[Is heart rate adequately controlled in chronic systolic heart failure patients in Germany? results from a nationwide survey (INDICATE)]. / Ist die Herzfrequenz bei Herzinsuffizienz-Patienten in Deutschland ausreichend kontrolliert?

BACKGROUND: Elevated resting heart rate is associated with increased morbidity and mortality in patients with chronic systolic heart failure (CHF). Lowering of heart rate improves cardiovascular outcome in these patients. Therefore, heart rate reduction is an important element of therapeutic management and consistently reflected in current European guidelines for heart failure. Methods: The INDICATE study was initiated as a multicenter nationwide cross-sectional survey aiming to analyze the current quality of care in outpatients with CHF (documented left ventricular systolic dysfunction) in Germany. 20 consecutive patients were to be included in the survey from February until June 2012 by 793 cardiologic private practices. Detailed documentation of each patient was performed using a standardized questionnaire. RESULTS: CHF was known for more than 6 months in 88 % of the 15 148 included patients. Mean heart rate in the study population was 73 ± 13 min⁻¹. In 42 % of patients the heart rate was ≥ 75 min⁻¹. 86 % were treated with betablockers. However, higher doses of betablockers were not associated with lower resting heart rate. 27 % of patients remained on heart rates ≥ 75 min⁻¹ although receiving at least 50 % of betablocker target dose. CONCLUSION: INDICATE reveals a considerable proportion of outpatients with CHF showing an elevated heart rate despite beta blockade - irrespective of applied dose. These results emphasize the importance of optimizing the pharmacological management of resting heart rate according to guidelines in these patients.

Noradrenaline enhances angiotensin II responses via p38 MAPK activation after hypoxia/re-oxygenation in renal interlobar arteries.

AIM: Hypoxia and sympathetic activation are main factors in the pathogenesis of acute kidney injury (AKI). We tested the hypothesis that noradrenaline (NE) in combination with hypoxia aggravates the vasoreactivity of renal arteries after hypoxia/re-oxygenation (H/R). We tested the role of adrenergic receptors and p38 MAPK using an in vitro H/R protocol. METHODS: Mouse interlobar arteries (ILA) and afferent arterioles (AA) were investigated under isometric and isotonic conditions respectively. The in vitro protocol consisted of 60-min hypoxia and control condition, respectively, 10-min re-oxygenation followed by concentration-response curves for Ang II or endothelin. RESULTS: Hypoxia reduced the response to Ang II. Hypoxia and NE (10(-9)  mol L(-1) ) together increased it in ILA and AA. In ILA, NE alone influenced neither Ang II responses under control conditions nor endothelin responses after hypoxia. Prazosin or yohimbine treatment did not significantly influence the NE+hypoxia effect. The combination of prazosin and yohimbine or propranolol alone inhibited the effect of NE+hypoxia. BRL37344 (ß3 receptor agonist) mimicked the NE effect. In contrast, the incubation with ß3 receptor blocker did not influence the mentioned effect. Phosphorylation of p38 MAPK and MLC(20) was increased after H/R with NE and Ang II treatment. The selective p38 MAPK inhibitor SB202190 blocked the NE+hypoxia effect on the Ang II response. CONCLUSION: The results suggest an interaction of NE and hypoxia in enhancing vasoreactivity, which may be important for the pathogenesis of AKI. The effect of NE+hypoxia in ILA is mediated by several adrenergic receptors and requires the p38 MAPK activation.

Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contractility.

AIM: We have recently reported that hypoxia stimulates transcription of the TrkB neurotrophin receptor in cultured cells via stabilization of hypoxia-inducible factor-1alpha. Here we investigated whether the expression of TrkB and other neurotrophin receptors is oxygen-sensitive also in vivo, and explored the functional consequences of an oxygen-regulated TrkB expression. METHODS: Rats were exposed either to 21% O(2) or 8% O(2) for 6 h and TrkB was analysed by reverse transcription real-time PCR, in situ mRNA hybridization, and immunological techniques. The importance of the brain-derived neurotrophic factor (BDNF)-TrkB pathway in the control of mechanical airway function was assessed on isolated tracheal segments from normoxic and hypoxic rats. RESULTS: TrkB transcripts were increased approx. 15-fold in the lungs of hypoxic rats, and the respiratory epithelium was identified as the site of enhanced TrkB expression in hypoxia. The TrkB ligand, BDNF, significantly increased the contractile response to acetylcholine (ACh) of isolated tracheal segments from hypoxic but not from normoxic rats. This effect of BDNF was prevented by pre-incubation of the tissue specimens with the tyrosine kinase inhibitor K252a and by mechanical removal of the TrkB containing airway epithelium. Likewise, the nitric oxide (NO) synthase inhibitor l-NAME abrogated the influence of BDNF on ACh-induced contractions of isolated tracheal segments from hypoxic rats. CONCLUSION: These results demonstrate that systemic hypoxia stimulates expression of the TrkB neurotrophin receptor in the airway epithelium. Furthermore, activation of TrkB signalling by BDNF in hypoxia enhances mechanical airway contractility to ACh through a mechanism that requires NO.

Adenosine increases calcium sensitivity via receptor-independent activation of the p38/MK2 pathway in mesenteric arteries.

AIM: Adenosine (Ado) restores desensitized angiotensin II-induced contractions in the renal arterioles via an intracellular, receptor-independent mechanisms including the p38 mitogen-activated protein kinase (MAPK). In the present study we test the hypothesis that MAPK-activated protein kinase 2 (MK2) mediates the Ado effect downstream from p38 MAPK resulting in an increased phosphorylation of the regulatory unit of the myosin light chain (MLC(20)). METHODS AND RESULTS: Contraction experiments were performed in rings of mesenteric arteries under isometric conditions in C57BL6 and MK2 knock out mice (MK2-/-). Ado pretreatment (10(-5) mol L(-1)) strongly increased Ang II sensitivity, calcium sensitivity and the phosphorylation of MLC(20). Treatment with Ado (3 x 10(-6) or 10(-5) mol L(-1) in between successive Ang II applications) enhanced the desensitized Ang II responses (second to fifth application). Ca(2+) transients were not effected by Ado. Further, blockade of type 1 and type 2 Ado receptors during treatment did not influence the effect. Type 3 receptor activation by inosine instead of Ado had no effect. Conversely, inhibition of nitrobenzylthioinosine-sensitive Ado transporters prevented the effects of Ado. Inhibition of p38 MAPK as well as use of MK2-/- mice prevented contractile Ado effects on the mesenteric arteries and the phosphorylation of MLC(20). CONCLUSION: The study shows that Ado activates the p38 MAPK/MK2 pathway in vascular smooth muscle via an intracellular action, which results in an increased MLC(20) phosphorylation in concert with increased calcium sensitivity of the contractile apparatus. This mechanism can significantly contribute to the regulation of vascular tone, e.g. under post-ischaemic conditions.