at low risk of falls. After adjustment, a high risk of falls was associated with clinically relevant nonmajor bleeding [subhazard ratio (SHR) = 1.74, 95% confidence interval (CI) = 1.23-2.46], but not with major bleeding (SHR = 1.24, 95% CI = 0.83-1.86). CONCLUSION: In elderly patients who receive anticoagulants because of VTE, a high risk of falls is significantly associated with clinically relevant nonmajor bleeding, but not with major bleeding. Whether or not a high risk of falls is a reason against providing anticoagulation beyond 3 months should be based on patient preferences and the risk of VTE recurrence.

Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism.

BACKGROUND: The Outpatient Bleeding Risk Index (OBRI) and the Kuijer, RIETE and Kearon scores are clinical prognostic scores for bleeding in patients receiving oral anticoagulants for venous thromboembolism (VTE). We prospectively compared the performance of these scores in elderly patients with VTE. METHODS: In a prospective multicenter Swiss cohort study, we studied 663 patients aged ≥ 65 years with acute VTE. The outcome was a first major bleeding at 90 days. We classified patients into three categories of bleeding risk (low, intermediate and high) according to each score and dichotomized patients as high vs. low or intermediate risk. We calculated the area under the receiver-operating characteristic (ROC) curve, positive predictive values and likelihood ratios for each score. RESULTS: Overall, 28 out of 663 patients (4.2%, 95% confidence interval [CI] 2.8-6.0%) had a first major bleeding within 90 days. According to different scores, the rate of major bleeding varied from 1.9% to 2.1% in low-risk, from 4.2% to 5.0% in intermediate-risk and from 3.1% to 6.6% in high-risk patients. The discriminative power of the scores was poor to moderate, with areas under the ROC curve ranging from 0.49 to 0.60 (P = 0.21). The positive predictive values and positive likelihood ratios were low and varied from 3.1% to 6.6% and from 0.72 to 1.59, respectively. CONCLUSION: In elderly patients with VTE, existing bleeding risk scores do not have sufficient accuracy and power to discriminate between patients with VTE who are at a high risk of short-term major bleeding and those who are not.

Prospective comparison of clinical prognostic scores in elder patients with a pulmonary embolism.

BACKGROUND: The Geneva Prognostic Score (GPS), the Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are well-known clinical prognostic scores for a pulmonary embolism (PE). OBJECTIVES: To compare the prognostic performance of these scores in elderly patients with a PE. PATIENTS AND METHODS: In a multicenter Swiss cohort of elderly patients with venous thromboembolism, we prospectively studied 449 patients aged ≥ 65 years with a symptomatic PE. The outcome was 30-day overall mortality. We dichotomized patients as low vs. higher risk in all three scores using the following thresholds: GPS scores ≤ 2 vs. > 2, PESI risk classes I-II vs. III-V and sPESI scores 0 vs. ≥ 1. We compared 30-day mortality in low- vs. higher-risk patients and the areas under the receiver-operating characteristic curve (ROC). RESULTS: Overall, 3.8% of patients (17/449) died within 30 days. The GPS classified a greater proportion of patients as low risk (92% [413/449]) than the PESI (36.3% [163/449]) and the sPESI (39.6% [178/449]) (P < 0.001 for each comparison). Low-risk patients based on the sPESI had a mortality of 0% (95% confidence interval [CI] 0-2.1%) compared with 0.6% (95% CI 0-3.4%) for low-risk patients based on the PESI and 3.4% (95% CI 1.9-5.6%) for low-risk patients based on the GPS. The areas under the ROC curves were 0.77 (95% CI 0.72-0.81), 0.76 (95% CI 0.72-0.80) and 0.71 (95% CI 0.66-0.75), respectively (P = 0.47). CONCLUSIONS: In this cohort of elderly patients with PE, the GPS identified a higher proportion of patients as low risk but the PESI and sPESI were more accurate in predicting mortality.

Decreased umbilical artery compliance and igf-I plasma levels in infants with intrauterine growth restriction - implications for fetal programming of hypertension.

Epidemiological studies link intrauterine growth restriction (IUGR) to arterial hypertension in adulthood. We compared umbilical arteries from IUGR (n=12, <5th weight percentile) vs. appropriate for gestational age (AGA) infants (n=12) using structural and functional analyses. The vessel wall area of umbilical arteries in the IUGR group was significantly smaller than in the AGA group (2.8 vs. 3.8mm(2), P<0.05). Myographic measurements showed that maximal tension [mN/mm] as well as maximal force [mN] were both significantly increased in IUGR arteries compared with AGA arteries (P<0.05). Serum levels of IGF-I, a regulator of elastin synthesis, were significantly lower in IUGR cord blood (P<0.01) than in AGA cord blood. These IGF-I serum levels correlated significantly with maximum tension in umbilical arteries (P<0.01). Low intrauterine IGF-I serum levels may account for thinner and stiffer umbilical arteries in IUGR infants in comparison to AGA infants thereby providing a potential link to arterial hypertension in adulthood.

[Bronchioloalveolar carcinoma of the lung associated with a highly positive pANCA-titer and clinical signs of microscopic polyangiitis]. / Bronchioloalveoläres Karzinom der Lunge assoziiert mit einem hochpositiven pANCA-Titer und dem klinischen Bild einer mikroskopischen Polyangiitis.

Autoimmune paraneoplastic processes are investigated in detail concerning the Lambert-Eaton-Myasthenic-Syndrome for bronchial carcinomas. For the cutaneous leukocytoclastic vasculitis as a non-ANCA-associated vasculitis the paraneoplastic genesis is described. Litttle is known about ANCA-associated vasculitis as a paraneoplastic autoimmune phenomenon. We present the case of a 62 year old woman referred to our hospital presenting air-space shadows mainly in both upper lobes, skin rash with petechial bleeding and a highly positive pANCA-titer. A bronchioloalveolar carcinoma was diagnosed by surgical biopsy. The patient developed renal failure postsurgically and died a few weeks after the diagnosis was established. This is the 5 (th) case in literature of the temporal concurrence of a bronchial carcinoma and an ANCA-associated vasculitis. So far only 24 cases of a solid tumor occuring simultaneously with an ANCA-positive vasculitis are reported in literature.

Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas.

The malignant potential among endocrine pancreatic tumors (EPTs) varies greatly and can frequently not be predicted using histopathological parameters. Thus, molecular markers that can predict the biological behavior of EPTs are required. In a previous comparative genomic hybridization study, we observed marked genetic differences between the various EPT subtypes and a correlation between losses of 3p and 6 and gains of 14q and Xq and metastatic disease. To search for genetic alterations that play a role during early tumor development, we have studied 38 small (< or =2 cm) EPTs, including 24 insulinomas and 10 nonfunctioning EPTs. Small EPTs are usually classified as clinically benign tumors in the absence of histological signs of malignancy. Using comparative genomic hybridization, we identified chromosomal aberrations in 27 EPTs (mean, 4.1). Interestingly, the number of gains differed strongly between nonfunctioning and functioning EPTs (3.4 versus 1.5, respectively; P = 0.0526), as did the number of aberrations in the benign (n = 30) and malignant (n = 8) tumors (3 versus 8.4, respectively; P = 0.0022). In the insulinomas, 9q gain (common region of involvement: 9q34) was most common (50%) and in nonfunctioning EPTs, gain of 4p was most common (40%). Most frequent losses in insulinomas involved 1p (20.8%), 1q, 4q, 11q, Xq, and Y (all 16.7%) and in nonfunctioning EPTs, 6q. Losses of 3pq and 6q and gains of 17pq and 20q proved to be strongly associated with malignant behavior in all of the small EPTs (P < or = 0.0219). Our results demonstrate marked genetic differences between small functioning and nonfunctioning EPTs, indicating that these subtypes evolve along different genetic pathways. In addition, our study endorses the importance of chromosomes 3 and 6q losses to discriminate EPTs with a malignant behavior from benign ones.

Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis.

Neuroendocrine tumors (carcinoids) are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Genetic changes underlying their tumorigenesis are primarily unknown. We used comparative genomic hybridization to screen 32 well-differentiated neuroendocrine tumors (21 gastrointestinal and 11 bronchial) and three associated metastases for genomic alterations. There were striking differences of genomic imbalances between the two subgroups of neuroendocrine tumors. Losses of chromosome 18q and 18p were shown in eight (38%) and seven (33%), respectively, out of 21 gastrointestinal tumors and in none of the 11 bronchial tumors. Conversely, deletions of 11q occurred in four of 11 (36%) bronchial tumors but only in one gastrointestinal tumor. These comparative genomic hybridization findings were confirmed by interphase cytogenetics. Our data indicate that neuroendocrine tumors of the two subgroups develop via different molecular pathways. Inactivation of one or several tumor suppressor genes on chromosome 18 may be important for the biological behavior of gastrointestinal tumors, whereas gene inactivation on 11q seems to be associated with tumor development of the bronchi.

Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells.

The pathogenesis of sporadic endocrine pancreatic tumors (EPTs) is still primarily unknown. Comparative genomic hybridization studies revealed loss of 10q in a significant number (nine of 31) of EPTs. The tumor suppressor gene PTEN lies on 10q23, and so, is a candidate to play some role in EPT pathogenesis. Germline PTEN mutations are found in Cowden and Bannayan-Riley-Ruvalcaba syndromes, whereas somatic mutations and deletions are found in a variety of sporadic cancers. The mutation and expression status of PTEN in EPTs has not yet been examined. Mutation analysis of the entire coding region of PTEN including splice sites was performed in 33 tumors, revealing one tumor with somatic L182F (exon 6). Loss of heterozygosity of the 10q23 region was detected in eight of 15 informative malignant (53%) and in none of seven benign EPTs. PTEN expression was assessed in 24 available EPTs by immunohistochemistry using a monoclonal anti-PTEN antibody. Of these 24, 23 tumors showed strong immunoreactivity for PTEN. Only the EPTs with PTEN mutation lacked PTEN protein expression. Although normal islet cells always exhibited predominantly nuclear PTEN immunostaining, 19 of 23 EPTs had a predominantly cytoplasmic PTEN expression pattern. Exocrine pancreatic tissue was PTEN-negative throughout. PTEN mutation is a rare event in malignant EPTs and PTEN protein is expressed in most (23 of 24) EPTs. Thus, intragenic mutation or another means of physical loss of PTEN is rarely involved in the pathogenesis of EPTs. Instead, either an impaired transport system of PTEN to the nucleus or some other means of differential compartmentalization could account for impaired PTEN function. Loss of heterozygosity of the 10q23 region is a frequent event in malignant EPTs and might suggest several hypotheses: a different tumor suppressor gene in the vicinity of PTEN might be principally involved in EPT formation; alternatively, 10q loss, including PTEN, seems to be associated with malignant transformation, but the first step toward neoplasia might involve altered subcellular localization of PTEN.

Hyperglycemia inhibits vascular smooth muscle cell apoptosis through a protein kinase C-dependent pathway.

We hypothesized that the pathogenesis of diabetic vasculopathy involves the abnormal regulation of vascular smooth muscle cell (VSMC) apoptosis. In nondiabetic mice, a reduction in carotid artery blood flow resulted in a significant loss of medial VSMCs via apoptosis (normal flow 84+/-1 viable VSMCs, reduced flow 70+/-5 viable VSMCs; n=12, P:<0.01). In contrast, flow-induced VSMC apoptosis was markedly attenuated in streptozotocin-induced diabetic mice (normal flow 85+/-2 viable VSMC, reduced flow 82+/-4 viable VSMC; n=13, NS). In accord with our in vivo findings, the exposure of cultured rat and human VSMCs to high glucose (17.5 mmol/L) significantly attenuated the induction of apoptosis in response to serum withdrawal (rat VSMCs in normal [5.5 mmol/L] glucose 28+/-1%, high D-glucose 19+/-2%; P:<0.0001). High glucose also inhibited apoptosis induced by Fas ligand (100 ng/mL) (normal 23+/-2%, high D-glucose 13+/-2%; P:<0.006). Supplementation with the nonmetabolized enantiomer L-glucose had no effect. We confirmed reports that high glucose activates protein kinase C (PKC) and demonstrated that PKC blockade with long-term phorbol ester treatment or calphostin C prevented the antiapoptotic effect (P:<0. 001). Moreover, the upregulation of either PKCalpha or PKCbetaII expression was sufficient to inhibit serum withdrawal-induced apoptosis (control 25+/-2%, PKCalpha 11+/-2%, PKCbetaII 8+/-2%; P:<0. 0001), whereas the upregulation of PKCdelta had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.

High level of cholesterol increases coronary vasomotor tone during exercise.

BACKGROUND: Coronary vasomotor tone plays an important role in the regulation of myocardial perfusion and influences ischemic threshold significantly. Endothelial dysfunction occurs in the presence of coronary risk factors and is closely linked to the development of atherosclerosis affecting myocardial perfusion and decreasing ischemic threshold. OBJECTIVE: To study the effect of hypercholesterolemia on coronary vasomotor tone in normal and stenotic coronary arteries at rest and during exercise. PATIENTS AND METHODS: In total 48 patients were included in the present analysis. Patients were divided into two groups according to the actual levels of serum cholesterol: 18 patients had normal (mean 181 +/- 28 mg%; group 1) and 30 had elevated (mean 263 +/- 46 mg%; group 2) levels of serum cholesterol according to the 4S criteria with a cutoff level of 213 mg% (5.5 mmol/l). Coronary vasomotor tone at rest and during supine bicycle exercise was calculated by dividing mean aortic pressure by radius of coronary vessel obtained using biplanar quantitative coronary angiography. A normal as well as a stenotic vessel segment in each patient were studied. RESULTS: Normal vessel segments in patients with normal levels of cholesterol (group 1) exhibited no exercise-induced change in coronary vascular tone (+3%, NS), whereas a significant increase in tone (+24%, P < 0.01 versus rest) occurred in those with high levels of cholesterol (group 2). In contrast, stenotic segments in members of both groups exhibited an increase in vascular tone irrespective of the actual level of serum cholesterol. CONCLUSIONS: Hypercholesterolemia causes a pathologic increase in coronary vasomotor tone of angiographically normal vessel segments during exercise. A similar pathologic response occurs in stenotic arteries, but this is independent of the actual level of serum cholesterol. These findings suggest that hypercholesterolemia influences vasomotor tone of the nonstenosed coronary arteries in patients with coronary artery disease probably through the occurrence of endothelial dysfunction.

Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy.

BACKGROUND: Previous experimental studies have shown that nitric oxide (NO) modulates cardiac function by an abbreviation of systolic contraction and an enhancement of diastolic relaxation. However, the response to NO donors of patients with severe pressure-overload hypertrophy and diastolic dysfunction is unknown. METHODS AND RESULTS: Intracoronary NO donors were given to 17 patients with severe aortic stenosis. A dose-response curve was obtained with nitroglycerin (30, 90, and 150 microg) in 11 patients and sodium nitroprusside (1, 2, and 4 microg/min) in 6. Left ventricular (LV) high-fidelity pressure measurements with simultaneous LV angiograms were performed at baseline and after the maximal dose of NO. The dose-response curve for intracoronary NO donors showed a marked fall in LV end-diastolic pressure, from 23 to 14 mm Hg (-39%; P<0.0001), whereas LV peak systolic pressure fell only slightly, from 206 to 196 mm Hg (-4%; P<0.01). End-diastolic chamber stiffness decreased from 0.12 to 0.07 mm Hg/mL (P<0.0001) and end-systolic stiffness from 1.6 to 1.3 mm Hg/mL (P<0.01). Heart rate, right atrial pressure, LV ejection fraction, the time constant of isovolumic pressure decay (tau), and LV filling rates remained unchanged. CONCLUSIONS: In patients with severe pressure-overload hypertrophy, intracoronary NO donors exert a marked decrease in LV end-diastolic pressure without affecting LV systolic pump function. Thus, the hypertrophied myocardium appears to be particularly susceptible to NO donors, with a marked improvement in diastolic function.

Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide.

AIMS: Glimepiride is a new sulfonylurea for diabetes treatment which is supposed to impact less on extra-pancreatic ATP-dependent K+ channels than the conventional drug glibenclamide. This study was performed to evaluate whether this results in a better maintenance of ATP-dependent K+ channel mediated ischaemic myocardial preconditioning. METHODS AND RESULTS: In a double-blind placebo-controlled study the period of total coronary occlusion during balloon angioplasty of high grade coronary artery stenoses was used as a model to compare the effects of both drugs. Quantification of myocardial ischaemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. All patients underwent three dilatations. The first dilatation (dilatation 1) served to determine the severity of ischaemia during vessel occlusion. During dilatation 2, baseline values were recorded. Thereafter, glimepiride (15 patients: 1.162 mg), glibenclamide (15 patients: 2.54 mg) or placebo (15 patients) were intravenously administered over 12 min. Dilatation 3 started 10 min after the beginning of the drug administration. Mean ST segment shifts in the placebo group decreased by 35% (dilatation 2: 0.23; dilatation 3:0.15 mV; CI -0.55 to 0.00 mV; P=0.049). A similar reduction also occurred in the glimepiride group, in which repetitive balloon occlusion led to a 34% reduction (dilatation 2: 0.35; dilatation 3: 0.23 mV; CI -0.21 to -0.02 mV; P=0.01). There was little influence however, on mean ST segment shifts in the glibenclamide group (dilatation 2 and dilatation 3: 0.24 mV; CI -0.10 to 0.25 mV; P=0.34). Accordingly, time to angina during balloon occlusion slightly increased (by 30%) in the placebo group (dilatation 2: 37 s; dilatation 3: 48 s; CI 0.0 to 15.0 s; P=0.16); increased by 13% in the glimepiride group (dilatation 2: 40 s; dilatation 3: 45 s; CI 0.0 to 14.0 s; P=0023); and remained unchanged in the glibenclamide group (dilatation 2 and dilatation 3: 30 s; CI -7.5 to 7.5 s; P=0.67). CONCLUSION: These results show that glimepiride maintains myocardial preconditioning, while glibenclamide might be able to prevent it.

[Diuretics in the treatment of heart failure: current pathophysiological aspects]. / Diuretika in der Behandlung der Herzinsuffizienz: neue pathophysiologische Aspekte.

From a pathophysiologic point of view heart failure can be divided into systolic and diastolic dysfunction. Systolic dysfunction is characterized by a decreased ejection fraction and increased chamber volume which can be typically found in young people with congestive cardiomyopathy. Diastolic dysfunction is associated with an enhanced filling pressure but with a normal systolic pump function. This disorder can be typically found in elderly patients with myocardial hypertrophy. Treatment of congestive heart failure includes. 1.) reduction of central blood volume (preload reduction) 2.) decrease of peripheral resistance afterload reduction) 3.) regression of myocardial hypertrophy (improving myocardial stiffness) 4.) maintenance of atrial contraction (atrial kick) 5.) decrease of heart rate (prolongation of diastolic filling time and increase in contractility) 6.) improvement of LV relaxation (positive lusitropic effect) and 7.) prevention of myocardial ischemia (improvement in contractility and relaxation). The primary goal of medical therapy is symptomatic improvement. Reduction in morbidity and mortality is only a secondary consideration. To achieve this goal ACE-inhibitors and in certain cases betablockers (cave: neg. inotropic action) are suited best. Additionally, digitalis-especially in the presence of atrial fibrillation- and vasodilators can be used to further improve quality of life. In the case of severe heart failure with or without atrial fibrillation oral anticoagulation is indicated to prevent systemic embolication. Diuretics are often used for symptomatic improvement but have no effect on long-term survival. Aldosterone antagonists (e.g, spironolactone) have a beneficial effect on LV remodeling and probably also on mortality. The role of endothelin antagonists and atriopeptidase inhibitors in the treatment of heart failure are not yet clear.

[Function of the residual myocardium after infarct and prognostic significance]. / Funktion des Restmyokards nach Infarkt und dessen prognostische Bedeutung.

Changes of the left ventricle after myocardial infarction are characterized by geometric, structural, and vascular alterations, which have been summarized under the term "remodeling". This process takes place in the infarct region as well as in the surviving myocardium. Depending on to the size of infarction and the degree of neurohumoral activation, the left ventricle demonstrates diastolic dysfunction which may finally lead to systolic failure. The residual myocardium develops progressive myocyte hypertrophy and interstitial fibrosis. These structural alterations are due to changes in loading conditions and stimulation of the neurohumoral system with an activation of local paracrine and autocrine factors. Myocardial function can be assessed by different non-invasive (echocardiography, radionuclide ventriculography, magnetic resonance imaging, etc.) or invasive methods (e.g., simultaneous pressure-volume measurements). "Myocardial tagging" based on magnetic resonance imaging allows the assessment of 3D-motion of the left ventricle by labelling specific myocardial regions with a rectangular grid. A systolic "wringing" motion with clock-wise rotation at the base and counter-clockwise rotation at the apex has been described in normal subjects. In the ischemic myocardium, delayed relaxation with a prolonged back-rotation (untwisting) has been reported during early diastole, whereas decreased systolic contraction with delayed diastolic rotation has been observed in non-Q-wave infarction. In patients with anterolateral aneurysms, a complete loss of systolic rotation has been demonstrated. The prognostic significance of LV "remodeling" has been emphasized by several authors: The size of infarction, LV volume, LV ejection fraction, as well as the degree of neurohumoral activation have been identified as being associated with an unfavorable clinical outcome. Yearly mortality rates have been reported to range between 15 and 17% in patients with large infarcts and marked LV dilatation and between 3 and 7% in patients with small to medium-sized infarcts.

Assessment of systolic and diastolic LV function by MR myocardial tagging.

Heart failure has been divided into several different forms depending on etiology, clinical course and pathophysiology of left ventricular (LV) dysfunction. Systolic and diastolic dysfunction are characterized by a reduced cardiac output with normal (= diastolic dysfunction) or depressed (= systolic dysfunction) LV pump function. New diagnostic techniques such as magnetic resonance imaging (MRI) allow to determine noninvasively LV 3D motion by labelling specific myocardial regions (= myocardial "tagging") with a rectangular or radial grid. From the deformation of this grid rotational and translational motion of the heart can be derived. A "wringing" motion of the left ventricle has been described during systole which includes a clockwise rotation at the base and a counterclockwise rotation at the apex. During diastole, an "untwisting" motion has been demonstrated. In the normal heart, diastolic "untwisting" occurs primarily during isovolumic relaxation, analogous to the systolic "wringing" which takes place mainly during isovolumic contraction. A prolongation of the "untwisting" motion was found in the hypertrophied (aortic stenosis) and hibernating myocardium. Thus, heart failure is associated with profound alterations in the mechanical function of the heart which are manifested by changes in systolic "wringing" and diastolic "untwisting" motion.