Magnus Baumhäkel

Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice

Background— Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I(f) current inhibitor ivabradine in apolipoprotein E–deficient mice. Methods and Results— Male apolipoprotein E–deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg · kg−1 · d−1) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472±9 versus 545±11 bpm; P<0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals (P<0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48±6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg · kg−1 · d−1 for 6 weeks) reduced blood pressure (−15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. Conclusions— Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E–deficient mice.

Vascular Pathophysiology in Response to Increased Heart Rate

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.

RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT1-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT1-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT1-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.

Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation: Current Clinical Evidence and Future Developments

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.

Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis

AIMS Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth. METHODS AND RESULTS The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments. CONCLUSION Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.

The Effects of Direct Thrombin Inhibition with Dabigatran on Plaque Formation and Endothelial Function in Apolipoprotein E-Deficient Mice

The recently developed oral anticoagulant dabigatran (Dabi) etexilate directly inhibits thrombin after activation by plasma esterases to dabigatran. Thrombin is involved in the pathogenesis of atherosclerosis. We investigated the effects of direct thrombin inhibition on atherosclerosis and endothelial function in a hypercholesterolemic mouse model with accelerated atherosclerosis {[apolipoprotein E-deficient (ApoE(−/−)] mice}. ApoE(−/−) mice were treated with a cholesterol-rich diet for 12 weeks and either dabigatran etexilate (900 mg/kg body weight) or vehicle. Wild-type (C57/B6) mice served as control. Endothelial function was assessed with carbachol (endothelium dependent) by using glyceroltrinitrate (endothelium independent) as control in aortic rings. Atherosclerotic lesion formation was evaluated with Oil Red staining, and vascular collagen content was determined by Sirius Red staining. Reactive oxygen species (ROS) production was determined by semiquantitative immunohistochemical staining. Measurement of dabigatran plasma levels (622.3 ± 169 ng/ml) and a performed coagulation test (diluted thrombin time) revealed a relevant anticoagulatory concentration. Dabigatran etexilate attenuated increased atherosclerotic plaque formation [ApoE(−/−) Dabi: 16.1 ± 3.8% of ApoE(−/−) control; p < 0.001], decreased collagen content [ApoE(−/−) Dabi: 49.1 ± 10% of ApoE(−/−) control; p = 0.01], and ROS production in dihydroethidium staining [ApoE(−/−) Dabi: 46.3 ± 5.4% of ApoE(−/−) control; p = 0.005] in parallel to an improvement of endothelial function [ApoE(−/−) control 42.6 ± 2.7 versus ApoE(−/−) Dabi 62.9 ± 3.3% of phenylephrine-induced contraction; p = 0.001] at 100 μmol carbachol. These data suggest that direct thrombin inhibition in a relevant dosage improved endothelial function and reduced atherosclerotic lesion size, collagen content, and oxidative stress in hypercholesterolemic atherosclerosis. Interference with the coagulation system might provide a therapeutic target to modify atherosclerotic disease progression.

Nebivolol, but Not Metoprolol, Improves Endothelial Function of the Corpus Cavernosum in Apolipoprotein E-Knockout Mice

To determine the effects and underlying mechanisms of treatment with the β-receptor blockers nebivolol and metoprolol on penile endothelial function in apolipoprotein E (ApoE)-/- mice, wild-type (WT) and ApoE-/- mice were fed with a cholesterol-rich diet for 7 weeks. ApoE-/- mice were treated with nebivolol (10 mg/kg/day) or metoprolol (90 mg/kg/day). Endothelial function of aortic and corpora cavernosal tissue was assessed by pharmacological stimulation with carbachol (endothelium dependent) or glycerol trinitrate (endothelium independent) in organ bath experiments. Atherosclerotic lesion formation was evaluated with oil-red staining, and modulation of reactive oxygen species (ROS) production was determined with lipid peroxidation. Heart rate, but not blood pressure, was decreased in nebivolol- and metoprolol-treated ApoE-/- mice (p < 0.01) compared with controls and WT mice without significant intergroup differences. Atherosclerotic lesion formation in the aortic root was increased in ApoE-/- mice (p < 0.01) with a more significant improvement in nebivolol- (p < 0.01) compared with metoprolol-treated mice (p < 0.05). Endothelium-dependent relaxation of the corpora cavernosa was significantly impaired in ApoE-/- mice (p < 0.05), which improved in nebivolol- versus metoprolol-treated mice. Efficacy of endothelium-dependent relaxation was comparable in aortic and penile tissue. Quantification of ROS production via lipid peroxidation revealed a significant reduction of superoxide anion production in nebivolol-treated (p < 0.05) but not metoprolol-treated mice compared with ApoE-/- controls. Nebivolol improves penile endothelial function as a surrogate of erectile function in ApoE-/- mice. These effects may be related to a reduction of ROS production, which is independent of heart rate reduction, because metoprolol did not increase endothelial function.

Improvement of Endothelial Function of the Corpus Cavernosum in Apolipoprotein E Knockout Mice Treated with Irbesartan

Angiotensin receptor blockers enhance endothelial function and are suggested to improve erectile function. The effects and underlying mechanisms of treatment with the angiotensin receptor blocker irbesartan on penile endothelial function in apolipoprotein E (ApoE)-/- mice were determined. Wild-type (C57/B6) and ApoE-/- mice were fed with a high-fat, cholesterol-rich diet for 7 weeks and treated with irbesartan (50 mg/kg · day) or hydralazine (250 mg/l). Vital parameters were measured with the tail-cuff method. Endothelial (aortic rings) and erectile function (corpora cavernosa) were assessed by pharmacological stimulation in an organ bath chamber. Oxidative stress and angiotensin receptor expression were determined. Blood pressure was significantly decreased in irbesartan- and hydralazine-treated ApoE-/- mice (p < 0.05) compared with controls and wild-type mice. Endothelial function of the aorta and corpus cavernosum was significantly impaired in ApoE-/- mice (p < 0.05) and could be restored by treatment with irbesartan (p < 0.05). Consistently, nitric oxide production of corpora cavernosa was impaired in ApoE-/- mice (p < 0.01), with a restoration in irbesartan- but not hydralazine-treated mice. Dihydroethidium-stained sections and lipid peroxidase assay revealed a reduction of superoxide production in irbesartan (p < 0.05) compared with hydralazine-treated and control ApoE-/- mice. In summary, irbesartan improves penile endothelial function in ApoE-/- mice by reduction of vascular and cavernosal oxidative stress. This result emphasizes the beneficial effect of inhibition of the renin-angiotensin system even in terms of erectile function.

Heart rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in ApoE-knockout mice

OBJECTIVE To determine the effect of heart rate reduction with ivabradine on atherosclerotic lesions and erectile dysfunction. METHODS Two different treatment regimes with ivabradine were applied in wild-type (C57/B6) and ApoE(-/-)-mice to study effects of ivabradine on erectile function and atherosclerosis in animals with and without present endothelial dysfunction. Preventive effects of ivabradine were evaluated in animals fed a high-cholesterol diet in parallel to treatment with ivabradine (orally via chow, 10 mg/kg per day). The other treatment regime started treatment with a high-cholesterol diet for 4 weeks to induce endothelial dysfunction. Thereafter, treatment with ivabradine (orally via chow, 15 mg/kg per day) was started in ApoE(-/-) mice for 3 months. Vital parameters were measured using the tail-cuff method. Erectile function was assessed by pharmacological stimulation of corpora cavernosa in organ bath chambers. Atherosclerotic plaque formation, oxidative stress, eNOS and collagen content were determined. RESULTS Treatment with ivabradine significantly reduced heart rate (p<0.01), with no effect on blood pressure. Aortic atherosclerotic lesion size decreased with ivabradine in both treatment regimes (p<0.05). Endothelium-dependent relaxation of corpora cavernosa significantly decreased in ApoE(-/-)-mice with a restoration by ivabradine in prevention and reversal. Dihydroethidium-stained penile sections (p<0.05) and lipid peroxidase assay (p<0.05) revealed a reduction in superoxide production in ivabradine-treated animals. Penile eNOS-expression increased and collagen content significantly decreased (p<0.01) in ivabradine-treated animals. CONCLUSION Ivabradine improves penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial effects were achieved in prevention and manifest endothelial dysfunction.

Recent achievements in the management of Raynaud's phenomenon.

Raynaud’s phenomenon is a clinical disorder with episodic digital ischemic vasospasm triggered by cold- or emotional-stress. It was first mentioned by Maurice Raynaud in 1862 describing “a local asphyxia of the extremities” and was further divided into primary Raynaud’s disease and secondary Raynaud’s phenomenon, which is often related to connective tissue diseases, but also physical or chemical strain. Though pathophysiology of Raynaud’s phenomenon is still poorly understood, systemic and local vascular effects are most likely to be involved in primary Raynaud’s disease. In secondary Raynaud’s phenomenon additional abnormalities in vascular structure and function may play the major role. Thus, medical treatment of Raynaud’s phenomenon remains unsatisfactory, due to limited understanding of pathophysiological mechanisms. This review addresses current evidence for medical treatment of primary and secondary Raynaud’s phenomenon with regard to pathophysiological mechanisms as well as future perspectives.