Katrin Walenta

Intravenous Transfusion of Endothelial Progenitor Cells Reduces Neointima Formation After Vascular Injury

&NA; —Endothelial cell damage is one important pathophysiological step of atherosclerosis and restenosis after angioplasty. Accelerated reendothelialization impairs neointima formation. We evaluated the role of intravenously transfused endothelial progenitor cells (EPCs) on reendothelialization and neointima formation in a mouse model of arterial injury. Spleen‐derived mouse mononuclear cells (MNCs) were cultured in endothelial basal medium. A total of 91.8±3.2% of adherent cells showed uptake of acetylated low‐density lipoprotein (Dil‐Ac‐LDL) and lectin binding after 4 days. Immunostaining and long‐term cultures confirmed the endothelial progenitor phenotype. To determine the effect of stem cell transfusion on reendothelialization, mice received either fluorescent‐labeled spleen‐derived MNCs or in vitro differentiated EPCs intravenously after endothelial injury of the carotid artery. Transfused cells were strictly restricted to the injury site, and lectin binding confirmed the endothelial phenotype. Homing of transfused cells to the site of injury was only detectable in splenectomized mice. Cell transfusion caused enhanced reendothelialization associated with a reduction of neointima formation. Systemically applied spleen‐derived MNCs and EPCs home to the site of vascular injury, resulting in an enhanced reendothelialization associated with decreased neointima formation. These results allow novel insights in stem cell biology and provide additional information for the treatment of vascular dysfunction and prevention of restenosis after angioplasty. The full text of this article is available online at http://www.circresaha.org. (Circ Res. 2003;93:e17‐e24.)

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.

Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes

AIMS CD31+/Annexin V+ microparticles (MPs) are increased in patients with cardiovascular risk factors and impaired coronary endothelial function. We evaluated whether MPs are an independent marker for cardiovascular events in patients with stable coronary artery disease (CAD). METHODS AND RESULTS The number of CD31+/Annexin V+ MP was determined by flow cytometry in 200 patients (age 66.1±10.4 years) and correlated with cardiovascular outcomes. The median follow-up time for major adverse cardiovascular and cerebral event (MACCE)-free survival was 6.1 (6.0/6.4) years. Four patients were lost to follow-up. A first MACCE occurred in 72 patients (37%). Microparticle levels were significantly higher in patients with MACCE compared with patients without event (P=0.004). The prevalence of diabetes (P=0.02) and male gender (P=0.05) was significantly related to the MP level. In multivariate analysis (cardiovascular risk factors, number of diseased vessels, use of angiotensin-converting enzyme-inhibitors and statins), high MP levels were associated with a higher risk for cardiovascular death [Hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.1-14.6; P=0.04], the need for revascularization (HR 2.4, 95% CI 1.3-4.4; P=0.005), and the occurrence of a first MACCE (HR 2.3, 95% CI 1.4-3.8; P=0.001). Inclusion of the MP level into a classical risk factor model substantially increased c-statistics from 0.637 (95% CI: 0.557-0.717) to 0.702 (95% CI: 0.625-0.780) (P=0.03). CONCLUSION The level of circulating CD31+/Annexin V+ MPs is an independent predictor of cardiovascular events in stable CAD patients and may be useful for risk stratification.

Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease

Endothelial progenitor cells (EPC) predict morbidity and mortality in patients at cardiovascular risk.Patients with low EPC counts and impaired endothelial colony forming activity have a higher incidence for cardiovascular events compared to patients with high EPC counts and favorable colony forming activity. The pathophysiological basis for this finding may be an insufficient endothelial cell repair by EPC.We postulate that EPC influence coronary endothelial function which itself is relevant for the outcome of patients at cardiovascular risk. To test this hypothesis in humans, endothelial function was invasively assessed in 90 patients with coronary heart disease by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry of mononuclear cells isolated from peripheral blood was performed to assess CD133+ or CD34+/KDR+ EPC. EPC function was assessed ex vivo by determination of endothelial colony forming units. Low EPC number as well as impaired endothelial colony forming activity correlated with severely impaired coronary endothelial function in univariate analysis. Multivariate analysis revealed that only the number of EPC predicts severe endothelial dysfunction independent of classical cardiovascular risk factors. Endothelial function closely correlates with the number of circulating EPC providing new mechanistic insights and options for risk assessment in patients with coronary heart disease.

Cognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair‐HF) study

The objective of this study was to examine cognitive and psychological processes systematically in patients with decompensated chronic heart failure (CHF) and to document changes in cognitive function after compensation. Executive functions, episodic memory, and attention are impaired in patients with stable CHF, influencing health behaviour and disease management. Cognitive function and psychological co‐morbidities are associated with hospitalization, disability, and mortality.

Circulating microparticles as indicators of peripartum cardiomyopathy

AIMS Peripartum cardiomyopathy (PPCM) is associated with high mortality and morbidity. Endothelial damage involving cathepsin-D to form a 16 kDa prolactin (PRL) peptide is pathogenetically relevant. Inhibiting PRL peptide with bromocriptine has yielded promising results. We investigated whether microparticles (MPs) can be quantified in serum as markers for diagnosis and treatment effects in PPCM. METHODS AND RESULTS Patients with PPCM were compared with age-matched healthy post-partum women (PPCTR), healthy pregnant women (PCTR), healthy non-pregnant women (NPCTR), patients with ischaemic cardiomyopathy (ICM), patients with stable coronary artery disease (CAD) and healthy controls (HCTR). Peripartum cardiomyopathy treated with bromocriptine (PPCM-BR) and with PPCM without bromocriptine-treatment as control (PPCM-BRCTR) were compared. Microparticles were determined by flow cytometry. Endothelial MPs (EMPs) were elevated in PPCM compared with PPCTR, PCTR, and NPCTR, each P< 0.001. They were significantly elevated compared with ICM, CAD, and HCTR (P< 0.001). Pregnancy (PCTR) exhibited only slight increases vs. ICM, CAD, NPCTR, and HCTR. The increase in PPCM was due to an increase of activated but not apoptotic EMPs. Platelet-derived microparticles were highly increased in PPCM compared with ICM (P< 0.001) but 9.3 ± 4.4-fold compared with CAD (P< 0.001). In NPCTR (P< 0.001) compared with NPCTR, the increase was 5.9 ± 1.7-fold (P< 0.001). Microparticles generated from monocytes (MMPs) were increased 2.4 ± 1.8-fold in PPCM compared with PCTR (P< 0.001) and 4.8 ± 3.6-fold compared with CAD (P< 0.001), whereas leucocyte MPs (LMPs) were not significantly elevated. Endothelial microparticles were significantly reduced in PPCM treated additionally with bromocriptine compared with PPCM treated only with heart failure therapy (P< 0.001). CONCLUSION Microparticle profiles may in long-term distinguish PPCM from normal pregnancy, heart failure, and vascular diseases and might be a diagnostic marker related to the pathomechanism of PPCM.

Hotline update of clinical trials and registries presented at the German Cardiac Society Meeting 2009

This review article gives an overview on a number of novel clinical trials and registries in the field of cardiovascular medicine. Key presentations made at the 75th annual meeting of the German Cardiac Society, held in Mannheim, Germany, in April 2009 are reported. The data were presented by leading experts in the field with relevant positions in the trials and registries. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine similar as previously reported (Rosenkranz et al. in Clin Res Cardiol 96:457–468, 9; Maier et al. in Clin Res Cardiol 97:356–363, 3).

Integrin-linked kinase is a central mediator in angiotensin II type 1- and chemokine receptor CXCR4 signaling in myocardial hypertrophy.

Inflammation and pro-hypertrophic signaling are important for development and progression of myocardial hypertrophy (LVH) and chronic heart failure (CHF). Here we investigated the relevance of integrin-linked kinase (ILK) for chemokine receptor CXCR4- and angiotensin II type 1-triggered signaling and its regulation and role in cardiac remodeling. Using ELISA, real-time-PCR, and Western blotting, the present study demonstrates that SDF-1 and its receptor CXCR4 are up-regulated in plasma and left ventricles, respectively, in mouse models of cardiac hypertrophy (transaortic constriction, transgenic cardiac-specific overexpression of rac1) and in human CHF in association with increased cardiac ILK-expression. In isolated cardiomyocytes, ILK is activated by CXCR4-ligation and necessary for SDF-1-triggered activation of rac1, NAD(P)H oxidase, and release of reactive oxygen species. Importantly, the pro-hypertrophic peptide angiotensin II induces ILK-activation dependent on rac1 in cardiomyocytes, where ILK is necessary for angiotensin II-mediated stimulation of hypertrophy genes and protein synthesis. We conclude that in both SDF-1- and angiotensin II-triggered signaling, ILK is a central mediator of rac1-induced oxidative stress and myocardial hypertrophy.

Differential chemokine receptor expression regulates functional specialization of endothelial progenitor cell subpopulations

Postnatal vasculogenesis is mediated by endothelial progenitor cells (EPCs) which consist of subpopulations with different functional capacities. Our goal was to profile chemokine receptor expression on relevant subsets of EPCs and to characterize their role for effector functions. CD34+/CD133+/VEGFR2+ EPCs were characterized by high expression of chemokine receptors CXCR4, CX3CR1, BLT1, and low level expression of CXCR2 and CCR2, while primordial CD34−/CD133+/VEGFR2+ EPCs express these chemokine receptors at comparably low levels. Migration assays revealed that SDF-1, fractalkine, and LTB4 significantly increase migration of CD34−/CD133+/VEGFR2+ EPCs, while SDF-1 was the only potent agonist of migration of CD34+/CD133+/VEGFR2+ EPCs. SDF-1, fractalkine, and LTB4 trigger significant increase adhesion of CD34+/CD133+/VEGFR2+ EPCs, while in CD34−/CD133+/VEGFR2+ EPCs SDF-1 and fractalkine are equipotent agonists and LTB4 triggers a smaller though still significant increase in adhesion. Differential expression of specific chemokine receptors is an important regulator in terms of migration and adhesion of biologically relevant EPC-subpopulations, which may have implications for cell therapeutic strategies for treatment of ischemic vascular disease.

Hotline update of clinical trials and registries presented at the American College of Cardiology Congress 2011

This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update Sessions during the Late Breaking Clinical Trial Sessions at the 60th annual meeting of the American College of Cardiology in New Orleans, USA, from 2nd April to 5th April 2011. This article gives an overview on a number of novel clinical trials in the field of cardiovascular medicine, which were presented. The comprehensive summaries have been generated from the oral presentation and the webcasts of the American College of Cardiology, similar as previousely reported (Gensch et al. Clin Res Cardiol 100:1–9, 2011; Lenski et al. Clin Res Cardiol 99:679–692, 2010) and should provide the readers with the most comprehensive information of relevant publications. The data were presented by leading experts in the field with relevant positions in the trials.