-
[show abstract]
[hide abstract]
ABSTRACT: Chronic heart failure (CHF) is one of the leading causes of hospitalization, morbidity, and mortality worldwide. This review summarizes current knowledge with regard to CHF as a risk factor for ischemic stroke. CHF is associated with an increased risk of thrombus formation and is accompanied by a 2- to 3-fold increased risk of stroke. Moreover, stroke in CHF patients is associated with poor outcome and higher mortality. Available evidence for additional "vascular" stroke risk factors in heart failure patients is inconsistent and is mostly derived from cohort studies or retrospective analyses. Current guidelines recommend anticoagulation for CHF patients with concomitant atrial fibrillation but not for those in sinus rhythm. Prospective studies are needed to test whether early detection and optimal treatment of CHF reduces the burden of stroke-associated neurologic and neuropsychological sequelae.
Stroke 09/2011; 42(10):2977-82. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aims: Microalbuminuria (MAU) is a marker for endothelial dysfunction and a predictor of increased cardiovascular risk. Physical activity improves endothelial function. This analysis aims to explore the impact of regular physical exercise on the prevalence and the degree of MAU in hypertensive individuals at high cardiovascular risk. Methods and results: The International Survey Evaluating microAlbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) studied the prevalence of MAU in 20,786 hypertensive patients at high cardiovascular risk. Herein, we investigated the relationship between self-reported physical activity and MAU in relation to the number of cardiovascular risk factors, medication and co-morbidities. A total of 7123 patients (34.3%) performed regular physical exercise (moderate or strenuous, at least 4 hours per week). The prevalence of MAU was significantly lower in active than in inactive patients (54% vs 61%; P < 0.0001). This association was observed in all classes of blood pressure and heart rate and was similar in patients with and without diabetes mellitus. Urinary albumin excretion (UAE) was lower in active than in inactive patients (UAE 80 mg/l: 11.6% vs 13.5%, P < 0.0001; UAE 150 mg/l: 7.5% vs 10%; P < 0.0001). In a multivariate analysis adjusted for age, gender, blood pressure, heart rate, renal function, medication and comorbidities, regular physical activity was associated with a 25% lower risk for MAU (odds ratio (OR) 0.75; 95% confidence interval (CI), 0.67-0.84; P < 0.0001). Risk reduction for MAU was more pronounced in strenuously active (OR 0.66; 95%CI, 0.47-0.95; P < 0.05) than in moderately active patients (OR 0.76; 95%CI, 0.68-0.85; P < 0.0001). Conclusion: In hypertensive patients at high cardiovascular risk, physical activity is an independent predictor for a decreased risk of microalbuminuria.
European journal of preventive cardiology. 09/2011; 19(5):1066-73.
-
Cathleen Endtmann,
Talin Ebrahimian,
Thomas Czech,
Omar Arfa, Ulrich Laufs,
Mathias Fritz,
Kerstin Wassmann,
Nikos Werner,
Vasileios Petoumenos,
Georg Nickenig,
Sven Wassmann
[show abstract]
[hide abstract]
ABSTRACT: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood. Stimulation with Ang II decreased the number of cultured human early outgrowth EPCs, which express both AT(1)-R and Ang II type 2 receptor, mediated through AT(1)-R activation and induction of oxidative stress. Ang II redox-dependently induced EPC apoptosis through increased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase phosphorylation; decreased Bcl-2 and increased Bax expression; and activation of caspase 3 but had no effect on the low cell proliferation. In addition, Ang II impaired colony-forming and migratory capacities of early outgrowth EPCs. Ang II infusion diminished numbers and functional capacities of EPCs in wild-type (WT) but not AT(1)a-R knockout mice (AT(1)a(-/-)). Reendothelialization after focal carotid endothelial injury was decreased during Ang II infusion. Salvage of reendothelialization by intravenous application of spleen-derived progenitor cells into Ang II-treated WT mice was pronounced with AT(1)a(-/-) cells compared with WT cells, and transfusion of Ang II-pretreated WT cells into WT mice without Ang II infusion was associated with less reendothelialization. Transplantation of AT(1)a(-/-) bone marrow reduced atherosclerosis development in cholesterol-fed apolipoprotein E-deficient mice compared with transplantation of apolipoprotein E-deficient or WT bone marrow. Randomized treatment of patients with stable coronary artery disease with the AT(1)-R blocker telmisartan significantly increased the number of circulating CD34/KDR-positive EPCs. Ang II through AT(1)-R activation, oxidative stress, and redox-sensitive apoptosis signal-regulating kinase 1-dependent proapoptotic pathways impairs EPCs in vitro and in vivo, resulting in diminished vascular regeneration.
Hypertension 09/2011; 58(3):394-403. · 6.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup.
The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. ≥ 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction.
TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co-morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients.
clinicaltrials.gov NCT01263964.
BMC Neurology 08/2011; 11:98. · 2.17 Impact Factor
-
Stephan H Schirmer,
Achim Degen,
Magnus Baumhäkel,
Florian Custodis,
Lisa Schuh,
Michael Kohlhaas,
Erik Friedrich,
Ferdinand Bahlmann,
Reinhard Kappl,
Christoph Maack,
Michael Böhm, Ulrich Laufs
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
European Heart Journal 08/2011; 33(10):1223-31. · 10.48 Impact Factor
-
Florian Custodis,
Karen Gertz,
Mustafa Balkaya,
Vincent Prinz,
Ilka Mathar,
Christoph Stamm,
Golo Kronenberg,
Andrey Kazakov,
Marc Freichel,
Michael Böhm,
Matthias Endres, Ulrich Laufs
[show abstract]
[hide abstract]
ABSTRACT: Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia.
129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days.
Stress increased HR from 514 ± 10 bpm to 570 ± 14 bpm, this was prevented by ivabradine (485 ± 7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333% ± 24% and vascular NADPH oxidase activity was upregulated to 223 ± 38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84% ± 3% and increased AT1 receptor mRNA to 168% ± 18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140% ± 11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7 ± 2.3 mm3 versus 23.9 ± 2.4 mm3). HR reduction led to a marked reduction of the infarct volume to 12.9 ± 3.3 mm3.
Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress.
Stroke 06/2011; 42(6):1742-9. · 5.73 Impact Factor
-
Journal of the American College of Cardiology 05/2011; 57(21):2206. · 14.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High dose daily intake of plant sterols decreases the uptake of cholesterol in the intestine by competitive mechanisms and thus leads to reduced serum levels of total and LDL-cholesterol. By this, the commercialization of plant sterol enriched 'functional food' products is rapidly increasing. Subjects using these kinds of diet present a duplication of their serum plant sterol levels after long-term intake. In analogy to cholesterol, plant sterols such as campesterol and sitosterol can be oxidized to oxyphytosterols and these may counteract the primary anti-atherosclerotic action of cholesterol lowering. In order to investigate the whole spectrum of the consequences following high plant sterol intake a highly sensitive and specific isotope dilution gas chromatography-mass spectrometry method for the analysis of 7-oxygenated campesterol/sitosterol in trace amounts in human serum is presented in this paper. The validation was based on limits for detection and quantification, recovery, precision and minimization of autoxidation during work-up. Our results show an overall coefficient of variation ≤10% for the precision. The lowest limits for detection and quantification for 7α-hydroxy-campesterol were 7 pg/mL and 23 pg/mL, respectively. Data for overall sum recovery ranged from 92% to 115%. We practically used this method for analysis of oxyphytosterols simultaneously with plant sterol concentrations in serum from healthy volunteers. Sixteen subjects were treated with plant sterol enriched margarine (3 g/day) for 28 days. The results showed a significant increase of the oxyphytosterol 7β-hydroxy-sitosterol from 1.19±0.54 (before intake) to 2.24±1.24 ng/mL (mean±SD; +86.7%; P=0.007) after intake of the margarine. There was a highly significant correlation between the serum levels of campesterol and the sum of 7-oxygenated campesterol (R(2)=0.915; P<0.001) and sitosterol and the sum of 7-oxygenated sitosterol (R(2)=0.915; P<0.001). We can conclude from this study that the analytic method is well suited for detection of OPS, even at trace amounts.
Chemistry and physics of lipids 05/2011; 164(6):425-31. · 2.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: EPC and hCASMC play an important role in the pathogenesis of restenosis and stent thrombosis. Drug-coated balloon catheters exert a local, short-term application of antiproliferative agents. This study investigates the time-dependent influence on growth and motility of paclitaxel and sirolimus alone and combined with the coating additive iopromide on EPC and hCASMC.
Treatment of cultured human EPC and hCASMC with paclitaxel and sirolimus 1.5 and 15 µM for three seconds, three minutes and 24 hours, alone or combined with iopromide 0.197 M, resulted in a concentration- and time- dependent inhibition of proliferation and of migration. Paclitaxel and sirolimus increase apoptosis in either cell type. However, the effects of paclitaxel and sirolimus differed between the cell types: short-term exposure with paclitaxel leads to stronger inhibition of cell-density and apoptosis of hCASMC compared to EPC. In comparison to paclitaxel, short-term incubation with sirolimus showed a more effective inhibition of cell-density and migration as well as increased apoptosis in EPC in contrast to hCASMC. The effects of paclitaxel and sirolimus were increased in combination with iopromide. Interestingly, the antiproliferative effect of the paclitaxel-iopromide formulation on hCASMC was more potent compared to its effect on EPC. Endothelialisation in a porcine coronary stent model was similar with drug-coated balloons and uncoated controls, whereas it was delayed with drug-eluting stents.
After short-term application, paclitaxel and sirolimus show differential, cell-specific effects on EPC and hCASMC. Iopromide used as a coating agent intensifies these effects.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 05/2011; 7 Suppl K:K32-42. · 3.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), and diabetes mellitus and statin treatment affect cholesterol metabolism. The aim of the present study was to evaluate markers of cholesterol metabolism and determine their relationship with CVD in patients without diabetes mellitus who were not receiving statin treatment.
In addition to conventional CVD risk factors, plasma levels of campesterol and sitosterol (indicators of cholesterol absorption) and lathosterol (an indicator of cholesterol synthesis) were determined in 835 consecutive patients referred for coronary angiography. Coronary artery disease was evaluated by coronary angiograms, carotid atherosclerosis and peripheral vascular disease were assessed by Doppler ultrasound, and cerebrovascular accidents and transient ischemic attacks were identified by medical history.
After excluding patients with known diabetes mellitus and those receiving statin treatment, 177 patients were included in the analysis. Compared to patients without CVDs (n=111), patients with concomitant CVDs (n=66) had a reduced lathosterol-to-cholesterol ratio (1.25±0.61 vs. 1.38±0.63, P<0.05) and an increased campesterol-to-cholesterol ratio (1.81±1.04 vs. 1.50±0.69, P<0.05), indicating that enhanced absorption and reduced synthesis of cholesterol is associated with CVD development. Logistic regression analysis including all established cardiovascular risk factors (age, sex, total cholesterol, arterial hypertension, body mass index and smoking) revealed that campesterol and the campesterol-to-cholesterol ratio were significant predictors of concomitant CVD in this patient population.
In patients without diabetes mellitus, markers of enhanced cholesterol absorption were a strong predictor for concomitant CVD.
Chemistry and physics of lipids 04/2011; 164(6):451-6. · 2.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles rather depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to "off-target" effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.
Current pharmaceutical design 03/2011; 17(9):861-70. · 4.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to “off-target” effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.
Current Pharmaceutical Design 02/2011; 17(9):861-870. · 3.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70% of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.
European Heart Journal 02/2011; 32(5):545-52. · 10.48 Impact Factor
-
European Heart Journal 02/2011; 32(3):264-8. · 10.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Telomeres and associated proteins are regulators of cellular survival, regeneration and aging. PPAR-γ agonists may mediate vascular effects in addition to insulin sensitizing. We therefore examined whether pioglitazone regulates vascular telomere biology.
C57/Bl6 mice were randomized to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks (n = 6-8 per group). Telomere repeat amplification protocols showed a 2-fold increase of aortic telomerase activity in the pioglitazone group. Telomere repeat-binding factor 2 protein and mRNA levels (236%+172% of vehicle) as well as phosphorylation of protein kinase Akt (479% of vehicle) were up-regulated. Western blots demonstrated reduced aortic expression of senescence markers p16, cell-cycle checkpoint kinase 2 and p53. These regulatory mechanisms were independent of acute changes of telomere length. Similar observations were made in mononuclear cells (MNC) from these mice and in cultivated bovine aortic endothelial cells, human MNC and endothelial progenitor cells (EPC). Telomerase activation by pioglitazone in cultivated cells was prevented by Akt inhibitors. To test the functional relevance of the findings, isolated mononuclear cells (MNC) were exposed to H(2)O(2). MNC from pioglitazone-treated mice exhibited reduced apoptosis (AnnexinV-FACS). In vivo, lipopolysaccharide-induced aortic endothelial apoptosis was potently prevented in pioglitazone-treated animals (hairpin oligonucleotide assay). Both, up-regulation of telomere-regulating proteins and prevention of oxidative stress-induced aortic apoptosis, were absent in telomerase reverse transcriptase (TERT)-deficient mice.
Pioglitazone treatment up-regulates telomerase activity, telomere-stabilizing proteins and reduces senescence markers in vascular cells. These effects and the reduction of LPS-induced endothelial apoptosis by thiazolidinediones depend on TERT. The findings underscore the important role of telomere-regulating proteins for vascular cell function and survival.
Atherosclerosis 02/2011; 216(1):23-34. · 3.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 'Functional foods' supplemented with plant sterol esters (PSE) and plant stanol esters (PSA) are therapeutic options for the management of hypercholesterolaemia. However, their effects on blood monocytes, endothelial function, atherogenesis, and sterol tissue concentrations are poorly understood.
Male apoE-/- mice (n= 30) were randomized to three different diets for 6 weeks (n= 10 per group): high-cholesterol (1.25%) western-type diet (WTD), WTD + 2% PSE, and WTD + 2% PSA. Both supplements reduced serum cholesterol. WTD + PSE resulted in increased plant sterol serum concentrations and increased inflammatory Ly-6C(high) monocyte numbers. WTD + PSA increased plant stanol serum concentrations and Ly-6C-monocyte numbers, but decreased vascular superoxide release, lipid hydroperoxides, and inflammatory cytokines in aortic tissue, in plasma, and in circulating monocytes. Despite reduced serum cholesterol concentrations, both supplements impaired endothelial vasodilation compared with WTD. WTD + PSA reduced the development of atherosclerotic lesions compared with WTD alone (12.7 ± 3.7 vs. 28.3 ± 3.5%), and WTD + PSE was less effective (17.5 ± 3.7%). WTD + PSE and WTD + PSA reduced the cholesterol content in the liver, but not in the brain. However, WTD + PSE and WTD + PSA increased plant sterol and plant stanol concentrations in the liver as well as in the brain.
PSE and PSA supplementation reduced serum cholesterol, but increased plant sterol and plant stanol concentrations. Elevated levels of PSE and PSA were associated with endothelial dysfunction and increased central nervous system depositions. Atherosclerotic lesion retardation was more pronounced in WTD + PSA, coinciding with higher regenerative monocyte numbers, decreased oxidative stress, and decreased inflammatory cytokines compared with WTD + PSE.
Cardiovascular research 02/2011; 90(3):484-92. · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Heart rate influences myocardial oxygen demand, coronary blood flow, and myocardial function. Clinical and experimental studies support an association between elevated resting heart rate and a broad range of maladaptive effects on the function and structure of the cardiovascular system. Heart rate has been shown to be an important predictor of mortality in cardiovascular disorders such as coronary artery disease, myocardial infarction, and chronic heart failure. This review summarizes the specific influence of heart rate on vascular morphology and function as well as on myocardial lesions leading from early impact on vascular homeostasis to myocardial hemodynamics in chronic heart failure. Heart rate can be easily determined during physical examination of the patient and therefore allows a simple hint on prognosis and efficiency of therapy.
Clinical Research in Cardiology 01/2011; 100(1):11-9. · 2.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling. Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 μg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 μg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 μg/mg protein; 5 ± 0.9). Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.
Journal of Molecular and Cellular Cardiology 01/2011; 50(4):678-85. · 5.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This article gives an overview on the late-breaking clinical trials in the field of cardiovascular medicine which were presented during the hotline sessions at the American Heart Association Congress, held in Chicago, USA, from 13 to 17th November 2010. The data have been presented by leading experts in the field with relevant positions in the trials. The summaries provided in the manuscript were generated from the oral presentations and the webcasts of the American Heart Association (Laufs in Clin Res Cardiol 97:1-11, 2008; Möllmann in Clin Res Cardiol 98:1-7, 2009). The following papers are discussed in alphabetical order: ACT, ADVANCE, ASCEND-HF, ASCOT-CRP, CLOSURE I, DEFINE, EMPHASIS-HF, GRAVITAS, P-OM3, RAFT, ROCKET-AF, SMART-AV, SYMPLICITY HTN-2, TELE-HF, TIM-HF.
Clinical Research in Cardiology 01/2011; 100(1):1-9. · 2.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of the American College of Cardiology 12/2010; 56(24):1973-83. · 14.16 Impact Factor
