Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). ␤-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences systemic vascular resistance. GPCR kinases (GRKs), including GRK2 (or ␤ARK1), phosphorylate and desensitize agonist-activated ␤ARs. Myocardial GRK2 levels are increased in heart failure and data suggest that vascular levels may also be elevated in hypertension. Therefore, we generated transgenic mice with vascular smooth muscle (VSM) targeted overexpression of GRK2, using a portion of the SM22␣ promoter, to determine its impact on vascular ␤AR regulation. VSM ␤AR signaling, as determined by adenylyl cyclase and mitogenactivated protein (MAP) kinase activation assays, was attenuated when GRK2 was overexpressed 2-to 3-fold. In vivo vasodilation in response to ␤AR stimulation using isoproterenol was attenuated and conscious resting mean arterial blood pressure was elevated from 96 Ϯ 2 mm Hg in nontransgenic littermate control (NLC) mice (n ϭ 9) to 112 Ϯ 3 mm Hg and 117 Ϯ 2 mm Hg in two different lines of SM22␣-GRK2 transgenic mice (n ϭ 7 and n ϭ 5, respectively; p Ͻ 0.05). Interestingly, medial VSM thickness was increased 30% from 29.8 Ϯ 1.6 m in NLC mice (n ϭ 6) to 39.4 Ϯ 1.6 m in SM22␣-GRK2 mice (n ϭ 7) (p Ͻ 0.05) and vascular GRK2 overexpression was sufficient to cause cardiac hypertrophy. These data indicate that we have developed a unique mouse model of hypertension, providing insight into the contribution that vascular ␤AR signaling makes toward resting blood pressure and overall cardiovascular regulation. Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension.␤-Adrenergic receptors (ARs) are critical G protein-coupled receptors (GPCRs) in the regulation of the cardiovascular system. ␤ARs (␤ 1 , ␤ 2 and ␤ 3 subtypes) are involved in the regulation of myocardial function as well as taking part in control of vascular tone (Brodde 1991;Chruscinski et al., 1999;Rohrer et al., 1999). ␤ 1 and ␤ 2 ARs primarily couple to the heterotrimeric G protein Gs, which then dissociates and activates adenylyl cyclase via the ␣-subunit and can also trigger signaling events mediated by the ␤␥-subunits (G ␤␥ ), such as the activation of mitogen-activated protein kinases (MAPKs). Studies so far suggest that stimulation of the ␤ 1 AR primarily mediates inotropy and chronotropy in the heart (Brodde and Michel, 1992;Chruscinski et al., 1999;. In contrast, studies from ␤ 1 AR, ␤ 2 AR, and ␤ 1 /␤ 2 knockout mice imply that vascular smooth muscle (VSM) relaxation seems to be controlled by all three ␤AR subtypes Rohrer et al., 1999).Importantly, several studies have shown that ␤AR levels and signaling can be significantly altered by cardiovascular disease. Among the most well characterized ␤AR derangements are those that take place in chronic heart failure, where ␤ 1 ARs are selectively down-regulated...

BackgroundCurrent reporting guidelines do not call for standardised declaration of follow-up completeness, although study validity depends on the representativeness of measured outcomes. The Follow-Up Index (FUI) describes follow-up completeness at a given study end date as ratio between the investigated and the potential follow-up period. The association between FUI and the accuracy of survival-estimates was investigated.MethodsFUI and Kaplan-Meier estimates were calculated twice for 1207 consecutive patients undergoing aortic repair during an 11-year period: in a scenario A the population’s clinical routine follow-up data (available from a prospective registry) was analysed conventionally. For the control scenario B, an independent survey was completed at the predefined study end. To determine the relation between FUI and the accuracy of study findings, discrepancies between scenarios regarding FUI, follow-up duration and cumulative survival-estimates were evaluated using multivariate analyses.ResultsScenario A noted 89 deaths (7.4%) during a mean considered follow-up of 30±28months. Scenario B, although analysing the same study period, detected 304 deaths (25.2%, P<0.001) as it scrutinized the complete follow-up period (49±32months). FUI (0.57±0.35 versus 1.00±0, P<0.001) and cumulative survival estimates (78.7% versus 50.7%, P<0.001) differed significantly between scenarios, suggesting that incomplete follow-up information led to underestimation of mortality. Degree of follow-up completeness (i.e. FUI-quartiles and FUI-intervals) correlated directly with accuracy of study findings: underestimation of long-term mortality increased almost linearly by 30% with every 0.1 drop in FUI (adjusted HR 1.30; 95%-CI 1.24;1.36, P<0.001).ConclusionFollow-up completeness is a pre-requisite for reliable outcome assessment and should be declared systematically. FUI represents a simple measure suited as reporting standard. Evidence lacking such information must be challenged as potentially flawed by selection bias.

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In the present limited cohort of patients younger than 60 years old, biologic aortic valve replacement was associated with reduced mid-term survival compared with survival after mechanical aortic valve replacement. Despite similar valve-related event rates in both groups, the better hemodynamic performance of the mechanical valves and/or protective effect of oral anticoagulation seemed to improve the outcome. The transcatheter valve-in-valve intervention as potential treatment of tissue valve degeneration should not be considered the sole bailout strategy for younger patients because no evidence is available that this would improve the outcome.

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SE is an excellent treatment option in massive PE with comparable early mortality rates and significantly less bleeding complications than TL. Patients having surgery after inefficient thrombolysis have the worst early outcome. The RV/LV CT-scan ratio might serve as a predictor to differentiate patients, who could profit from direct surgical intervention than thrombolytic treatment attempts. Further studies are required to confirm these results.

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This paper presents a novel mock circulation for the evaluation of ventricular assist devices (VADs), which is based on a hardware-in-the-loop concept. A numerical model of the human blood circulation runs in real time and computes instantaneous pressure, volume, and flow rate values. The VAD to be tested is connected to a numerical-hydraulic interface, which allows the interaction between the VAD and the numerical model of the circulation. The numerical-hydraulic interface consists of two pressure-controlled reservoirs, which apply the computed pressure values from the model to the VAD, and a flow probe to feed the resulting VAD flow rate back to the model. Experimental results are provided to show the proper interaction between a numerical model of the circulation and a mixed-flow blood pump.