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Georg Nickenig

Publications and source records attributed to Georg Nickenig.

At least 19 recordsLinked to original sources
PubMed2025

Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

IMPORTANCE: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. OBJECTIVE: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. DESIGN, SETTING, AND PARTICIPANTS: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. EXPOSURES: Genetic variants. MAIN OUTCOMES AND MEASURES: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. RESULTS: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. CONCLUSIONS AND RELEVANCE: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

Humans↗
PubMed2006

Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome.

AIMS: HMG-CoA reductase inhibitors (statins) reduce cardiovascular mortality and morbidity in patients with stable coronary artery disease as well as acute coronary syndrome (ACS). It is unclear how rapidly the beneficial effects of statins occur in patients with ACS and whether these drug properties are related to lipid lowering. METHODS AND RESULTS: Patients with troponin-positive ACS (n=35) were randomized to 20 mg/day rosuvastatin therapy or to placebo treatment. Anti-inflammatory effects of rosuvastatin measured by lymphocyte intracellular cytokine production were taken before initiation of treatment and on days 1, 3, and 42. Compared with placebo, rosuvastatin treatment significantly reduced plasma concentrations of pro-inflammatory cytokines TNF-alpha and IFN-gamma at 72 h. Rosuvastatin also induced a rapid and significant reduction of TNF-alpha and IFN-gamma production in stimulated T-lymphocytes at 72 h. When compared with placebo, rosuvastatin inhibited the Th-1-immune response measured at 72 h. CONCLUSION: Rosuvastatin exerts rapid immunomodulatory effects on the level of T-cell activation in patients with ACS.

Aged↗
PubMed2006

Improvement of endothelial function by systemic transfusion of vascular progenitor cells.

Endothelial dysfunction is characterized by abnormalities in vasoreactivity and is a marker of the extent of atherosclerosis. Cellular repair by circulating progenitor cells of ongoing vascular injury may be essential for vascular integrity and function and may limit abnormalities in vasoreactivity. Apolipoprotein E-deficient (apoE-/-) mice were splenectomized and treated with high-cholesterol diet for 5 weeks, resulting in marked impairment of endothelium-dependent vasodilation of aortic segments as compared with wild-type mice. Intravenous transfusion of 2x10(7) spleen-derived mononuclear cells (MNCs) isolated from wild-type mice on 3 consecutive days restored endothelium-dependent vasodilation in the apoE-/- mice, as measured 7, 14, and 45 days after transfusion. Histological analyses of aortic tissue identified fluorescent-labeled, exogenously applied progenitor cells that expressed the endothelial cell marker CD31 in the endothelial cell layer of atherosclerotic lesions. Progenitor cell treatment led to increased vascular nitric oxide synthase activity. Transfusion of either in vitro-differentiated Dil-Ac-LDL/lectin-positive endothelial progenitor cells, CD11b-positive (monocyte marker), CD45R-positive (B-cell marker), or Sca-1-positive (stem cell marker) MNC subpopulations significantly improved endothelium-dependent vasodilation, although these treatments were not as effective as transfusion of total MNCs. Depletion of MNCs of either CD11b-positive, CD45R-positive, or Sca-1-positive cells resulted in significant attenuation of endothelium-dependent vasodilation as compared with nondepleted MNCs; however, vasoreactivity was still significantly improved as compared with saline-treated apoE-/- mice. Intravenous transfusion of spleen-derived MNCs improves endothelium-dependent vasodilation in atherosclerotic apoE-/- mice, indicating an important role of circulating progenitor cells for the repair of ongoing vascular injury. More than 1 subpopulation of the MNC fraction seems to be involved in this effect.

Animals↗
PubMed2006

Tracking of systemically administered mononuclear cells in the ischemic brain by high-field magnetic resonance imaging.

This study was designed to track systemically administered mononuclear cells (MNCs) in the ischemic mouse brain using 7 T magnetic resonance imaging (MRI). Splenectomized wild-type mice were subjected to brain ischemia by 30 or 60 min filamentous occlusion of the middle cerebral artery (MCAo) and reperfusion. Spleen-derived MNCs were labeled with very small superparamagnetic iron-oxide particles (VSOP) and transfused into recipient mice 30 min, 8 h, or 24 h after MCAo via the tail vein. High-resolution MRI sequences were designed to monitor the dynamics of brain ischemia and to observe the migration and engraftment of transfused cells into the ischemic brain. T2*-weighted (gradient-echo) hypointense signal changes became apparent at 24-48 h after transfusion, were typically associated with the ischemic lesion border, and could be followed up to 5 weeks after the insult. Such presumed MNC-associated signal changes in MRI were confirmed by histochemical detection of iron (Prussian blue staining) and detection of constitutively expressed green fluorescent protein (GFP) in a subset of animals transfused with MNCs derived from GFP transgenic mice. Taken together, our results demonstrate that brain engraftment of systemically administered mononuclear cells can be visualized non-invasively over time and space using high-resolution MRI.

Animals↗
PubMed2006

Role of integrin-linked kinase in vascular smooth muscle cells: regulation by statins and angiotensin II.

Our goal was to characterize the role of integrin-linked kinase (ILK) in vascular smooth muscle cells (VSMC), which play a crucial role in atherogenesis. Transfection of VSMC with wild-type and dominant-negative ILK cDNA constructs revealed that ILK mediates migration and proliferation of VSMC but has no effect on VSMC survival. The pro-atherogenic mediator angiotensin II increases ILK protein expression and kinase activity while statin treatment down-regulates ILK in VSMC. Functionally, ILK is necessary for angiotensin II-mediated VSMC migration and proliferation. In VSMC transduced with dominant-negative ILK, statins mediate an additive inhibition of VSMC migration and proliferation, while transfection with wild-type ILK is sufficient to overcome the inhibitory effects of statin treatment on VSMC migration and proliferation. In vivo, ILK is expressed in VSMC of aortic sections from wild-type mice where it is down-regulated following statin treatment and up-regulated following induction of atherosclerosis in apoE-/- mice. These data identify ILK as a novel target in VSMC for anti-atherosclerotic therapy.

Angiotensin II↗
PubMed2006

Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease.

AIMS: The aim of the study was to determine the influence of endothelial progenitor cells (EPC) on erectile dysfunction (ED). EPC play a major role in repair mechanisms of the endothelial monolayer, but the role of EPC in ED is unclear. METHODS AND RESULTS: Circulating levels of CD34(+)/KDR(+) and CD133(+) EPC were determined in 119 patients with known coronary artery disease. ED was evaluated with an ED-score generated from the KEED questionnaire. Prevalence of ED was 59.7%. In univariate analysis, age, hypertension, reduced left ventricular ejection fraction (LVEF), diabetes, and circulating levels of CD133(+) EPC, but not cardiovascular drug treatment were associated with ED. Body mass index (BMI) was positively (r = 0.319, P=0.003) and high-density lipoprotein was negatively (r=-0.246, P=0.034) correlated with ED. Adjustment for age, diabetes, hypertension, BMI, smoking, LVEF, use of statins and lower urinary tract symptoms, and prior coronary intervention revealed low levels of circulating immature CD133(+) EPC as independent risk factor for ED (95% CI -11.183 to -1.7371, P=0.008). CONCLUSION: Reduced levels of circulating CD133(+) EPC are an independent risk factor for ED. Thus, EPC may be a link between cardiovascular risk factors, endothelial dysfunction, and ED.

Adult↗
PubMed2006

Identification of "substrate fibrillators" and "trigger fibrillators" by pacemaker diagnostics.

BACKGROUND: The population of patients likely to respond to selected pacing algorithms for maintenance of sinus rhythm is unknown. OBJECTIVES: The purpose of this study was to identify patients with specific onset patterns of paroxysmal atrial fibrillation (AF). METHODS: Dual-chamber pacemakers with advanced diagnostic functions were implanted in 112 patients with conventional indications for antibradycardia pacing and a history of paroxysmal AF. Pacemaker diagnostic data were analyzed after 97.5 +/- 40.9 days. According to the frequency of premature atrial contractions (PACs) during the 5 minutes before AF onset, patients were assigned to one of three groups: group A (high PAC activity), group B (moderate PAC activity), or group C (low PAC activity). RESULTS: AF burden was lower in group A (4.6% +/- 2.4%) than group B (15.8% +/- 3.0%, P = .003) and group C (15.5% +/- 3.1%, P = .003). Fewer AF episodes occurred in group A (2.1 +/- 1.3 per day) than group B (3.8 +/- 1.2 per day, P = .006). Mean AF episode duration was shorter in group A (11.4 +/- 10.2 hours) than group C (41.4 +/- 27.5 hours, P = .03). CONCLUSION: The coincidence of low PAC activity before AF onset, high AF burden, and extended arrhythmia episode duration appears to be the consequence of a high atrial substrate factor. In these "substrate fibrillators," the efficacy of pacing algorithms for maintenance of sinus rhythm may be limited. In contrast, "trigger fibrillators" exhibiting low AF burden despite high PAC incidence may represent the target population for specific PAC-suppressing pacing algorithms.

Aged↗
PubMed2006

Differential antiplatelet effects of angiotensin converting enzyme inhibitors: comparison of ex vivo platelet aggregation in cardiovascular patients with ramipril, captopril and enalapril.

BACKGROUND: Increasing evidence suggests that angiotensin converting enzyme (ACE) inhibitors exert antithrombotic effects. Based on the assumption of differential effects of various ACE inhibitors on coagulation, the aim of the present study was to evaluate the coagulative activities of cardiovascular (CV) patients treated with either ramipril, captopril, and enalapril, and to compare these with patients treated with established antithrombotics such as aspirin (ASA) and clopidogrel or none of these medication. METHODS: Blood samples of 320 CV patients with coronary artery disease and/or arterial hypertension were analyzed by wholeblood aggregometry. Platelet aggregation was determined by measuring the increase in impedance across paired electrodes in response to the aggregatory agents collagen and adenosine diphosphate (ADP), respectively. These data were correlated with medical treatment. RESULTS: Platelet aggregation was attenuated ex vivo by ramipril and captopril as well as by ASA and clopidogrel. While collagen-induced platelet aggregation was significantly reduced by ramipril (35%; P <0.01) and captopril (27%; P = 0.01), no change was seen with enalapril. After induction with ADP, platelet aggregation was reduced in the presence of captopril therapy by 46% (P <0.05). There was a trend of inhibition with ramipril (32%, P = n.s.), whereas no antithrombotic effect was seen with enalapril. CONCLUSION: Our findings demonstrate that ACE inhibitors decrease platelet aggregation ex vivo. The differential antiaggregatory profile may explain at least in part different effects of ACE inhibitors on cardiovascular endpoints as observed in large clinical trials.

Adenosine Diphosphate↗
PubMed2006

CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities.

Our goal was to identify functionally important subpopulations within the heterogenous group of endothelial progenitor cells (EPC). Fluorescence-activated cell sorter analysis of CD133+ progenitor cells revealed the presence of CD34+ and CD34- subpopulations. CD34-/133+ progenitors differentiate into CD34+/133+ EPC, adhere more potently than these in response to SDF-1, and rapidly home to sites of limb ischemia in human volunteers. In human coronary atherectomy samples, fewer CD34-/133+ than CD34+/133+ EPC are present in stable plaques, whereas cell numbers increase with a reversion of the ratio in unstable lesions. In CD34-/133+ EPC-injected nude mice, more transplanted cells coexpressing endothelial markers home to carotid artery lesion endothelium than in CD34+/133+-injected mice. In the former, lesions were smaller and reendothelialization higher than in the latter. We identified a new CD34-/133+ EPC subpopulation, which is apparently a precursor of "classical" CD34+/133+ EPC, and functionally more potent than these with respect to homing and vascular repair.

AC133 Antigen↗
PubMed2006

AT1 receptor antagonism improves endothelial dysfunction in postmenopausal women.

The menopause is associated with an increased incidence of atherosclerotic disease. Estrogen deficiency causes AT1 receptor overexpression which is involved in the development of vascular dysfunction. The effect of a 6 week-treatment with the AT1 receptor antagonist candesartan (16 mg/d) on endothelium-dependent vasorelaxation was compared to the treatment with placebo or the calcium channel antagonist felodipine (5 mg/d) in 29 postmenopausal women in the absence or presence of hormone replacement therapy (HRT) in a prospective, double-blind, randomized cross-over study. Endothelial function was assessed by measurement of forearm blood flow (FBF) by venous occlusion plethysmography. FBF during reactive hyperemia was significantly improved by candesartan in patients without HRT (hyperemic peak flow and area under the FBF curve), whereas felodipine and placebo exerted no effect. In patients with HRT, no treatment regimen showed a significant effect on endothelial function. Nitroglycerin-induced vasorelaxation and basal FBF were not significantly altered in all groups. AT1 receptor antagonism improves vascular function in postmenopausal women without HRT. Thus, AT1 receptor blockade may resemble an efficient approach for the prevention of vascular dysfunction in estrogen-deficient women.

Aged↗
PubMed2006

Regulation of antioxidant and oxidant enzymes in vascular cells and implications for vascular disease.

Data from numerous studies demonstrate that oxidative stress plays an important role in the pathogenesis of vascular disease. Oxidative stress leads to many pathologic events, such as inactivation of nitric oxide, lipid oxidation, enhanced mitogenicity and apoptosis of vascular cells, and increased expression and activation of redox-sensitive genes, which contribute to atherogenesis at all stages of the disease. Multiple enzymes are expressed in vascular cells that are involved in the elimination and production of reactive oxygen species, including the superoxide dismutases, catalase, thioredoxin reductase, glutathione peroxidase, NAD(P)H oxidase, xanthine oxidase, myeloperoxidase, and endothelial nitric oxide synthase. Several agonists and pathologic conditions that predispose to vascular disease induce changes in the expression and activity levels of these antioxidant and oxidant enzyme systems, leading to modulation of vascular oxygen radical load. Identification of key enzymes and mechanisms of vascular oxidative stress is important for the development of novel, specific pharmacologic interventions.

Animals↗
PubMed2006

Pathophysiological regulation of the AT1-receptor and implications for vascular disease.

BACKGROUND: Numerous studies have demonstrated that activation of the angiotensin II type 1 (AT1) receptor plays an important role in the pathogenesis of cardiovascular diseases. RESULTS: AT1-receptor activation by angiotensin II is not only involved in the regulation of blood pressure, water and sodium homeostasis, and control of other neurohumoral systems, but also leads to excessive production of reactive oxygen species and to hypertrophy, proliferation, migration, and apoptosis of vascular cells. AT1-receptor-induced oxidative stress may cause nitric oxide inactivation, lipid oxidation, and activation of redox-sensitive genes, such as chemotaxis and adhesion molecules, pro-inflammatory cytokines, and matrix metalloproteinases, all of which are involved in the initiation and progression of endothelial dysfunction and manifested atherosclerosis. The expression levels of the AT1-receptor define the biological efficacy of angiotensin II. Many agonists, such as, for example, angiotensin II, growth factors, low-density lipoprotein cholesterol, insulin, glucose, estrogen, progesterone, reactive oxygen species, cytokines, nitric oxide, and many others, are known to regulate AT1-receptor expression in vascular cells. The pathophysiological relevance of dysregulated AT1-receptor expression has been demonstrated in many cell culture and animal studies and interventional trials in humans. Hypercholesterolemia, estrogen deficiency, and diabetes mellitus are associated with enhanced vascular AT1-receptor expression, increased oxidative stress, and endothelial dysfunction. Importantly, treatment with AT1-receptor blockers may inhibit the onset and progression of vascular oxidative stress and inflammation, endothelial dysfunction, atherosclerosis, and related organ damage. CONCLUSION: Inhibition of AT1-receptor activation is presumably a primary treatment goal in patients suffering from cardiovascular risk factors or manifested atherosclerotic diseases.

Angiotensin II↗
PubMed2006

Telmisartan inhibits beta2-integrin MAC-1 expression in human T-lymphocytes.

OBJECTIVE: The pathogenesis of atherosclerosis, a chronic inflammatory disease, is influenced by the renin-angiotensin system and especially by angiotensin II subtype 1 (AT1) receptor activation. Although pro-inflammatory properties of angiotensin II as well as anti-inflammatory effects of AT1 receptor antagonists are well known, the underlying mechanisms are poorly understood. METHOD AND RESULTS: In a prospective double-blind study, patients with hypertension and coronary artery disease were treated with either 40 mg telmisartan (n = 21) or placebo (n = 21) for 12 weeks. General markers of inflammation, such as high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), and cell adhesion molecules, such as soluble intercellular adhesion molecule (s-ICAM-1) and the leucocyte adhesion molecule soluble-L-selectin (sL-selectin), as well as the lymphocytic expression of the beta2 integrin MAC-1, were assessed before and after treatment. Telmisartan therapy significantly decreased the lymphocyte beta2 integrin MAC-1 expression, whereas hs-CRP, IL-6, s-ICAM and sL-selectin remained unaltered. In-vitro experiments were conducted to clarify the mode of action. Cultured human lymphocytes were stimulated with either angiotensin II or phorbol-12-myristate-13-acetate (PMA)/ionomycin, alone or after pretreatment with telmisartan. Whereas angiotensin II exerted no effect on beta2-integrin MAC-1 expression in lymphocytes, telmisartan dose-dependently inhibited beta2-integrin expression in lymphocytes in the absence or presence of angiotensin II. CONCLUSION: The AT1 receptor antagonist telmisartan inhibits the expression of the pro-inflammatory beta2-integrin MAC-1 expression in lymphocytes independently of angiotensin II, suggesting an AT1 receptor-independent atheroprotective effect of this AT1 receptor antagonist.

Aged↗
PubMed2006

Paroxysmal atrial flutter caused by cardiac lymphoma.

Atrial flutter is a relatively frequent macro-reentrant tachycardia that can be caused by a variety of structural and functional atrial changes. Cardiac lymphoma is rare and usually carries a poor prognosis. It preferentially involves the right atrium. This report describes a patient with cardiac follicular B-cell lymphoma who developed paroxysmal atrial flutter. The large tumor mass created a macroscopic substrate for an area of slow conduction which is essential for atrial flutter. It also caused sinus arrest and intermittent obstruction of the tricuspid valve inlet.

Aged↗
PubMed2006

Is the degeneration of aortic valve bioprostheses similar to that of native aortic valves? Insights into valvular pathology.

Aortic stenosis (AS) is the most common valvular disease requiring valve replacement with a prevalence of 2-4% in adults greater than or equal to 65 years of age. There is increasing evidence that AS is an active inflammatory process that is highly regulated, displaying multiple hallmarks of atherosclerosis. Clinically, the definite therapy of advanced AS is prosthetic valve replacement. Herein, bioprosthetic tissue valves (BPs) possess superior thromboresistant and hemodynamic properties compared with mechanical valves. However, cusp degeneration and calcification also limit their long-term outcome. The pathogenesis of BP calcification as well as that of native valves is still poorly understood. Recent studies suggest a similar valvular pathology, that underlies both types of valvular degeneration, but also an even more important role of inflammatory and repair processes in the case of BP degeneration.

Aortic Valve↗
PubMed2006

Essential role of bone marrow fibroblast growth factor-2 in the effect of estradiol on reendothelialization and endothelial progenitor cell mobilization.

17beta-Estradiol (E2) accelerates reendothelialization and increases the number of circulating endothelial progenitor cells (EPCs), but whether fibroblast growth factor-2 (FGF2) is involved in these processes remains unknown. Here we explored the role of FGF2 in the effect of E2 on reendothelialization and EPC levels in a mouse model. As previously reported, E2 increased both the velocity of reendothelialization and the number of circulating EPCs in ovariectomized wild-type (Fgf2+/+) mice. In contrast, the effect of E2 on both parameters was abolished in FGF2-deficient mice (Fgf2-/-), demonstrating that FGF2 is absolutely required for these effects of E2. To test the implication of medullary and extramedullary FGF2, we developed chimeric mice by grafting Fgf2-/- bone marrow to Fgf2+/+ [Fgf2-/- bone marrow (BM) = > Fgf2+/+] mice and observed that the effect of E2 on both reendothelialization and EPC levels was abolished. In contrast, both effects of E2 in Fgf2+/+BM = >Fgf2-/- mice were similar to those observed in Fgf2+/+ mice, demonstrating that only BM-derived, but not extramedullary, FGF2 is required for both effects. Interestingly, E2 was found to markedly increase both FGF2(lmw) and FGF2(hmw) in bone marrow. In conclusion, FGF2, specifically medullary FGF2, is necessary and sufficient to mediate the accelerative effect of E2 on both reendothelialization and EPC mobilization.

Animals↗
PubMed2006

Clinical evidence for the cardiovascular benefits of angiotensin receptor blockers.

Targeting the renin-angiotensin-aldosterone system (RAAS), specifically the effector peptide angiotensin II (Ang II), represents a major opportunity for slowing the progression of cardiovascular disease (CVD) and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE) and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors (ACE-Is) in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough. By blocking Ang II at the AT1 receptor level, Ang II receptor blockers (ARBs) provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but mat also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor). Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.

Angiotensin II↗