Hypertension does not Affect Intracellular Calcium uptake in Human Platelets

The relationship between the Ca2+ transport of platelet endoplasmic reticulum and hypertension was analyzed in 17 untreated patients exhibiting various degrees of hypertension. Each patient underwent a 24-h recording of ambulatory blood pressure. Platelets from patients were permeabilized with saponin and the rate of ATP-driven thapsigargin-sensitive Ca2+ uptake determined using the fluorescent Ca2+ indicator fluo-3. No relationship between blood pressure (systolic, diastolic, day, night) and the rate of Ca2+ uptake into the sacroplasmic reticulum of platelets was found. A weak but insignificant correlation between Ca2+ uptake and the heart rate was noted. Therefore, the increase in cytosolic Ca2+ of platelets in hypertension may not be due to changes of the activity of Ca2+ uptake into the sacroplasmic reticulum. Am J Hypertens 1996;9:136-14

Cost-Effectiveness of Losartan Versus Atenolol in Treating Hypertension—An Analysis of the LIFE Study from a Swiss Perspective

Aims: To determine the economic benefit of losartan versus atenolol in patients with essential hypertension from the perspective of the Swiss healthcare system. Methods and results: The cost-effectiveness of losartan versus atenolol in the treatment of hypertension was analyzed by applying the results of the LIFE study to the Swiss healthcare system using a decision analysis framework. The cost-effectiveness shows the losartan cohort to provide an additional life expectancy of 0.05 years per patient compared to the atenolol cohort, over a mean follow-up period of 4.8 years. Losartan therapy in hypertensive patients produced net cost savings of CHF 24 per patient and per 4.8 years compared to atenolol from the perspective of the Swiss health care system. This result was robust after varying costs of medication, stroke, myocardial infarction and life expectancy. Conclusion: The use of a losartan-based regimen in hypertensive patients with left ventricular hypertrophy in Switzerland is net cost-saving compared with a atenolol-based regime

Noninvasive Detection of Left-Ventricular Systolic Dysfunction by Acoustic Cardiography in Atrial Fibrillation

Objectives. Assessment of left ventricular (LV) systolic function in patients with atrial fibrillation can be difficult. Acoustic cardiography provides several parameters for quantifying LV systolic function. We evaluated the ability of acoustic cardiography to detect LV systolic dysfunction in patients with and without atrial fibrillation. Design. We studied 194 patients who underwent acoustic cardiography and cardiac catheterization including measurement of angiographic ejection fraction (EF) and maximum LV dP/dt. LV systolic dysfunction was defined as LV maximum dP/dt <1600 mmHg/s. Acoustic cardiographic parameters included electromechanical activation time (EMAT) and the systolic dysfunction index (SDI). Results. Acoustic cardiography detected systolic dysfunction with high specificity and moderate sensitivity with similar performance to EF (sensitivity/specificity without afib: EMAT 30/96, SDI 40/90, EF at 35% 30/96; sensitivity/specificity with afib: EMAT 64/82, SDI 59/100, EF at 35% 45/82). Conclusions. Acoustic cardiography can be used for diagnosis of LV systolic dysfunction in atrial fibrillation

Determinants of Costs and the Length of Stay in Acute Coronary Syndromes: A Real Life Analysis of More Than 10 000 Patients

Aims: The aim of this study was to investigate inpatient costs of acute coronary syndromes (ACS) in Switzerland and to assess the main cost drivers associated with this disease. Methods and Results: We used the national multicenter registry AMIS (acute myocardial infarction in Switzerland) which includes a representative number of 65 hospitals and a total of 11.623 patient records. The following cost modules were analyzed: hospital stay, percutaneous coronary interventions (PCI) and thrombolysis. Expenses were assessed using data from official Swiss national statistical sources. Mean total costs per patient were 12.101 Euro (median 10.929 Euro; 95% CI: 1.161-27.722 Euro). The length of stay ranged from one to 129days with a mean of 9.5days (median 8.0days; 95% CI: 1-23). Overall costs were independently influenced by age, gender and existent co-morbidities, e.g. cerebrovascular disease and diabetes (p < 0.0001). Conclusion: Our study determined specific causes for the high costs associated with hospital treatment on a large representative sample. The results should highlight unnecessary expenses and help policy makers to evaluate the base case for a DRG (Diagnosis Related Groups) scenario in Switzerland. Cost weighting of the identified secondary diagnosis should be considered in the calculation and coding of a primary diagnosis for AC

T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells

Objective: In vascular tissue, T-cadherin (T-cad) levels correlate with the progression of atherosclerosis, restenosis and tumour neovascularization. This study investigates whether T-cad influences proliferation of vascular cells. Methods and Results: Cultures of human umbilical vein endothelial cells (HUVEC) and rat and human aortic smooth muscle cells (rSMC, hSMC) were used. T-cad was overexpressed in HUVEC and hSMC using an adenoviral expression system. In cultures released from G1/G0 synchrony parallel immunoblot analysis of T-cad and cell cycle phase specific markers (p27Kip1, cyclin D1, E2F1, PCNA, cyclin B) showed increased T-cad protein levels subsequent to entry into early S-phase with sustained elevation through S-and M-phases. T-cad was increased in G2/M-phase (colchicine) synchronized cultures. In FACS-sorted cell populations, expression of T-cad in S-and G2/M-phase was higher than G1/G0-phase. Compared with empty-and LacZ-vector infected controls, HUVEC and hSMC overexpressing T-cad exhibited increased proliferation as assessed in enumeration and DNA synthesis assays. Additionally, following release from G1/G0 synchrony, HUVEC and hSMC overexpressing T-cad enter S-phase more rapidly. Flow cytometry after BrdU/propidium labelling confirmed increased cell cycle progression in T-cad overexpressing cells. Conclusion: In vascular cells, T-cad is dynamically regulated during the cell cycle and its expression functions in the promotion of proliferation. T-cad may facilitate progression of proliferative vascular disorders such as atherosclerosis, restenosis and tumour angiogenesi

Polarisation of T-cadherin to the leading edge of migrating vascular cells in vitro: a function in vascular cell motility?

Both histological and in vitro studies indicate a relationship between T-cadherin levels and acquisition of a modulated, migratory phenotype by vascular cells. This study further examines a role for T-cadherin in relation to cell migration and adhesion. Fluorescence microscopic examination of T-cadherin localisation in confluent cultures of human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells and the human carcinoma cell line ECV-304 revealed global distribution over the entire cell body, and with only slight enrichment at cell borders. This contrasts with restricted cell-cell junction localisation of classical cadherin (for example, VE-cadherin in HUVEC). In wounded cultures, T-cadherin polarised to the leading edge of cells migrating into the wound area, again contrasting with classical VE-cadherin, which was undetectable in this region. Confocal microscopy demonstrated that potential signalling functions of T-cadherin at the leading edge are unrelated to physical interactions with caveolin. Adherence of HUVEC onto a monolayer of T-cadherin-transfected L929 cells is significantly reduced compared with adhesion onto control (T-cadherin-negative) L929. Thus T-cadherin is not required for maintenance of intercellular adhesion, but may rather function as a signalling molecule involved in cell-cell recognition and sensing of the environment in processes where cell detachment occur

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Objectives. Assessment of left ventricular (LV) systolic function in patients with atrial fibrillation can be difficult. Acoustic cardiography provides several parameters for quantifying LV systolic function. We evaluated the ability of acoustic cardiography to detect LV systolic dysfunction in patients with and without atrial fibrillation. Design. We studied 194 patients who underwent acoustic cardiography and cardiac catheterization including measurement of angiographic ejection fraction (EF) and maximum LV dP/dt. LV systolic dysfunction was defined as LV maximum dP/dt &lt; 1600 mmHg/s. Acoustic cardiographic parameters included electromechanical activation time (EMAT) and the systolic dysfunction index (SDI). Results. Acoustic cardiography detected systolic dysfunction with high specificity and moderate sensitivity with similar performance to EF (sensitivity/specificity without afib: EMAT 30/96, SDI 40/90, EF at 35% 30/96; sensitivity/specificity with afib: EMAT 64/82, SDI 59/100, EF at 35% 45/82). Conclusions. Acoustic cardiography can be used for diagnosis of LV systolic dysfunction in atrial fibrillation

Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study

Aims To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. Methods and results In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 ± 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (−0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (−6.0%, P = 0.006). Conclusion Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considere

Cost-Effectiveness of Eplerenone in Patients with Left Ventricular Dysfunction after Myocardial Infarction—An Analysis of the EPHESUS Study from a Swiss Perspective

Objective: The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting. Materials and methods: A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%. Results: The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively. Conclusion: Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AM

T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells

Aims T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes. Methods and results We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC. Conclusion T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRe