Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with <scp>HCN</scp>‐channels

Ebelt, Henning; Geißler, Isabel; Ruccius, Sara; Otto, Volker; Hoffmann, Sophie; Korth, Heinrich; Klöckner, Udo; Zhang, Ying; Li, Yang; Großmann, Claudia; Rueckschloss, Uwe; Gekle, Michael; Stieber, Juliane; Frantz, Stefan; Werdan, Karl; Müller‐Werdan, Ursula; Loppnow, Harald

doi:10.1111/1440-1681.12415

Cited by 9 publications

(10 citation statements)

References 36 publications

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“…In mice in vivo, endotoxin does not lower but increase heart rate,63 as can also be seen in humans. However, when autonomous nervous system in these mice is blocked by propranolol and atropine, endotoxin induces a significant reduction of heart rate 63. Thus, both effects can be demonstrated in the mice, while under in vivo conditions, the positive chronotropic effect of endotoxin by sensitization of I f to the positive chronotropic beta-adrenoceptor stimulation prevails the direct negative chronotropic effect on I f .…”

Section: Ivabradine – Mode Of Action and Pharmacologymentioning

confidence: 54%

“…In addition to this direct inhibitory effect of endotoxin on I f , endotoxin in human atrial cardiomyocytes also sensitizes I f to beta-adrenergic stimulation, thereby increasing heart rate 36. In mice in vivo, endotoxin does not lower but increase heart rate,63 as can also be seen in humans. However, when autonomous nervous system in these mice is blocked by propranolol and atropine, endotoxin induces a significant reduction of heart rate 63.…”

Section: Ivabradine – Mode Of Action and Pharmacologymentioning

confidence: 92%

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Advances in the management of heart failure: the role of ivabradine

Müller‐Werdan

Stöckl

Werdan

2016

VHRM

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A high resting heart rate (≥70–75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class “IIa” = weight of evidence/opinion is in favor of usefulness/efficacy: “should be considered”; level of evidence “B” = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5–7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication “HF with reduced EF” together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF.

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Section: Ivabradine – Mode Of Action and Pharmacologymentioning

confidence: 54%

Section: Ivabradine – Mode Of Action and Pharmacologymentioning

confidence: 92%

Advances in the management of heart failure: the role of ivabradine

Müller‐Werdan

Stöckl

Werdan

2016

VHRM

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“…In addition to the participation of the autonomic nervous system, recent studies in animals and cell cultures have shown that Lipopolysaccharides (amphiphilic components of the outer wall of Gram-negative bacteria) act in two ways on the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN) of the atrial cells: directly inhibiting HCN-channels and indirectly sensitizing HCN-channels for sympathetic activation[34, 35]. …”

Section: Discussionmentioning

confidence: 99%

Heart rate variability as predictor of mortality in sepsis: A prospective cohort study

et al. 2017

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BackgroundSepsis is a serious medical condition with increasing prevalence and high mortality. The role of the autonomic nervous system in pathophysiology of sepsis has been increasingly researched. The objective of this study is to evaluate the Heart rate variability (HRV) as a predictor of mortality in septic patients.MethodsThis was a prospective cohort of patients diagnosed with sepsis. Patient recruitment was carried out at ICU in tertiary university hospital between March 2012 and February 2014. Clinical data and laboratory exams were collected at admission. Each patient underwent a 20-minute Holter and a 24-hour Holter on the first day of enrollment. The primary outcome was the 28-day all-cause mortality.ResultsA total of 63 patients were included. Patients were categorized into nonsurvivor group (n = 16) or survivor group (n = 47) depending on this endpoint. Survivors were younger (48.6 years vs. 63.0 years), had better renal function and lower values in severity scores (APACHE II and SOFA) compared to nonsurvivors. In the 20-minute Holter, SDNN, Total Power, VLF Power, LF Power and LF/HF of nonsurvivors were significantly lower than those of survivors (p = <0.001, p = 0.003, p = 0.002, p = 0.006, p = 0.009 respectively). ROC curve of SDNN was built, showing area under the curve of 0.772 (0.638–0.906) for mortality. The value of 17ms was chosen as best SDNN cutoff to discriminate survivors and nonsurvivors. In the Cox proportional regression, adjusted for SOFA score and for APACHE II, a SDNN ≤ 17ms was associated with a greater risk of death, with hazard ratios of 6.3 (1.4–28.0; p = 0.015) and 5.5 (1,2–24,8; p = 0.027), respectively. The addition of the dichotomized SDNN to the SOFA model reduced AIC and increased the concordance statistic and the R2, indicating that predictive power of the SDNN + SOFA model is better than predictive power of SOFA only.ConclusionsSeveral HRV parameters are reduced in nonsurviving septic patients. SDNN ≤17 is a risk factor for death in septic patients, even after adjusting for severity scores.

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“…This probably resulted from the direct action of LPS on the sinus node (Ebelt et al. ) and/or from the occurrence of hypothermia (Romanovsky et al. ), which is known to decrease intrinsic HR (Bolter and Atkinson ).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, HR decreased after LPS administration. This probably resulted from the direct action of LPS on the sinus node (Ebelt et al 2015) and/or from the occurrence of hypothermia (Romanovsky et al 2005), which is known to decrease intrinsic HR (Bolter and Atkinson 1988). Because all rats were euthanized at the end of the recordings, we do not know whether MAP would have continued to decrease.…”

Section: Vol 5 | Iss 4 | E13139mentioning

confidence: 99%

Renal sympathetic nerve activity and vascular reactivity to phenylephrine after lipopolysaccharide administration in conscious rats

et al. 2017

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It has been proposed that sympathoexcitation is responsible for vascular desensitization to α 1‐adrenoceptor stimulation during lipopolysaccharide (LPS)‐induced systemic inflammation. The present study tested this hypothesis by examining the effects of sympatho‐deactivation with the α 2‐adrenoceptor agonist, dexmedetomidine, on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and vascular reactivity to phenylephrine in conscious rats with cardiac autonomic blockade (methylatropine and atenolol) following LPS administration. In male, adult Sprague‐Dawley rats (n = 5 per group), RSNA and MAP were continuously recorded over 1‐h periods, before and after LPS administration (20 mg/kg iv), and finally after infusion of either saline or dexmedetomidine (5 μg/kg, then 5 μg/kg/h iv). A full dose–response curve to phenylephrine was constructed under each condition. After pooling data from both groups of rats (n = 10), LPS significantly (P = 0.005) decreased MAP (from 115 ± 1 to 107 ± 2 mmHg), increased RSNA (to 403 ± 46% of baseline values) and induced 4 to 5‐fold increases in the half‐maximal effective dose (ED 50) of phenylephrine (from 1.02 ± 0.09 to 4.76 ± 0.51 μg/kg). During saline infusion, RSNA progressively decreased while vascular reactivity did not improve. Treatment with dexmedetomidine decreased MAP, returned RSNA to near pre‐endotoxemic levels, but only partially restored vascular reactivity to phenylephrine (ED 50 was still threefold increased as compared with baseline values). These findings indicate that only part of the decrease in vascular reactivity to α 1‐adrenoceptor stimulation during endotoxemia can be accounted for by sympathetic activation, at least on a short‐term basis.

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Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with HCN‐channels

Cited by 9 publications

References 36 publications

Advances in the management of heart failure: the role of ivabradine

Advances in the management of heart failure: the role of ivabradine

Heart rate variability as predictor of mortality in sepsis: A prospective cohort study

Renal sympathetic nerve activity and vascular reactivity to phenylephrine after lipopolysaccharide administration in conscious rats

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