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Background: Vitamin K-dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR)., Objectives: This study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial., Methods: Of the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated., Results: GFR declined in all treatment groups. After an average of 30 months, the mean ± SE decline in GFR was significantly greater with warfarin (-3.68 ± 0.24 ml/min) compared with DE 110 mg (-2.57 ± 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (-2.46 ± 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range <65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes., Conclusions: Patients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to investigate the interaction between blood pressure (BP) and heart rate (HR) reduction and changes in left ventricular (LV) structure and function following renal sympathetic denervation (RDN)., Background: Hypertension results in structural and functional cardiac changes. RDN reduces BP, HR, and LV mass and improves diastolic dysfunction., Methods: We evaluated LV size, mass, and function before and 6 months after RDN in 66 patients with resistant hypertension and analyzed results in relation to systolic BP (SBP) and HR., Results: SBP decreased by 11 ± 3 mm Hg in the first, 18 ± 5 mm Hg in the second, and 36 ± 7 mm Hg in the third tertile of SBP at baseline (p < 0.001). HR decreased by 13 ± 4 beats/min, 8 ± 3 beats/min, and 11 ± 6 beats/min in tertiles of SBP (p for interaction between tertiles = 0.314). In all SBP tertiles, LV mass index (LVMI) decreased similarly (LVMI -6.3 ± 2.2 g/m(2.7), -8.3 ± 2.1 g/m(2.7), and -9.6 ± 1.9 g/m(2.7); p for interaction = 0.639). LVMI decreased unrelated to HR at baseline (p for interaction = 0.471). The diastolic parameters E-wave deceleration time, isovolumetric relaxation time, and E'-wave velocity improved similarly in all tertiles of SBP and HR. Changes in LV mass and function were also unrelated to reduction in SBP or HR. Vascular compliance improved dependently on BP but independently of HR reduction., Conclusions: In patients with resistant hypertension, LV hypertrophy and diastolic function improved 6 months after RDN, without significant relation to SBP and HR. These findings suggest a direct effect of altered sympathetic activity in addition to unloading on cardiac hypertrophy and function., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the effect of catheter-based renal sympathetic denervation (RD) on left ventricular hypertrophy (LVH) and systolic and diastolic function in patients with resistant hypertension., Background: LVH and diastolic dysfunction are associated with elevated sympathetic activity and increased morbidity and mortality. The effect of RD on LVH and LV function is unclear., Methods: Forty-six patients underwent bilateral RD, and 18 patients served as controls. Transthoracic echocardiography was performed at baseline, and after 1 month and 6 months., Results: Besides reduction of systolic and diastolic blood pressure (-22.5/-7.2 mm Hg at 1 month and -27.8/-8.8 mm Hg at 6 months, p < 0.001 at each time point), RD significantly reduced mean interventricular septum thickness from 14.1 ± 1.9 mm to 13.4 ± 2.1 mm and 12.5 ± 1.4 mm (p = 0.007), and LV mass index from 53.9 ± 15.6 g/m(2.7) (112.4 ± 33.9 g/m(2)) to 47.0 ± 14.2 g/m(2.7) (103.6 ± 30.5 g/m(2)) and 44.7 ± 14.9 g/m(2.7) (94.9 ± 29.8 g/m(2)) (p < 0.001) at 1 month and 6 months, respectively. The mitral valve lateral E/E' decreased after RD from 9.9 ± 4.0 to 7.9 ± 2.2 at 1 month and 7.4 ± 2.7 at 6 months (p < 0.001), indicating reduction of LV filling pressures. Isovolumic relaxation time shortened (baseline 109.1 ± 21.7 ms vs. 85.6 ± 24.4 ms at 6 months, p = 0.006), whereas ejection fraction significantly increased after RD (baseline: 63.1 ± 8.1% vs. 70.1 ± 11.5% at 6 months, p < 0.001). No significant changes were obtained in control patients., Conclusions: Besides the known effect on blood pressure, our study showed for the first time that RD significantly reduces LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its anticoagulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Recently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are available for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate-independent of the underlying trigger-contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed., (Published by Elsevier Inc. All rights reserved.)

Objectives: Our aim was to determine cytokine and oxygen gradients over the collateral circulation in humans., Background: The molecular background of the maturation of the collateral circulation in response to coronary narrowing is poorly understood in humans, partly because of difficulties in obtaining local samples from the human collateral circulation., Methods: Coronary collateral blood was sampled in 60 patients with nontotal (n = 25) or total coronary occlusions (n = 35) using a special wide-lumen catheter. Coronary collateral flow index (CFI) was assessed by intracoronary pressure measurements. Oxygenation and lactate content was measured as well as 30 cytokines potentially involved in collateral artery growth, using a custom-made multiplex assay., Results: No rise in lactate or change in pH was found in collateral blood. Oxygen gradient between coronary and collateral arterial blood correlated inversely with CFI (r = -0.61, p < 0.001). Locally increased plasma levels were found for basic fibroblast growth factor, eotaxin, macrophage migration inflammatory factor, monocyte chemoattractant protein-1, and transforming growth factor-beta, while stem cell factor and stem cell growth factor-beta were significantly decreased. The highest cytokine gradients were found in patients with the least developed collateral circulation. The majority of cytokines correlated more strongly with the pO(2) gradient across the collateral bed than with CFI., Conclusions: Intravascular ischemia during brief balloon coronary occlusion is absent in human coronary collateral arteries. The oxygen gradient found over the collateral circulation is increased in patients with a less matured collateral circulation and relates to local levels of several known pro-arteriogenic cytokines. In case of a more developed collateral circulation, relatively low levels of cytokines are present, suggesting that growth factor therapy might be beneficial at this stage.