Impact of a telemonitoring intervention in patients with chronic heart failure in Germany: A difference-in-difference matching approach using real-world data.

INTRODUCTION: The aim of this study was to evaluate the effects of a non-invasive telemonitoring intervention on mortality, healthcare costs, and hospital and pharmaceutical utilisation in patients with chronic heart failure (CHF) of a large statutory health insurer in Germany. METHODS: In a retrospective observational cohort study using real-world data, we assessed differences between 635 patients who received a telemonitoring intervention versus 635 receiving usual care covering 36 months after intervention. We used propensity score matching on a set of 102 parameters collected in the 24-month pre-intervention period to correct for observed differences, as well as difference-in-difference (DiD) estimators to account for unobserved differences. We analysed the effect of the intervention for up to three years on (i) all-cause mortality; (ii) costs (i.e. inpatient stays, ambulatory care, pharmaceuticals, and medical aids and appliances); and (iii) healthcare utilisation (i.e. length and number of hospital stays, number of prescriptions). RESULTS: DiD estimates suggest lower inpatient costs of the telemonitoring group of up to €1160 (95% confidence interval (CI): -2253 to -69) in year three. Ambulatory care costs increased significantly in all three years up to €316 (95% CI: 1267 to 505) per year. Telemonitoring had a positive effect on survival (hazard ratio = 0.71; 95% CI: 0.51 to 0.99) and increased the number of prescriptions for diuretics. Effects were more prominent for patients with severe CHF. DISCUSSION: The study suggests that the telemonitoring intervention led to a significant decrease in mortality and a shift in costs from the inpatient to the ambulatory care sector 36 months after intervention.

Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+ subpopulations and cardiac repair.

SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia. PH inhibition with 500 µM DMOG induced upregulation of SDF-1 mRNA in human microvascular endothelial cells (HMEC-1) and aortic vascular smooth muscle cells (HAVSMC). CXCR4 was highly elevated in HMEC-1 but almost no detectable in HAVSMC. In vivo, systemic administration of the PH inhibitor DMOG without pretreatment upregulated nuclear HIF-1α and SDF-1 in the ischemic mouse heart associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ cell subsets. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+ CD11b+/CD206+ cells compared to inflammatory M2-like CXCR4-EGFP+ CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size, and an improved heart function after MI. In summary, our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. KEY MESSAGES: DMOG-induced prolyl-hydroxylase inhibition upregulates SDF-1 and CXCR4 in human endothelial cells. Systemic application of DMOG upregulates nuclear HIF-1α and SDF-1 in vivo. Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells. DMOG increased reparative M2-like CD11b+/CD206+ cells compared to M1-like cells after MI. Enhanced prolyl-hydroxylase inhibition improved cardiac repair and heart function.

Gliptins and their target dipeptidyl peptidase 4: implications for the treatment of vascular disease.

Gliptins are accepted as a standard therapy for diabetes mellitus today. By inhibition of the enzyme dipeptidyl peptidase 4 (DPP4), gliptins prolong the GLP1-dependent insulin secretion in the pancreatic ß-cells and thus support physiological blood glucose control. Various studies have now raised hope for an additional protective effect of pharmacological DPP4 inhibition in vascular diseases. Besides GLP1, especially, the inhibition of SDF1 cleavage has been shown to depict a relevant mechanism to enhance endothelial regeneration and reduce atherosclerosis progression via the SDF1-CXCR4 axis. Furthermore, several clinical trials have now shown an excellent safety profile of gliptin therapy in cardiovascular risk patients. In this review, we give a comprehensive overview on DPP4-dependent vascular functions and pathophysiological mechanisms with a detailed discussion of the underlying molecular mechanisms. We further analyse the role of pharmacological DPP4 inhibitors and their potential therapeutic impact on endothelial function and regeneration besides their effect during atherosclerosis development. Finally, we discuss presently available data from in vitro and in vivo studies with respect to the results of the recent clinical trials in diabetic and non-diabetic patients.

Combined therapy with sitagliptin plus granulocyte-colony stimulating factor in patients with acute myocardial infarction - Long-term results of the SITAGRAMI trial.

BACKGROUND: Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. METHODS: In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. RESULTS: The median [IQR] follow-up duration was 4.50 [3.56-5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28-1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48-1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). CONCLUSION: These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI.

FDG-PET reveals improved cardiac regeneration and attenuated adverse remodelling following Sitagliptin + G-CSF therapy after acute myocardial infarction.

AIMS: Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1α/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET). METHODS AND RESULTS: AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice (n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo (n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice (n = 12 in both groups). CONCLUSION: Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI.

Cardiac index after acute ST-segment elevation myocardial infarction measured with phase-contrast cardiac magnetic resonance imaging.

OBJECTIVES: Phase-contrast CMR (PC-CMR) might provide a fast and robust non-invasive determination of left ventricular function in patients after ST-segment elevation myocardial infarction (STEMI). METHODS: Cine sequences in the left-ventricular (LV) short-axis and free-breathing, retrospectively gated PC-CMR were performed in 90 patients with first acute STEMI and 15 healthy volunteers. Inter- and intra-observer agreement was determined. The correlations of clinical variables (age, gender, ejection fraction, NT pro-brain natriuretic peptide [NT-proBNP] with cardiac index (CI) were calculated. RESULTS: For CI, there was a strong agreement of cine CMR with PC-CMR in healthy volunteers (r: 0.82, mean difference: -0.14 l/min/m(2), error ± 23 %). Agreement was lower in STEMI patients (r: 0.61, mean difference: -0.17 l/min/m(2), error ± 32 %). In STEMI patients, CI measured with PC-CMR showed lower intra-observer (1 % vs. 9 %) and similar inter-observer variability (9 % vs. 12 %) compared to cine CMR. CI was significantly correlated with age, ejection fraction and NT-proBNP values in STEMI patients. DISCUSSION: The agreement of PC-CMR and cine CMR for the determination of CI is lower in STEMI patients than in healthy volunteers. After acute STEMI, CI measured with PC-CMR decreases with age, LV ejection fraction and higher NT-proBNP. KEY POINTS: • Cine CMR and PC-CMR correlate well in healthy volunteers. • Agreement is lower in STEMI patients. • Cardiac Output should be measured with one method longitudinally. • Cardiac output decreases with age after myocardial infarction.

High-sensitivity troponin T for prediction of left ventricular function and infarct size one year following ST-elevation myocardial infarction.

BACKGROUND: Data relating high-sensitivity cardiac troponin T (hs-cTnT) to long-term myocardial function and infarct size in patients after ST-elevation myocardial infarction (STEMI) are lacking. We aimed to evaluate the use of early hs-cTnT concentrations for prediction of myocardial function and infarct size assessed by cardiac magnetic resonance imaging (CMR) one year following STEMI. METHODS: Sixty-six patients, revascularized by primary percutaneous coronary intervention (PCI) for first-time STEMI, were enrolled in this observational study. Serial hs-cTnT, creatine kinase (CK), high-sensitivity C-reactive protein (hs-CRP) and lactate dehydrogenase (LDH) levels were measured on admission, 6 h, 12 h, and 24 h post-PCI. Patients underwent CMR within the first week and 12months thereafter. RESULTS: Except for admission hs-cTnT, all single time point and peak hs-cTnT concentrations showed significant correlations with left ventricular ejection fraction (LVEF: r=-0.404 to -0.517, all ps<0.01) and infarct size (IS: r=0.421 to 0.700, all ps<0.01) at baseline and follow-up. The area under the curve (AUC) of peak hs-cTnT was 0.82 (95% CI 0.71-0.92) for the prediction of decreased LVEF (<55%) and 0.89 (95% CI 0.81-0.97) for the prediction of large IS (>8%) at 12months. The combination of all four biomarkers resulted in an AUC of 0.82 and 0.92 for the prediction of reduced LVEF and large IS at 12months, respectively (both ps>0.05). CONCLUSION: In stable STEMI patients successfully revascularized by primary PCI, serial and peak concentrations of hs-cTnT are closely correlated to long-term LVEF and IS. Combination of hs-cTnT with CK, hs-CRP, or LDH did not add any significant prognostic value as compared with hs-cTnT alone.

Generation of cardiac pacemaker cells by programming and differentiation.

A number of diseases are caused by faulty function of the cardiac pacemaker and described as "sick sinus syndrome". The medical treatment of sick sinus syndrome with electrical pacemaker implants in the diseased heart includes risks. These problems may be overcome via "biological pacemaker" derived from different adult cardiac cells or pluripotent stem cells. The generation of cardiac pacemaker cells requires the understanding of the pacing automaticity. Two characteristic phenomena the "membrane-clock" and the "Ca(2+)-clock" are responsible for the modulation of the pacemaker activity. Processes in the "membrane-clock" generating the spontaneous pacemaker firing are based on the voltage-sensitive membrane ion channel activity starting with slow diastolic depolarization and discharging in the action potential. The influence of the intracellular Ca(2+) modulating the pacemaker activity is characterized by the "Ca(2+)-clock". The generation of pacemaker cells started with the reprogramming of adult cardiac cells by targeted induction of one pacemaker function like HCN1-4 overexpression and enclosed in an activation of single pacemaker specific transcription factors. Reprogramming of adult cardiac cells with the transcription factor Tbx18 created cardiac cells with characteristic features of cardiac pacemaker cells. Another key transcription factor is Tbx3 specifically expressed in the cardiac conduction system including the sinoatrial node and sufficient for the induction of the cardiac pacemaker gene program. For a successful cell therapeutic practice, the generated cells should have all regulating mechanisms of cardiac pacemaker cells. Otherwise, the generated pacemaker cells serve only as investigating model for the fundamental research or as drug testing model for new antiarrhythmics. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: A double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial).

OBJECTIVE: In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI. RESULTS: At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS. CONCLUSION: Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

N-terminal pro-B-type natriuretic peptide is associated with aortic stiffness in patients presenting with acute myocardial infarction.

BACKGROUND: Aortic stiffness is associated with increased left ventricular (LV) afterload, a process which is accompanied by a release of natriuretic peptides. Aortic pulse wave velocity (PWV) has been demonstrated to be the functional surrogate of aortic stiffness. We sought to investigate the impact of aortic PWV on N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in patients with acute myocardial infarction (AMI). METHODS: This prospective observational study included 86 consecutive patients undergoing percutaneous coronary intervention for AMI. Aortic PWV was determined 47 h (interquartile range (IQR) 27-64 h) after AMI using an established oscillometric device. NT-proBNP values were measured using a commercially available immunoassay. RESULTS: The mean age of the study cohort was 60±11 years; 19% were female. Median aortic PWV was 7.8 m/s (IQR 6.8-9.4 m/s). Patients with a PWV above the median showed significantly higher NT-proBNP peak concentrations (median=1330 ng/l, IQR: 729-3180 ng/l vs median=498 ng/l, IQR: 124-1575 ng/l, p=0.001). Aortic PWV (beta=0.373, p=0.014) was independently associated with NT-proBNP peak concentrations even after correction for LV function, cardiac troponin T levels, heart rate, blood pressure, body mass index and the primary prevention European Society of Cardiology (ESC) SCORE (model: R=0.542, p=0.014). CONCLUSION: In patients with AMI, aortic PWV is independently associated with NT-proBNP concentrations. This finding suggests an impact of aortic PWV on myocardial wall stress after AMI.

Prognostic value of left ventricular global function index in patients after ST-segment elevation myocardial infarction.

AIMS: The left ventricular global function index (LVGFI) is a novel indicator of left ventricular performance. Its prognostic value in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. We sought to evaluate the prognostic significance of LVGFI measured by cardiovascular magnetic resonance (CMR) imaging after STEMI. METHODS AND RESULTS: Two hundred eligible STEMI patients (56 ± 11 years, 16% female) revascularized by primary percutaneous coronary intervention were followed-up for 3.1 [2-4.1] years for major adverse cardiac events (MACE). MACE was defined as a composite of death, non-fatal myocardial re-infarction, and new congestive heart failure. All patients underwent CMR imaging within 2 [2-4] days after STEMI. Late enhancement and cine images were acquired to assess myocardial injury as well as myocardial function, including LVGFI. Patients suffering a MACE event (n = 20, 10%) had a significantly lower LVGFI (P = 0.001). In Kaplan-Meier analysis, a decreased LVGFI was associated with a reduced MACE-free survival (P < 0.001). Multivariate Cox regression analysis revealed a decreased LVGFI as a predictor for MACE [hazard ratio = 4.79, 95% confidence interval (CI) 1.46-15.67, P = 0.010] after adjusting for microvascular obstruction, left ventricular mass, and multivessel disease. In receiver operating characteristic analysis, LVGFI was a strong predictor for MACE (area under the curve = 0.73, CI 0.61-0.85). However, c-statistics revealed that LVGFI does not provide incremental prognostic information over left ventricular ejection fraction (LVEF) (P = 0.38). CONCLUSION: LVGFI assessed by CMR is a strong predictor of MACE within 3 years after first STEMI. A superior predictive value as compared with LVEF was not found in this study.

Prognostic significance of transaminases after acute ST-elevation myocardial infarction: insights from a cardiac magnetic resonance study.

BACKGROUND: In patients with ST-elevation myocardial infarction (STEMI), the relationship between transaminases and myocardial damage detected by cardiac magnetic resonance (CMR) imaging is unknown and the prognostic value incompletely investigated. MATERIALS AND METHODS: CMR imaging was performed in 167 STEMI patients 2.3 [1.6-3.9] days after primary percutaneous coronary intervention (PPCI). Blood samples for transaminase measurement (aspartate transaminase (AST) and alanine transaminase (ALT)) were obtained serially from day 1 to day 4 after PPCI. Patients were followed for major adverse cardiac events (MACE) for 2.7 [1.1-3.3] years. RESULTS: Admission and peak concentrations of AST and ALT were significantly associated with ejection fraction (p < 0.001), infarct size (p < 0.001), and the presence of microvascular obstruction (p < 0.01). Peak values of both transaminases showed a stronger correlation with CMR parameters than admission values (all p < 0.05). In Kaplan-Meier analysis, a high peak AST or high peak ALT was associated with reduced MACE-free survival (both p < 0.01), whereas admission values were not (both p > 0.05). Peak AST (hazard ratio (HR): 4.93 [1.70-14.32], p = 0.003) and peak ALT (HR: 5.67 [1.94-16.56], p = 0.002) were independent predictors of MACE after adjusting for clinical risk factors. CONCLUSIONS: Transaminases measured in the acute phase after PPCI for STEMI are associated with systolic dysfunction, more extensive myocardial necrosis and microvascular injury with subsequent prognostic information on MACE at long-term follow-up.

Aortic stiffness is associated with elevated high-sensitivity cardiac troponin T concentrations at a chronic stage after ST-segment elevation myocardial infarction.

OBJECTIVES: Aortic pulse wave velocity (PWV)--the proposed gold standard for the assessment of aortic stiffness--is a major determinant of left ventricular after-load and coronary perfusion. We aimed to investigate the association between aortic PWV and subclinical elevation of high-sensitivity cardiac troponin T (hs-TnT) concentrations at a chronic stage after acute ST-segment elevation myocardial infarction (STEMI). METHODS: Seventy-four patients with acute STEMI were included in this cross-sectional single-centre study at the University Hospital of Innsbruck. All patients underwent cardiac MRI for the assessment of left ventricular function, morphology, infarct size and aortic PWV 12 months after acute STEMI. Blood samples were drawn at 12 months by peripheral venipuncture. Levels of hs-TnT were measured by a commercially available immunoassay (Roche Diagnostics). RESULTS: hs-TnT levels (6.4 ng/l, inter-quartile range 5.0-8.6) were significantly associated with age (r = 0.417, P < 0.001), plasma creatinine levels (r = 0.257, P = 0.027), high-sensitivity C-reactive protein levels (r = 0.281, P = 0.015) and aortic PWV (r = 0.435, P < 0.001). Multiple linear regression analysis revealed aortic PWV (ß = 0.330, P = 0.025), apart from plasma creatinine concentrations (ß = 0.279, P = 0.010), to be independently associated with hs-TnT concentrations (model: R = 0.597, P < 0.001). CONCLUSION: The present study showed an association of aortic stiffness and hs-TnT concentrations at a chronic stage after STEMI.

Fetuin-A is related to infarct size, left ventricular function and remodelling after acute STEMI.

OBJECTIVE: To investigate the relationship between plasma fetuin-A, an anti-inflammatory glycoprotein which might be involved in myocardial healing after acute infarction, and infarct size, left ventricular (LV) function and dimensions as well as the occurrence of adverse remodelling at 4 months after acute ST segment elevation myocardial infarction (STEMI). METHODS: In this single-centre prospective, observational study, 89 patients underwent cardiac MR within the first week and 4 months after mechanical reperfusion for first STEMI. Infarct size, LV function and dimensions were assessed at both time points. Fetuin-A levels were determined from blood samples drawn at a median of 49 h (IQR 30-59 h) after STEMI by an immunofluorescent assay. RESULTS: Fetuin-A levels (median 568 µg/mL, IQR 478-763 µg/mL) were significantly correlated with infarct size and LV ejection fraction at baseline and follow-up (all p<0.05). Moreover, fetuin-A was related to the increase in the end-diastolic volume index (r=-0.383, p<0.001). According to multivariate logistic regression analysis, fetuin-A concentrations (HR=0.17, 95% CI 0.03 to 0.89, p=0.036) besides the presence of late microvascular obstruction (HR=10.03, 95% CI 0.98 to 102.43, p=0.05) were significantly related to the occurrence of adverse LV remodelling at 4 months. CONCLUSIONS: Circulating fetuin-A at day 2 after STEMI is related to acute and chronic infarct size, LV function and dimensions. In addition, it might be useful to identify patients at increased risk for adverse LV remodelling.

Biomarkers of hemodynamic stress and aortic stiffness after STEMI: a cross-sectional analysis.

AIM: Increased aortic stiffness might adversely affect cardiac structure, function, and perfusion. Release of biomarkers of hemodynamic stress is thought to be enhanced by these alterations. We aimed to evaluate the association between biomarkers of hemodynamic stress and aortic stiffness assessed at a chronic stage after ST-segment elevation myocardial infarction (STEMI). METHODS: Fifty-four patients four months after STEMI were enrolled in this cross-sectional, single-center study. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using phase-contrast cardiovascular magnetic resonance. RESULTS: NT-proBNP, MR-proANP, and MR-proADM concentrations were all correlated with aortic stiffness in univariate analysis (r = 0.378, r = 0.425, and r = 0.532; all P < 0.005, resp.). In multiple linear regression analysis, NT-proBNP (ß = 0.316, P = 0.005) and MR-proADM (ß = 0.284, P < 0.020) levels were associated with increased aortic stiffness independently of age, blood pressure, and renal function. NT-proBNP was the strongest predictor for high aortic stiffness (area under the curve: 0.82, 95% CI 0.67-0.96). CONCLUSION: At a chronic stage after STEMI, concentrations of biomarkers for hemodynamic stress, especially NT-proBNP, are positively correlated with aortic stiffness. These biomarkers might also be useful as predictors of high aortic stiffness after STEMI.

(124)I-PET Assessment of Human Sodium Iodide Symporter Reporter Gene Activity for Highly Sensitive In Vivo Monitoring of Teratoma Formation in Mice.

PURPOSE: Pluripotent stem cell (PSC)-based therapies possess great potential to restore the function of irreversibly damaged organs. PSCs can be differentiated in vitro into any cell type. However, pluripotent potential bears the risk of teratoma formation. In vivo monitoring of teratoma formation is indispensable, as 100 % purity of the cell preparation cannot be achieved. We aimed at establishing the human sodium iodide symporter (hNIS) as reporter gene for PET monitoring of teratoma formation. PROCEDURES: Murine PSC stably expressing hNIS were injected into the hind limbs of SCID mice to induce teratoma formation. Positron emission tomography (PET) scans were acquired weekly between days 14 and 42 after transplantation. Two teratomas were excised at each time point for histology and size measurement. Tracer uptake was correlated with teratoma weight. Specificity of tumoural iodine uptake was assessed by blocking hNIS in vivo with perchlorate. RESULTS: Neither hNIS expression nor I-124 exposure adversely impacted viability or differentiation potential of PSCs. Iodine uptake was highly specific in teratomas, as in vivo blocking of hNIS with perchlorate led to uptake rates comparable to tracer uptake in non-transgene tumours. Tumour mass and tracer uptake showed a positive correlation. CONCLUSIONS: This is the first study to generate stably hNIS-expressing murine PSCs. Since the differentiation potential was preserved, hNIS-expressing cells are suitable for PSC-based forward programming approaches. Teratoma formation from undifferentiated cells can be monitored in vivo by PET with high specificity on a quantitative level. Due to its anticipated lack of immunogenicity in humans, hNIS is a promising reporter gene for clinical translation.

Attenuation of cardiac hypertrophy by G-CSF is associated with enhanced migration of bone marrow-derived cells.

Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 µg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4(+) and c-kit(+) BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4(+) and c-kit(+) BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.

Comparison of an oscillometric method with cardiac magnetic resonance for the analysis of aortic pulse wave velocity.

OBJECTIVES: Pulse wave velocity (PWV) is the proposed gold-standard for the assessment of aortic elastic properties. The aim of this study was to compare aortic PWV determined by a recently developed oscillometric device with cardiac magnetic resonance imaging (CMR). METHODS: PWV was assessed in 40 volunteers with two different methods. The oscillometric method (PWVOSC) is based on a transfer function from the brachial pressure waves determined by oscillometric blood pressure measurements with a common cuff (Mobil-O-Graph, I.E.M. Stolberg, Germany). CMR was used to determine aortic PWVCMR with the use of the transit time method based on phase-contrast imaging at the level of the ascending and abdominal aorta on a clinical 1.5 Tesla scanner (Siemens, Erlangen, Germany). RESULTS: The median age of the study population was 34 years (IQR: 24-55 years, 11 females). A very strong correlation was found between PWVOSC and PWVCMR (r = 0.859, p < 0.001). Mean PWVOSC was 6.7 ± 1.8 m/s and mean PWVCMR was 6.1 ± 1.8 m/s (p < 0.001). Analysis of agreement between the two measurements using Bland-Altman method showed a bias of 0.57 m/s (upper and lower limit of agreement: 2.49 m/s and -1.34 m/s). The corresponding coefficient of variation between both measurements was 15%. CONCLUSION: Aortic pulse wave velocity assessed by transformation of the brachial pressure waveform showed an acceptable agreement with the CMR-derived transit time method.

Secretoneurin gene therapy improves hind limb and cardiac ischaemia in Apo E⁻/⁻ mice without influencing systemic atherosclerosis.

AIMS: Hypercholesterolaemia is a major risk factor for cardiovascular diseases and has been shown to influence angiogenesis in the hind limb ischaemia (HLI) model. The impaired up-regulation of angiogenic factors seems to be one of the underlying mechanisms for reduced vessel formation. Since we found that secretoneurin (SN) is up-regulated in hypoxic skeletal muscle cells and exerts beneficial effects in myocardial and HLI, we hypothesized that SN therapy might improve neovascularization in hypercholesterolaemic Apo E(-/-) (Apo E knockout) mice suffering from an impaired vascular response. METHODS AND RESULTS: For in vitro experiments, endothelial cells (ECs) were incubated with oxidized low-density lipoprotein (oxLDL) to mimic hypercholesterolaemia. EC function was impaired by oxLDL, but SN induced EC proliferation and in vitro tube formation under these conditions. In the HLI model, injection of SN plasmid resulted in a significant better outcome regarding blood flow recovery, amputation rate, and vessel density. In the myocardial infarction (MI) model, the SN group showed improvement in cardiac parameters. Aortic plaque area was not influenced by local SN injection. Interestingly, SN-induced recruitment of angiogenic monocytic cells was abolished under hypercholesterolaemia. CONCLUSIONS: SN gene therapy exerts beneficial effects in cardiovascular animal models in Apo E(-/-) mice without influencing atherosclerosis and might qualify as a promising therapy for cardiovascular disorders.