Florian Custodis

Universitätsklinikum des Saarlandes, Homburg, Saarland, Germany

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Publications (41)234.02 Total impact

  • Florian Custodis · Ulrich Laufs ·
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    ABSTRACT: The term "LDL-Hypothesis" is frequently used to describe the association between LDL cholesterol (LDL-C) and cardiovascular outcomes. In the light of recent results of randomized trials the question arises whether the term hypothesis is still adequate. Considering the causal importance of LDL for the pathogenesis of atherosclerosis, epidemiological evidence and the clear genetic association of LDL-C with cardiovascular risk as well as the large statin trials and the reduction of events by a non-statin intervention in the IMPROVE-IT study, the term "hypothesis" appears to be outdated and should be replaced by "LDL-causality". © Georg Thieme Verlag KG Stuttgart · New York.
    DMW - Deutsche Medizinische Wochenschrift 05/2015; 140(10):761-4. DOI:10.1055/s-0041-102254 · 0.54 Impact Factor

  • Journal of the American College of Cardiology 03/2015; 65(10):A1498. DOI:10.1016/S0735-1097(15)61498-X · 16.50 Impact Factor
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    ABSTRACT: Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to < 24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P<0.01, unadjusted). After adjustment, only SBP-CV (P=0.0030) and mean HR (P=0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10-1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18-1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk. http://www.clinicaltrials.gov. Unique identifier: NCT 00153101. © 2015 American Heart Association, Inc.
    Hypertension 01/2015; 65(3). DOI:10.1161/HYPERTENSIONAHA.114.04568 · 6.48 Impact Factor
  • F Custodis · J-C Reil · S H Schirmer · O Adam · S Möhlenkamp · U Laufs · M Böhm ·
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    ABSTRACT: Heart rate is an easily accessible clinical variable with wide-ranging prognostic impact. Elevated resting heart rate predicts an elevated cardiovascular risk. Epidemiological studies demonstrate a relevant association between heart rate and survival in individuals without diagnosed cardiovascular disease and with cardiovascular disease like hypertension, coronary artery disease (CAD) and heart failure. Whereas a goal directed pharmacological heart rate reduction is not supported by clinical evidence for primary prevention it plays a prognostic role for patients with CAD and chronic heart failure. Moreover heart rate can be characterized as an independent risk factor for patients with heart failure and potentially for those with CAD. As a result the common guidelines recommend heart rate reduction as a target of therapy.
    DMW - Deutsche Medizinische Wochenschrift 08/2014; 139(33):1661-1672. DOI:10.1055/s-0034-1370223 · 0.54 Impact Factor
  • F Custodis · U Laufs ·
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    ABSTRACT: Lipid disorders play an essential role in the pathogenesis of atherosclerotic diseases. An integral part of the clinical evaluation is the estimation of the individual cardiovascular risk using risk scores and patient history. Due to the long established prognostic relevance, reduction of low-density lipoproteins (LDL) using statins remains beyond doubt the central intervention both in primary and secondary prevention of atherosclerotic diseases. Indispensible components of treatment in all patients with elevated triglyceride levels are lifestyle changes contributing to a reduction of accompanying risk factors, in particular physical activity and smoking cessation.
    Herz 01/2014; 39(1). DOI:10.1007/s00059-013-4013-x · 0.69 Impact Factor
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    ABSTRACT: Heart rate was proposed as an emergent cardiovascular (CV) risk factor. Previous studies have shown associations between increased heart rate and CV risk in various populations. We aimed to evaluate the prognostic relevance of heart rate in a large contemporaneous medically optimized cohort of patients with stable chronic CV disease. In a post hoc analysis of the ONTARGET/TRANSCEND trials, we evaluated associations between baseline and average heart rate in trial with CV risk in 31, 531 patients followed for a median of 5 years. The primary outcome, major vascular events (MVE), was a composite of CV death, myocardial infarction (MI), stroke, and congestive heart failure (CHF). Pre-specified secondary outcomes included all-cause death and the individual components of the primary outcome. Associations between heart rate and outcomes were computed with heart rate as a continuous variable, baseline heart rate >70 vs ≤70 bpm, and across heart rate quintiles, adjusting for other markers of risk, beta-blocker and non-dihydropyridine calcium channel blocker use. For each 10 bpm increase in baseline and average heart rate, we observed a significant increase in risk of MVE, CV death, CHF and all-cause death. There was a continuous relationship between MVE and baseline and, more importantly, average in-trial heart rate, with no observed threshold. MVE, CV death, stroke, CHF, and all-cause death increased across heart rate quintiles. There was no association between MI and HR. Results were consistent in clinically relevant subgroups. There were modest but significant improvements in C-statistic and in statistical measures of model calibration for models that included heart rate for MVE, CV death, CHF and all-cause death. This large study examined and quantitated associations between heart rate and CV events in a contemporary medically optimized population with stable CV disease. Resting and, in particular, in-trial average heart rate are independently associated with significant increases in CV events and all-cause death.
    Clinical Research in Cardiology 12/2013; 103(2). DOI:10.1007/s00392-013-0644-4 · 4.56 Impact Factor
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    Florian Custodis · Jan-Christian Reil · Ulrich Laufs · Michael Böhm ·
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    ABSTRACT: Heart rate is a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease. Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum initiating from endothelial dysfunction and continuing via atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease. As a therapeutic target, heart rate is accessible via numerous pharmacological interventions. The concept of selective heart rate reduction by the I(f) current inhibitor ivabradine provides an option to intervene effectively along the chain of events and to define the specific and prognostic role of heart rate for patients with coronary artery disease and heart failure. Future interventional studies will further clarify the significance of heart rate and targeted heart rate reduction for primary and secondary prevention in cardiovascular and cerebrovascular events.
    Journal of Cardiology 06/2013; 62(3-4). DOI:10.1016/j.jjcc.2013.02.018 · 2.78 Impact Factor
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    ABSTRACT: Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases. Omega-3 fatty acids (n3-FA) lower fasting TG levels. The effects of n3-FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood. 23 healthy volunteers and 30 non-diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H(2)O). Patients were treated with 4 g n3-FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 ± 10.9% of baseline). n3-FA reduced fasting TG from 137.1 ± 12.9 to 112.2 ± 8.6 mg/dl (p < 0.05), and maximum ppTG concentrations from 243.6 ± 24.6 to 205.8 ± 17.1 mg/dl (p < 0.05), while relative TG increase (192.8 ± 12.7%) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3-FA and also detectable in the H(2)O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3-FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16(+)CD14(high) and CD16(+)CD14(low), sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3-FA. The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. n3-FA reduce fasting TG and the postprandial TG increase. n3-FA may therefore allow to prospectively study whether selected patients benefit from TG-lowering independent of LDL- and HDL-cholesterol.
    Atherosclerosis 09/2012; 225(1):166-72. DOI:10.1016/j.atherosclerosis.2012.09.002 · 3.99 Impact Factor
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    ABSTRACT: AimsRecurrent stroke is a frequent and disabling event. A high heart rate is associated with cardiovascular outcomes. We investigated the effects of the resting heart rate on cardiovascular and neurological outcomes after recurrent stroke in the high-risk population of the PRoFESS study.Methods and resultsA total of 20 165 patients after ischaemic stroke (mean age 66.1, SD 8.6 years) assigned to the treatment arms of the PRoFESS trial were pooled divided by quintiles of the baseline heart rate and analysed according to cardiovascular and functional outcomes after stroke: recurrent stroke and major cardiovascular outcomes such as stroke, myocardial infarction, and worsening or new-onset heart failure as well as death from cardiovascular and non-cardiovascular causes. Pre-defined endpoints were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and the Barthel index at 3 months, and cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit. Patients in the two highest quintiles of heart rate (77-82 and >82 b.p.m.) were at a higher risk for total death [hazard ratio (HR) 1.42, 95% CI 1.19-1.69 and HR 1.74, 95% CI 1.48-2.06, P < 0.0001] compared with the lowest quintile. Similar results were observed for vascular death [71-≤76 b.p.m., HR 1.39 (1.11-1.74), P < 0.0001] and non-vascular death [from >82 b.p.m., HR 1.66 (1.29-2.13), P = 0.0016]. Myocardial infarction (P = 0.7084) and recurrent stroke (P = 0.1379) were not significantly associated with the baseline heart rate. Hazard ratios were adjusted to multiple confounders including the baseline blood pressure. In the group of patients with a recurrent stroke, an association of a lower heart rate to better outcomes was measured with the Barthel index across all heart rate groups. In addition, there was a significant association of the baseline heart rate to the occurrence of significant cognitive decline according to an MMSE score ≤24 points at 1 month and at the penultimate visit or a decline of ≥2 points between these two time periods. Better independence score at a low heart rate were observed.Conclusion The heart rate is a risk indicator for mortality in patients with stroke and, importantly, a low heart rate is associated with a better functional outcome and less cognitive decline after an ischaemic stroke.Trial registration: ClinicalTrials.gov, number NTC00153062.
    European Heart Journal 08/2012; 33(22). DOI:10.1093/eurheartj/ehs250 · 15.20 Impact Factor
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    ABSTRACT: AimsIn diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by I(f)-inhibition in this HFPEF-model.Methods and resultsControl mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the I(f)-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (E(es)) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered E(es) (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva.Conclusion In db/db, a model of HFPEF, selective HR reduction by I(f)-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, I(f)-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.
    European Heart Journal 07/2012; 34(36). DOI:10.1093/eurheartj/ehs218 · 15.20 Impact Factor
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    ABSTRACT: Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE(-)/(-)) mice. ApoE(-)/(-) mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Ivabradine reduced heart rate by 113 ± 31 bpm (~19%) in WT mice and by 133 ± 6 bpm (~23%) in ApoE(-)/(-) mice. Compared to WT controls, ApoE(-)/(-) mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE(-)/(-) mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE(-)/(-) mice. Moreover, membrane translocation of p47(phox) was inhibited. In ApoE(-)/(-) mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. HRR by ivabradine improves vascular compliance in ApoE(-)/(-) mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.
    Journal of Vascular Research 07/2012; 49(5):432-40. DOI:10.1159/000339547 · 2.90 Impact Factor
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    ABSTRACT: A critical problem in cardiovascular MRI in small rodents is adjusting the sequence acquisition to the high heart and respiratory rates. The aim of this study was to compare a retrospectively self-gated fast low angle shot navigator (RSG-FLASH) sequence with a conventional prospectively triggered (PT-FLASH) sequence for cine imaging of the ascending aorta in mice at 9.4 T. Ten C57/BL6 mice were examined with a horizontal bore 9.4 Tesla MRI animal scanner using a dedicated 2 × 2 phased-array surface coil. We acquired a RSG-FLASH sequence (RSG-FLASH sequences (repetition time (TR) / echo time (TE) = 6.5/2.5 ms, flip angle (FA) = 10 degrees, field of view (FOV) = 2 × 2 cm, matrix = 384 × 384, slice thickness = 1 mm, 25 movie frames) perpendicular to the ascending aorta using the IntraGate technique. At the same position, we performed a PT-FLASH sequence (TR/TE = 6.5/2.1 ms, FA = 10 degrees, FOV = 2 × 2 cm, matrix = 384 × 384, slice thickness = 1 mm) in which the maximum number of movie frames had to be adjusted to the interval between two R-peaks (RR interval) of the electrocardiogram (ECG) with: number of frames = RR interval / TR." Cross-sectional vessel areas at end-systole (AES) and end-diastole (AED) were measured to determine the aortic strain (ΔA = (AES-AED)/AED). Two blinded readers rated the sequences for presence of flow and trigger artifacts and their influence on the depiction of the blood/vessel-wall interface. Irregularities in displaying the cardiac cycle and the overall suitability of the sequence for aortic strain evaluation were assessed using a 5-level ordinal scale. Statistical differences were analyzed using Student t test and Wilcoxon signed rank test (P < 0.05). Intra- and interobserver variability was evaluated using Bland-Altman analyses. No significant differences were noted between techniques regarding the measured vessel areas (AED: P = 0.07, AES: P = 0.34), ΔA: P = 0.1). Similarly, there were no significant differences in heart (P = 0.06) and respiratory (P = 0.24) rates. The acquisition time for RSG-FLASH sequence was significantly shorter (P = 0.04). Significantly fewer flow and trigger artifacts were noted by both readers with the RSG-FLASH sequence. Likewise, both readers considered the RSG-FLASH sequence to be superior for depiction of the blood/vessel-wall interface. The RSG-FLASH sequence was also rated superior regarding irregularities in displaying the cardiac cycle and in terms of overall suitability for evaluation of AED, AES, and aortic strain (P < 0.05 each). RSG-FLASH is preferable for cine imaging of the aorta. It provides the same quantitative data as PT-FLASH cine imaging but is less prone to flow and trigger artifacts. RSG-FLASH permits more homogeneous depiction of the cardiac cycle and is faster than the PT-FLASH sequence. PT-FLASH is more prone to misregistration of the respiratory cycle or the ECG by the external monitoring device used for acquisition. This effect may be even more pronounced in animals with disease models that are less stable in terms of heart and respiration rate during anesthesia.
    Investigative radiology 02/2012; 47(4):259-66. DOI:10.1097/RLI.0b013e31823d3eb6 · 4.44 Impact Factor
  • F Custodis ·
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    ABSTRACT: The main treatment goals of conservative treatment of patients with stable coronary heart disease are prevention of symptoms, prevention of myocardial infarction, and heart failure and reduction of mortality. Lifestyle changes (smoking cessation, physical activity) are essential to reduce risk factors. For symptomatic treatment and prevention of angina pectoris, beta-blockers, calcium channel blockers, nitrates, I((f)) (funny channel) blockers and ranolazine are effective. Cornerstones of pharmacological prevention are drugs with prognostic effects, specifically aspirin and statins, as well as treatment of co-existing disorders such as hypertension and diabetes.
    Herz 02/2012; 37(1):85-96. DOI:10.1007/s00059-011-3578-5 · 0.69 Impact Factor
  • F Custodis · J-C Reil · U Laufs · M Böhm ·
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    ABSTRACT: Resting heart rate represents a cardiovascular risk indicator and an important target of therapy in chronic heart failure and potentially in coronary artery disease. Clinical and experimental evidence suggests that sustained elevation of heart rate - independent of the underlying trigger - plays a causal role in the pathogenesis of vascular disease. Results of the SHIFT trial support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the role of heart rate as a risk factor for patients with severe left ventricular dysfunction. Results of the BEAUTIFUL trial show that patients with ischemic heart disease and a heart rate above 70 bpm exhibit an adverse prognosis concerning coronary events.
    Der Internist 11/2011; 53(1):6-13. · 0.31 Impact Factor
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    ABSTRACT: Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model. 129/SV mice were treated with glucocorticoid receptor antagonist mifepristone (25 mg kg(-1)/d) or vehicle and exposed to 28 days of chronic stress consisting of exposure to rat, restraint stress, and tail suspension. Heart rate and blood pressure were continuously recorded by telemetry. Endothelial nitric oxide synthase mRNA and protein expression as well as superoxide production and lipid hydroperoxides were quantified. Endothelium-dependent vasorelaxation was measured in aortic rings. Ischemic lesion volume was quantified after 30 minutes filamentous middle cerebral artery occlusion and 72 hours reperfusion. Chronic stress caused a significant increase in heart rate, impaired endothelium-dependent vasorelaxation, increased superoxide production, and reduced aortic and brain endothelial nitric oxide synthase levels. Animals exposed to chronic stress showed major increases in ischemic lesion size. These deleterious effects of stress were completely reversed by treatment with mifepristone. Chronic stress increases stroke vulnerability likely through endothelial dysfunction, which can be reversed by a glucocorticoid receptor antagonist.
    Stroke 09/2011; 42(11):3258-64. DOI:10.1161/STROKEAHA.110.607705 · 5.72 Impact Factor
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    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. DOI:10.1093/eurheartj/ehr255 · 15.20 Impact Factor
  • F Custodis · U Laufs ·
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    ABSTRACT: Elevated Triglyceride levels are associated with increased risk for atherosclerotic disease and additional vascular risk factors such as obesity, hypertension and impaired glucose tolerance. To estimate the individual cardiovascular risk of a patient with elevated triglycerides LDL- and HDL-cholesterol levels, concomitant diseases, composition of triglyceride rich lipoproteins and a family history for premature coronary heart disease are important. Primary goals for the management of hypertriglyceridemia are a reduction of cardiovascular risk and prevention of triglyceride associated complications such as the chylomicronemia syndrome. The basis of treatment are lifestyle changes: dietary intervention, alcohol avoidance, regular physical activity, weight loss and smoking cessation to modify risk factors. If triglyceride levels can not be sufficiently reduced by lifestyle intervention pharmacotherapy (nicotinic acid, fibrates and omega-3-acid ethyl esters) is indicated. Beyond reduction of triglyceride levels optimization of non-HDL-cholesterol by statin treatment is warranted to reduce vascular risk.
    DMW - Deutsche Medizinische Wochenschrift 07/2011; 136(30):1533-42. DOI:10.1055/s-0031-1281550 · 0.54 Impact Factor
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    ABSTRACT: Atherosclerosis is a progressive disease characterised in part by an imbalance of endothelial decline and endothelial repair. Erythropoietin has been connected to vasculoprotective effects such as enhanced nitric oxide production in endothelial cells and mobilisation of endothelial progenitor cells (EPC). To determine the effect of erythropoietin on endothelial function and EPC mobilisation in humans with atherosclerosis. A prospective single-blind monocentric study of 20 patients randomly assigned to the test drug or placebo treatment over 4 weeks. 20 Patients with stable coronary artery disease receiving optimal medical treatment with either weekly subcutaneous injections of saline (placebo) or the recombinant erythropoietin darbepoetin (60 μg/injection) over 3 consecutive weeks. At the initial and final visits, flow mediated dilatation (FMD) was determined by ultrasound. The number of EPC was determined as the number of CD34/CD133 positive mononuclear cells in peripheral blood. Treatment with darbepoetin resulted in a significantly improved FMD in each patient, whereas no difference was seen in placebo-treated patients. The FMD of darbepoetin-treated patients increased by 7.5±1.64%. Additionally, an increase in peripheral blood EPC of 50±24% was seen. Darbepoetin given in addition to optimal medical treatment resulted in a significantly improved endothelial function in patients with coronary artery disease, indicating a promising new atheroprotective treatment option.
    Heart (British Cardiac Society) 06/2011; 97(18):1474-8. DOI:10.1136/hrt.2010.220798 · 5.60 Impact Factor
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    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. DOI:10.1161/STROKEAHA.110.598607 · 5.72 Impact Factor
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    Journal of the American College of Cardiology 05/2011; 57(21):2206. DOI:10.1016/j.jacc.2011.02.024 · 16.50 Impact Factor

Publication Stats

952 Citations
234.02 Total Impact Points


  • 2006-2015
    • Universitätsklinikum des Saarlandes
      Homburg, Saarland, Germany
    • Universität des Saarlandes
      • Klinik für Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin
      Saarbrücken, Saarland, Germany
  • 2011
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany