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An increased pool of secretory hormones and peptides in adrenal medulla of stroke-prone spontaneously hypertensive rats.
- M Schober,
- P R Howe,
- G Sperk,
- R Fischer-Colbrie and
- H Winkler
Hypertension Volume 13, Issue 51 May 1989

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Secretory components of the adrenal medulla were compared in normotensive Wistar-Kyoto (WKY) rats and in stroke-prone spontaneously hypertensive rats (SHRSP) at both 4 and 12 months of age. Noradrenaline, adrenaline, dopamine, neuropeptide Y, and chromogranins A and B were significantly higher in adrenal glands of SHRSP than those of WKY rats at 4 months. At 12 months, the levels of these components in SHRSP had increased even more (about 200% in WKY rats). There was no change in the relative composition of the adrenal "secretory cocktail." Neither the chromogranin A/chromogranin B ratio nor their apparent proteolytic processing in chromaffin granules differed between SHRSP or WKY rats. The lack of a significant change in membrane-bound cytochrome b561 and the small increase in dopamine beta-hydroxylase suggest that the higher levels of secretory components in SHRSP are not simply caused by an increase in the number of chromaffin granules, but possibly by a selective increase in the secretory content of these organelles providing a larger package for quantal release by exocytosis. This may be relevant for the elevation of blood pressure in this strain. The immunological methods described in this paper allow for the first time a determination of the secretory quantal levels in catecholamine storage. This should be useful for further studies in hypertensive models.
Inhibition of Proliferation and Stimulation of Migration of Endothelial Cells by Secretoneurin In Vitro
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 17, Issue 51 May 1997

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Abstract Vascular cell responses in inflammation are affected by several neuropeptides of perivascular nerve fibers. Secretoneurin is a 33–amino acid peptide that is coreleased from these nerve endings with other proinflammatory neuropeptides, eg, substance P and calcitonin gene–related peptide. Furthermore, secretoneurin has been shown to be chemotactic for human skin fibroblasts and human blood monocytes in vitro and in vivo. An action on cellular components of the vascular wall is not yet reported. We therefore investigated in vitro effects of this novel sensory neuropeptide on endothelial cells. Secretoneurin exerted a potent and reversible inhibitory effect both on endothelial cell growth under low serum conditions (1% fetal calf serum) and endothelial cell growth factor–activated endothelial cell proliferation. We show in the present study that secretoneurin exerts this effect on aortic (rat) and pulmonary artery (bovine) endothelial cells, as well as venous (human umbilical vein) endothelium. Endothelial cell chemotaxis was tested by means of three different migration assays employing nitrocellulose and polycarbonate micropore filters. Secretoneurin consistently exhibited potent chemoattractant activity. The effective concentrations for the observed effects were in the picomolar range. The combination of chemotactic and antiproliferative effects on endothelial cells suggests that secretoneurin may act as a regulatory factor of vascular cell functions.
Secretoneurin, an Angiogenic Neuropeptide, Induces Postnatal Vasculogenesis
- Rudolf Kirchmair,
- Margot Egger,
- Dirk H. Walter,
- Wolfgang Eisterer,
- Andreas Niederwanger,
- Ewald Woell,
- Markus Nagl,
- Michael Pedrini,
- Toshinori Murayama,
- Silke Frauscher,
- Allison Hanley,
- Marcy Silver,
- Marianne Brodmann,
- Wolfgang Sturm,
- Reiner Fischer-Colbrie,
- Douglas W. Losordo,
- Josef R. Patsch and
- Peter Schratzberger
Circulation Volume 110, Issue 931 August 2004

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Background— Induction of postnatal vasculogenesis, the mobilization of bone marrow–derived endothelial progenitor cells and incorporation of these cells into sites of blood vessel formation, is a well-known feature of angiogenic cytokines such as vascular endothelial growth factor. We hypothesized that the angiogenic neuropeptide secretoneurin induces this kind of neovascularization.Methods and Results— Secretoneurin induced mobilization of endothelial progenitor cells to sites of vasculogenesis in vivo in the cornea neovascularization assay. Progenitor cells were incorporated into vascular structures or were located adjacent to them. Systemic injection of secretoneurin led to increase of circulating stem cells and endothelial progenitor cells. In vitro secretoneurin induced migration, exerted antiapoptotic effects, and increased the number of these cells. Furthermore, secretoneurin stimulated the mitogen-activated protein kinase system, as shown by phosphorylation of extracellular signal–regulated kinase, and activated the protein kinase B/Akt pathway. Activation of mitogen-activated protein kinase was necessary for increase of cell number and migration, whereas Akt seemed to play a role in migration of endothelial progenitor cells.Conclusions— These data show that the angiogenic neuropeptide secretoneurin stimulates postnatal vasculogenesis by mobilization, migration, and incorporation of endothelial progenitor cells.
The Neuropeptide Secretoneurin Acts as a Direct Angiogenic Cytokine In Vitro and In Vivo
- Rudolf Kirchmair,
- Roland Gander,
- Margot Egger,
- Allison Hanley,
- Marcy Silver,
- Andreas Ritsch,
- Toshinori Murayama,
- Nicole Kaneider,
- Wolfgang Sturm,
- Marianne Kearny,
- Reiner Fischer-Colbrie,
- Brigitte Kircher,
- Hannes Gaenzer,
- Christian J. Wiedermann,
- Allan H. Ropper,
- Douglas W. Losordo,
- Josef R. Patsch and
- Peter Schratzberger
Circulation Volume 109, Issue 617 February 2004

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Background— Secretoneurin is an abundant neuropeptide of the central, peripheral, and autonomic nervous systems, located in nerve fibers characterized by a close interaction with blood vessels and known to stimulate endothelial cell migration.Methods and Results— We hypothesized that secretoneurin might act as an angiogenic cytokine and tested for these effects in vivo using a mouse cornea neovascularization model and in vitro by assessing capillary tube formation in a matrigel assay. In vivo, secretoneurin-induced neovasculature is characterized by a distinct pattern of arterial and venous vessels of large diameter and length. Immunohistochemical staining for CD-31 revealed endothelial lining of the inner surface of these vessels, and recruitment of α-smooth muscle actin–positive perivascular cells suggests vessel maturation. In vitro, secretoneurin-induced capillary tube formation was dose dependent and specific, confirming that effects of secretoneurin occur directly on endothelial cells. Secretoneurin also stimulated proliferation and exerted antiapoptotic effects on endothelial cells and activated intracellular phosphatidylinositol 3′ kinase/Akt and mitogen-activated protein kinase pathways, as demonstrated by increased phosphorylation of Akt and extracellular signal–regulated kinase.Conclusions— These data show that secretoneurin represents a novel direct angiogenic cytokine and reiterate the coordinated relationship between nervous and vascular systems.
The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
- Karin Albrecht-Schgoer,
- Wilfried Schgoer,
- Johannes Holfeld,
- Markus Theurl,
- Dominik Wiedemann,
- Christina Steger,
- Rajesh Gupta,
- Severin Semsroth,
- Reiner Fischer-Colbrie,
- Arno G.E. Beer,
- Ursula Stanzl,
- Eva Huber,
- Sol Misener,
- Daniel Dejaco,
- Raj Kishore,
- Otmar Pachinger,
- Michael Grimm,
- Nikolaos Bonaros and
- Rudolf Kirchmair
Circulation Volume 126, Issue 2120 November 2012

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Background—Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.Methods and Results—In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein.Conclusions—Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.
Gene Therapy With the Angiogenic Cytokine Secretoneurin Induces Therapeutic Angiogenesis by a Nitric Oxide–Dependent Mechanism
- Wilfried Schgoer,
- Markus Theurl,
- Johannes Jeschke,
- Arno G.E. Beer,
- Karin Albrecht,
- Roland Gander,
- Song Rong,
- Danijela Vasiljevic,
- Margot Egger,
- Anna Maria Wolf,
- Silke Frauscher,
- Bernhard Koller,
- Ivan Tancevski,
- Josef R. Patsch,
- Peter Schratzberger,
- Hildegunde Piza-Katzer,
- Andreas Ritsch,
- Ferdinand H. Bahlmann,
- Reiner Fischer-Colbrie,
- Dominik Wolf and
- Rudolf Kirchmair
Circulation Research Volume 105, Issue 106 November 2009

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Rationale: The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells.Objective: We sought to investigate the effects of secretoneurin on therapeutic angiogenesis.Methods and Results: We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells.Conclusions: In summary, our data indicate that gene therapy with secretoneurin induces therapeutic angiogenesis, arteriogenesis, and vasculogenesis in the hindlimb ischemia model by a nitric oxide–dependent mechanism.
Evaluation of Cerebral Vascular Disease With Radionuclide Angiography
- Ronald J. Fischer and
- August Miale
Stroke Volume 3, Issue 11 January 1972

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Experience with radionuclide angiography (RA) utilizing radiosodium pertechnetate and the scintillation camera as a practical means of evaluating cerebral vascular disease (CVD) is presented. The normal RA patterns were established in more than 500 patients without clinical evidence of CVD. Detailed study of the arterial and venous perfusion patterns in cases of CVD showed that certain discrete changes can be classified. The RA patterns were evaluated in 143 patients with strokes and in 120 patients with transient ischemic attacks (TIA) and correlated with symptomatology, clinical hospital course and cerebral angiograms. Although static brain scanning in patients with strokes is reportedly positive in approximately 42%, such scans are rarely positive (3%) in patients with TIA. However, by using the RA in combination with static camera imaging, in those patients wth documented stroke, positive studies were obtained in more than 80%, a twofold increase compared to previous experience. In patients with TIA, a tenfold (33%) increase in positive studies was found related to CVD and, in addition, another 7% were positive as mass lesions. The data presented stress the importance of establishing specific criteria for analysis of RA as well as the greatly enhanced sensitivity of this combined approach in detecting CVD.
Abstract 16580: A Novel Synthetic Omega-3 Epoxyeicosanoid Analogue Mediates Cardioprotection by Modulating Mitochondrial Function
- Robert Fischer,
- Tim Wesser,
- Victor Samokhvalov,
- Anne Konkel,
- Janine Lossie,
- John R. Falck,
- John Seubert and
- Wolf-Hagen Schunck
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: OMT-28 is a first-in-class drug candidate developed for rhythm stabilization and cardioprotection that has just entered clinical phase-1 (EudraCT No.: 2016-003445-28). OMT-28 was designed to mimic 17,18-EEQ, a highly potent lipid mediator generated by CYP epoxygenases from the omega-3 fatty acid EPA.Hypotheses: Aside from mediating antiarrhythmic effects, OMT-28 triggers an endogenous pathway preserving cardiomyocyte viability and mitochondrial function under stress conditions, such as hypoxia/reoxygenation (H/R)- and LPS-induced inflammation.Methods: OMT-28 mediated protective effects were analyzed in neonatal rat cardiomyocytes (NRCMs), immortalized mouse cardiomyocytes (HL-1 cells), isolated perfused mouse hearts (Langendorff system), and in a rat model of reversible coronary artery ligation.Results: OMT-28 dose-dependently (10 - 1000 nM) improved cardiomyocyte survival both after H/R (24 h 1 % O2/ 6 h reoxygenation) and LPS-treatment (24 h, 1 μg/ml). OMT-28 increased PPAR-alpha DNA binding in the H/R model and suppressed LPS-induced NF-kappaB activation and TNF-alpha release. Under basal conditions, OMT-28 moderately increased the mitochondrial respiratory reserve capacity as well as mitochondrial respiration rate (RCR) of cardiomyocytes. After H/R, RCR remained at basal rate in OMT-28 (1 μM) treated cardiomyocytes, compared to a 60 % reduction in vehicle controls. OMT-28 mediated signalling included activation of the PI3K/Akt/NO/PKG pathway as well as that of sirtuin1 and PPAR-alpha, as indicated by pharmacological interventions. In isolated mouse hearts, perfusion with OMT-28 (100 nM) significantly improved post-ischemic functional recovery from 17±7 (vehicle control) to 68±13%. A single i.v. dose of 0.5 mg OMT-28/kg reduced the infarct size/area of risk-ratio from 48±5 % (vehicle control) to 32±6 % in the rat myocardial infarction model.Conclusions: OMT-28 activates a pro-survival pathway in cardiomyocytes that leads to sirtuin- and PPAR-alpha-mediated protection of mitochondrial function. This mechanism may be relevant for the treatment of various cardiac diseases associated with mitochondrial dysfunction, like myocardial infarction, heart failure, and atrial fibrillation.
Abstract 16481: A Novel Synthetic Omega-3 Epoxyeicosanoid Analogue Modulates Ca²⁺ Handling and Exerts Anti-Arrhythmic Effects
- Robert Fischer,
- Tim Wesser,
- Anne Konkel,
- Janine Lossie,
- John R. Falck,
- Azinwi Phina Khan,
- Markus Kamler,
- Dobromir Dobrev and
- Wolf-Hagen Schunck
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: OMT-28 is a first-in-class drug candidate for rhythm stabilization and cardioprotection that has just entered clinical phase I (EudraCT No.: 2016-003445-28).Hypothesis: As a synthetic analogue of the EPA-derived lipid mediator 17,18-EEQ, OMT-28 exerts both cardioprotective and anti-arrhythmic effects via modulation of Ca²⁺ handling in cardiomyocytes.Methods: Neonatal rat cardiomyocytes (NRCM) and human atrial myocytes (HAMs) from patients undergoing cardiac surgery were used for mechanistic studies. Effects on atrial fibrillation (AF) vulnerability were analysed in mice after chronic β-adrenergic stress (14-days isoprenaline infusion via osmotic mini pumps).Results: 17,18-EEQ and OMT-28 reduced spontaneous beating of NRCMs with EC₅₀ values of 9.7±1.3 and 1.6±1.3 nM. Pertussis toxin abolished these effects, implicating a G_i-protein coupled receptor. As evidenced with specific inhibitors, postreceptor signalling required PI3K, Akt, eNOS, PKG, PKC, and the activation of sarcolemmal and mitochondrial K_ATP channels. 17,18-EEQ and OMT-28 increased Akt phosphorylation at Ser473 and Thr308 and significantly enhanced Ser16 phosphorylation of the SERCA regulator phospholamban. Simultaneous current (patch clamp) and intracellular Ca²⁺ (Fluo-3) recordings of HAMs showed no effects of OMT-28 (100 nM) on L-type calcium-current (I_Ca,L) amplitude, although the integrated I_Ca,L was significantly higher. OMT-28 significantly decreased the Ca²⁺-transient amplitude, but increased the caffeine-induced integrated Na⁺/Ca²⁺ exchanger current, suggesting increased sarcoplasmic reticulum Ca²⁺ load in HAMs. In line with the increased Ca²⁺-reuptake into the sarcoplasmic reticulum, cell shortening measurements in HAMs revealed accelerated relaxation times and a shorter time to peak in the presence of OMT-28. In the mouse model of inducible AF, single i.v. doses of OMT-28 (0.625, 2.0 and 6.25 mg/kg) significantly reduced AF burden and episode duration. Atrial or ventricular effective refractory periods and QT interval were unchanged.Conclusions: OMT-28 shows a unique mode of antiarrhythmic action that may establish a novel concept for AF treatment.
Abstract 16115: Switching From β-blockers to Ivabradine: Effects on Cardiopulmonary Function in Patients With Stable Coronary Artery Disease and Hypertension
Circulation Volume 128, Issue suppl_2226 November 2013

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Purpose: Ivabradine (Iva) is recommended for patients with stable coronary artery disease (CAD) who do not tolerate β-blockers. As Iva does not affect cardiac contractility or central hemodynamics, we speculated, that switching therapy from β-blockers to Iva may improve cardiopulmonary performance.Methods: 19 patients (3 women, age 61 ± 10 years, LVEF 61 ± 5 %) with CAD were included. Chronic β-blocker therapy was going to be replaced by Iva due to side-effects of β-blockade. We performed cardiopulmonary exercise testing, pulmonary function testing and echocardiography and determined NT-proBNP serum levels both under β-blockade and 6 weeks after Iva therapy.Results: Mean HR (68 ± 8 vs. 67 ± 10 bpm; p=0.508), systolic blood pressure (p=0.224), pulmonary vital capacity (p=0.726) and forced expiratory volume in 1 second (p=0.969) were not different under β-blocker or Iva at resting conditions. Left ventricular filling index (E/e’) was slightly lower under Iva (11.4 ± 4.8 vs. 9.2 ± 3.2; p=0.085). No patient showed signs of myocardial ischemia at rest or under exercise. Patients achieved the same level of exercise duration (p=0.620), maximal power (p=0.846), serum lactate levels (p=0.529) and heart rate increase (p=0.967) with or without β-blockade. Although peak oxygen uptake (21.9 ± 5.4 vs. 22.3 ± 4.4 ml/min/kg; p=0.470) did not change, oxygen uptake at the anaerobic threshold increased from 9.8 ± 1.5 to 11.5 ± 1.8 ml/min/kg (p=0.008) and peak oxygen pulse revealed a increase from 193 ± 41 to 210 ± 37 μl/beat/kg (p=0.010) after switching therapy to Iva. NT-proBNP serum levels were not different under β-blockade or Iva at rest (177 ± 179 vs. 162 ± 169 pg/ml; p=0.472), but the increase of serum levels during exercise tended to be lower under Iva (17 ± 45 vs. 7 ± 18 pg/ml; p=0.070).Conclusions: Switching therapy from β-blockers to Iva in patients with CAD leads to a significant delay in the onset of anaerobic metabolism as demonstrated by higher oxygen uptake at the anaerobic threshold during exercise. Moreover, left ventricular fillings pressures and NT-proBNP serum levels tended to be lower under Iva therapy. The results of this pilot study suggest, that compared to β-blockade, therapy with Iva could make patients more resistant to fatigue in everyday life and activity.
Abstract 699: Intracoronary Infusion Of Bone Marrow-derived Progenitor Cells In Patients With Non-ischemic Dilated Cardiomyopathy Is Associated With An Increase Of Coronary Blood Flow In The Target Vessel
- Ulrich Fischer-Rasokat,
- Birgit Assmus,
- Florian Seeger,
- Joerg Honold,
- Volker Schaechinger,
- Stephan Fichtlscherer,
- Hans Martin,
- Stefanie Dimmeler and
- Andreas M. Zeiher
Circulation Volume 116, Issue suppl_1616 October 2007

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We recently could demonstrate that intracoronary administration of bonemarrow-derived progenitor cells (BMC) is associated with improved target area contractility and enhanced cardiac function in patients (pts) with nonischemic dilated cardiomyopathy (DCM). The influence of coronary microvascular dysfunction on development and progression of DCM in the absence of epicardial artery atherosclerosis has been demonstrated in experimental studies. Therefore, to get insights into potential mechanisms of BMC therapy in pts with DCM, we performed a substudy of the TOPCARE-DCM trial, assessing coronary blood flow (CBF) by intracoronary Doppler measurements.Methods 13 pts (age 31 to 64 yrs; ejection fraction 28 ± 14 %) were included. A mean number of 353 ± 119 * 10⁶ BMC were infused into the left anterior descending (LAD) artery using the stop-flow technique. Doppler-derived CBF velocities in the target (LAD) as well as in a reference vessel (left circumflex artery, ref) were obtained at baseline prior to BMC administration and at 3 months’ angiographic follow up (FU).Results Heart rate, blood pressure and coronary artery lumen diameter did not differ between initial and FU measurements. Basal coronary vascular resistance (VR) decreased after 3 months in the target and in the ref vessel (target 6.32 ± 2.43 vs 5.43 ± 2.28, p < 0.01; ref 6.72 ± 2.15 vs 5.41 ± 1.94 mmHg*s/cm, p = 0.03). In contrast, adenosine-induced minimal VR decreased only in the target vessel but not in the ref vessel (target 1.53 ± 0.60 vs 1.31 ± 0.65, p < 0.01; ref 1.60 ± 0.45 vs 1.49 ± 0.45 mmHg*s/cm, p = ns). Due to the selective decrease in adenosine-induced minimal VR of the target vessel, the coronary flow reserve normalized for the ref vessel increased from 1.0 ± 0.2 to 1.2 ± 0.3 (p < 0.05). Likewise, the CBF increased in the target vessel (from 48 ± 18 to 62 ± 25 ml/min, p = 0.02), but remained unchanged in the ref vessel (from 40 ± 21 to 48 ± 18 ml/min, p = ns).Conclusions In pts with nonischemic DCM, intracoronary BMC infusion is associated with a significant improvement in microvascular function of the target area. Whether improved microvascular function as a potential mechanism underlying the beneficial effects of BMC is causally linked to an improved cardiac contractile function has to be analysed in larger studies.
Cardiomyopathy Resulting From Primary Hyperoxaluria Type II
- Rolf Wachter,
- Matthias R. Schulze,
- Alexander Schmeisser,
- Rainer Fischer and
- Ruth H. Strasser
Circulation Volume 113, Issue 324 January 2006

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Abstract 3160: The Initial Slope of the VO₂/VCO₂ Curve (s1) in Cardiopulmonary Exercise Testing is the Strongest Predictor of Outcome in Patients with Chronic Post-Infarction Heart Failure
- Joerg Honold,
- Lenka Geiger,
- Birgit Assmus,
- Ulrich Fischer-Rasokat,
- Volker Schaechinger and
- Ioakim Spyridopoulos
Circulation Volume 114, Issue suppl_1831 October 2006

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Prognosis of chronic heart failure (HF) remains poor despite novel therapeutic strategies, making identification of parameters to detect patients (pts) at risk a major goal. We assessed 103 HF-pts with previous myocardial infarction (MI) by sequential cardiopulmonary exercise testing (CPET), repetitive measurements of BNP and LV ejection fraction (EF), determined by volumetric analysis of LV angiograms. Anaerobic threshold (AT) was calculated by the v-slope method. All pts received optimized medical therapy (beta blocker, ACE inhibitor and diuretics).Results: EF (41 %) and CPET-parameters (VO_2max: 16 ml/kg/min, maximal O₂ pulse O₂P_max: 12ml) were reduced, BNP-levels were elevated (1250 pmol/ml). After a mean follow up of 351 days, the combined endpoint of cardiac death, stroke, MI, HF-rehospitalization and progression of CAD (determined as de novo lesions in previously affected or unaffected coronary arteries) occured in 23 pts. Surprisingly, neither EF, NYHA class or VO_2max was associated with an elevated risk for adverse outcome. Instead, BNP (p = 0.03) and the submaximal CPET parameter s1 (p= 0.02), which represents the slope of the VO₂/VCO₂ curve until reaching the AT, were associated with an adverse event. Both, VO_2max and O₂P_max only correlated with cardiac death. Multivariate analysis disclosed s1 as the predominant independent predictor of death (p = 0.001). In contrast to VO_2max and O₂P_max, s1 did not correlate with BNP levels. Repetitive CPET after 3 and 12 months did not provide additional information about adverse outcome, whereas repetitive measurement of BNP after 1 year indicated pts at risk: Δ-BNP correlated significantly with death, stroke, MI and HF-rehospitalization.Conclusion: In pts with moderate to severe HF, EF and NYHA-class did not provide sufficient predictive information for future events. In contrast, s1 proved to be the strongest independent predictor of outcome. As some pts are not capable or willing to attain maximal exertion, prognostic impact of maximal CPET-parameters might be overestimated. s1, in contrast, is easily obtained at submaximal exercise levels and might provide a more reliable prognostic parameter for HF-pts under optimized treatment.
Abstract 17874: Comparison of the Seattle Heart Failure Model (SHFM) and Cardiopulmonary Exercise Testing (CPET) for Predicting Mortality of Patients With Ischemic Heart Failure
- Joerg Honold,
- Salvatore DeRosa,
- Ioakim Spyridopoulos,
- Ulrich Fischer-Rasokat,
- Birgit Assmus and
- Andreas M Zeiher
Circulation Volume 122, Issue suppl_2123 November 2010

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Background: Despite many therapeutic advances, prognosis of patients with heart failure remains poor. Assessment of prognosis and risk stratification remains a major diagnostic challenge. Cardiopulmonary exercise testing provides important prognostic information by peak O2 uptake (peak VO2), O2 pulse (O2P), O2 uptake efficiency slope (OUES) and VE/VCO2-slope (VE/VCO2). The Seattle heart failure model is based on clinical data (age, gender, NYHA class, body weight, LVEF, blood pressure, etiology of heart failure, ECG, medication, laboratory findings and resynchronization therapy) to calculate the estimated annual mortality. A comparison of the prognostic value of CPET and SHFM has not been performed so far.Patients and methods: 119 patients (age 59±12 years, 13% female) with ischemic heart failure (LVEF 40±11 %, NYHA 2.3 ± 0.7; NT-proBNP 1061 ± 1151 pg/ml) were analyzed for death during a median follow-up of 3 years. CPET with analysis of peak VO2, O2Pmax, OUES and VE/VCO2 was performed in all patients at inclusion into the study. SHFM was calculated for every patient.Results: During follow up, 10 patients died (8.4%). Non-survivors had significantly worse initial CPET results (peak VO2: 14±2 vs. 18±5 ml/min/kg, VE/VCO2 slope: 40±9 vs. 35 ±12, O2Pmax: 10±4 vs. 14±5, p<0.05) and a significantly higher SHFM score (16.4 vs. 6.1% predicted 1-year mortality, p<0.01). Receiver-operating-curve analysis of sensitivity and specificity for SHFM and CPET revealed the largest area-under-the-curve value for SHFM (0.74), followed by VE/VCO2-slope (0.66), whereas other CPET parameters had substantially lower values (OUES: 0.29, O2Pmax: 0.28, peak VO2: 0.25). Kaplan-Meier-analysis using cut-off points of SHFM and VE/VCO2-slope with highest sensitivity and specifity (SHFM: 21.5%; VE/VCO2: 39.5) resulted in significant discrimination of survivors and non-survivors in log-rank test by both parameters. In multivariate analysis, only SHFM persisted as independent predictor of mortality in these patients (p = 0.001, exponent beta 1.096, 95% CI 1.039 – 1.155). Summary These data indicate superior prognostic power of SHFM compared to CPET in patients with ischemic heart failure.
A Pilot Trial to Assess Potential Effects of Selective Intracoronary Bone Marrow–Derived Progenitor Cell Infusion in Patients With Nonischemic Dilated Cardiomyopathy: Final 1-Year Results of the Transplantation of Progenitor Cells and Functional Regeneration Enhancement Pilot Trial in Patients With Nonischemic Dilated Cardiomyopathy
- Ulrich Fischer-Rasokat,
- Birgit Assmus,
- Florian H. Seeger,
- Jörg Honold,
- David Leistner,
- Stephan Fichtlscherer,
- Volker Schächinger,
- Torsten Tonn,
- Hans Martin,
- Stefanie Dimmeler and
- Andreas M. Zeiher
Circulation: Heart Failure Volume 2, Issue 51 September 2009

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Background— Intracoronary administration of bone marrow–derived progenitor cells (BMC) was shown to improve coronary microvascular function in ischemic heart disease. Because coronary microvascular dysfunction is implicated in the pathogenesis and prognosis of nonischemic dilated cardiomyopathy (DCM), we investigated the effects of intracoronary BMC administration in patients with DCM.Methods and Results— Intracoronary infusion of BMC was performed in 33 patients with DCM by using an over-the-wire balloon catheter. Left ventricular contractility at baseline and after 3 months was assessed by analysis of left ventricular angiograms. Coronary hemodynamics were determined by intracoronary Doppler wire measurements. After 3 months, regional wall motion of the target area (contractility from −1.08�0.39 to −0.97�0.47 SD/chord, P=0.029) and global left ventricular ejection fraction (from 30.2�10.9 to 33.4�11.5%, P<0.001) were improved. Increase of regional contractile function was directly related to the functionality of the infused cells as measured by their colony-forming capacity. Minimal vascular resistance index was significantly reduced in the BMC-treated vessel after 3 months (from 1.53�0.63 to 1.32�0.61 mm Hg � s/cm; P=0.002, n=24), whereas no changes were observed in the reference vessel (from 1.60�0.45 to 1.49�0.45 mm Hg � s/cm; P=0.133, n=13). Twelve months after BMC infusion, N-terminal prohormone brain natriuretic peptide (NT-proBNP) serum levels were decreased, suggesting a beneficial effect on left ventricular remodeling processes (from 1610�993 to 1473�1147 pg/mL; P=0.038 for logNT-proBNP, n=26).Conclusions— Intracoronary administration of BMC seems to be associated with improvements in cardiac contractile and microvascular function in patients with DCM. Thus, randomized blinded studies are warranted to evaluate potential clinical benefits of intracoronary BMC administration in patients with DCM.
Aspirin (5 mmol/L) Inhibits Leukocyte Attack and Triggered Reactive Cell Proliferation in a 3D Human Coronary In Vitro Model
- Rainer Voisard,
- Robert Fischer,
- Markus Oßwald,
- Sami Voglic,
- Regine Baur,
- Milorat Susa,
- Wolfgang Koenig and
- Vinzenz Hombach
Circulation Volume 103, Issue 1227 March 2001

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Background—Leukocyte attack (LA) and the triggered reactive proliferation of smooth muscle cells (SMCs) are key events for the development of early atherosclerosis and restenosis. In the present study, we used a 3D human coronary in vitro model of LA (3DLA model) to examine the effect of high-dose aspirin on the adhesion and chemotaxis of leukocytes and the reactive proliferative response of SMCs.Methods and Results—For dose-finding, the effect of aspirin (1, 2, 5, and 10 mmol/L) on the tumor necrosis factor-α–induced upregulation of intercellular adhesion molecule-1 was analyzed in monocultures of human coronary endothelial cells (HCAEC) and the SMCs of the human coronary media (HCMSMC). In cytoflow and Northern blot experiments, the expression of intercellular adhesion molecule-1 was slightly reduced after incubation with 5 mmol/L aspirin, and strong inhibition was found after incubation with 10 mmol/L. In 3DLA models, HCAECs and HCMSMCs were cultured on both sides of a porous filter. For LA, human monocytes or CD4⁺ lymphocytes were seeded on the HCAEC side of the 3DLA unit. A dose of 5 mmol/L aspirin inhibited the adherence of monocytes or CD4⁺ lymphocytes by 50% (P<0.01) and the chemotaxis of monocytes by 90% (P<0.01). The reactive proliferative response of cocultured HCMSMCs after LA, as measured by the uptake of bromodeoxyuridine, was significantly reduced by 83% after selective monocyte attack (P<0.001) and by 42% after selective CD4⁺ lymphocyte attack (P<0.05).Conclusions—A local concentration of 5 mmol/L aspirin should be accepted as the lowest rational concentration for the beneficial in vitro effects of high-dose aspirin to be reproduced in clinical studies.
Abstract 1894: 5 Years Follow-Up Indicate Safety and Sustained Improvement of Cardiac Function in the TOPCARE-AMI Trial
- Birgit Assmus,
- David Leistner,
- Ulrich Fischer-Rasokat,
- Jörg Honold,
- Volker Schächinger,
- Stefanie Dimmeler and
- Andreas M Zeiher
Circulation Volume 118, Issue suppl_1828 October 2008

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Currently, there are no data investigating the long-term clinical effects (> 2 years) and safety of intracoronary progenitor cell therapy in patients with acute myocardial infarction (AMI). The TOPCARE-AMI trial was the first randomized clinical study investigating the effects of intracoronary infusion of circulating (CPC) or bone marrow-derived progenitor cells (BMC) in 59 patients with successfully reperfused AMI. Therefore, we assessed the clinical course and NT-proBNP serum levels as objective markers of cardiac function of the TOPCARE-AMI patients at 5 years follow-up. 5 years follow-up data were completed in 54 patients, 4 patients were lost to follow-up. One patient died (during the initial hospital stay at 19 days after cell administration), no patient was rehospitalized for heart failure and 16 patients underwent target vessel revascularization (TVR; all patients initially received bare metal stents), without differences between the 2 cell groups. Only 2 TVRs occurred later than 1 year after cell administration making it very unlikely that the infused progenitor cells accelerate atherosclerotic disease progression. In addition, 1 patient had successful operation of a solid bowel carcinoma after 4 years. Echocardiographic analysis in all 54 patients and cardiac MRI imaging in 36 patients excluded intramyocardial calcification in all patients at 5 years follow-up. Serum levels of NT-proBNP were significantly reduced from 902±1006pg/ml at baseline prior to cell administration to 274±250pg/ml at 4 months follow-up (p<0.001), and further decreased to 210±288pg/ml at 5 years follow-up (p<0.001 vs. baseline, p = 0.05 vs. 4 months follow-up). There were no differences between both groups. 5 years follow-up analysis of patients treated with intracoronary infusion of CPC or BMC after AMI demonstrates an excellent clinical long-term safety profile, excludes the induction of intramyocardial calcification, and documents sustained improvement of cardiac function as evidenced by persistently normal NT-proBNP serum levels demonstrating absence of overt heart failure. Complete analysis of echocardiographic and cardiac MRI assessment at 5 years follow-up will be presented.
Abstract 2424: Improvement Of Cardiopulmonary Exercise Capacity In Patients With Chronic Post-infarction Heart Failure (CHF) After Intracoronary Infusion Of Bone Marrow-derived Progenitor Cells (BMC)
- Joerg Honold,
- Lenka Geiger,
- Ulrich Fischer-Rasokat,
- Birgit Assmus,
- Volker Schaechinger,
- Ioakim Spyridopoulos and
- Andreas M Zeiher
Circulation Volume 118, Issue suppl_1828 October 2008

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Intracoronary (i.c.) infusion of BMC in patients (pts.) with CHF is associated with improvements in left ventricular ejection fraction (LVEF) and reduction of NT-proBNP serum-levels, especially in pts. with more severe heart failure. However, ist is unknown whether the modest improvements in cardiac function translate into an increase in cardiopulmonary exercise capacity. A total of 52 CHF-pts. performed cardiopulmonary exercise tests (CPET) according to a modified Bruce protocol before and 3 months after i.c. infusion of BMC into the infarct-related artery. Anaerobic threshold (AT) was determined by the v-slope method. Overall, pts. were 58±12 years old with a moderately impaired LVEF (mean 42±11%) and a median NYHA-class 2±0.75. NT-proBNP-serum levels were elevated (1007±154 pmol/ml). All pts. received chronic optimized medical therapy with betablockers, ACE-inhibitors and combined diuretics, which was kept constant during the study duration. Initial CPET revealed reduced peak oxygen uptake (peak VO2: 14.0 ml/min/kg), maximal oxygen Pulse (O2Pmax: 11.4 ml/beat) and oxygen uptake at AT (VO2AT: 10.9 ml/min/kg), whereas CO2-equivalents (EqCO2) were elevated (29.7). 3 months after therapy, repeated CPET showed an increase in peak VO2 (14.0±3.9 to 15.3±4.3 ml/min/kg, p=0.07), whereas VO2 AT (10.8±2.5 to 10.8±2.5 ml/min/kg, p= n.s.), O2Pmax (11.2 ± 3.1 to 12.0±3.3 ml/beat, p= n.s.) or EqCO2 (29.7±6.4 to 29.8±6.8, p= n.s.) remained unchanged. However, after dichotomizating the patient cohort according to the median of VO2max at baseline, pts. with lower initial VO2max showed a significant improvement in VO2max (12.8±1.5 to 13.5±2.7ml/min/kg, p= 0.03) and an improvement in VO2AT (9.1±1.8 to 9.5±2.2 ml/min/kg, p= ns), as well as a reduction of EqCO2 (34.7±7.1 to 33.8±8.0, p= ns). In contrast, pts. with initial VO2max > median did not show any significant improvements. These findings indicate that intracoronary BMC-therapy improves exercise capacity in CHF-patients with more advanced heart failure. Therefore, cardiopulmonary exercise testing might help to identify pts. more likely to derive functional benefit from intracoronary BMC administration.
Abstract 569: Parathyroid Hormone Reduces LV Perfusion Defects After Myocardial Infarction Quantified by [99mTc]-Sestamibi Pinhole Spect and Promotes Homing of BM-derived Progenitor Cells to the Ischemic Myocardium
- Bruno C Huber,
- Michael Groebner,
- Stefan Brunner,
- Rebekka Fischer,
- Christoph Rischpler,
- Tim Wollenweber,
- Marcus Hacker and
- Wolfgang M Franz
Circulation Volume 120, Issue suppl_183 November 2009

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Aims: Parathyroid hormone (PTH) was recently shown to effectively induce SC mobilization and to promote cardiac repair after myocardial infarction (MI) by enhanced neovascularization and cell survival. In this study, we non-invasively, repetitively, and quantitatively investigated PTH effects on perfusion by a pinhole single-photon emission computed tomography (SPECT) system and analyzed migration and homing capacity of bone marrow-derived progenitor cells (BMCs) after MI in mice.Methods: Mice (C57BL/6J) were irradiated, and BM from GFP-transgenic mice was transplanted. Coronary artery ligation was performed 10 weeks later. PTH (80 μg/kg, s.c.) was daily injected for 6 days. Extent of left ventricular (LV) perfusion defects was determined with a [99mTc]-sestamibi triple headed pinhole SPECT system at 6 days (baseline) and 30 days after LAD occlusion. Primary endpoint was change of defect size from baseline to 30 days after MI. Subpopulations of EGFP⁺ cells in peripheral blood, bone marrow and heart were characterized by flow cytometry. SDF-1α expression was analyzed by ELISAResults: At baseline mean infarct size was similar in both groups (PTH vs. control). However, change of perfusion defect size was significantly different between PTH (−1,96%±0,86) and control animals (+1,16%±0,87) at day 30. Furthermore, PTH treated animals revealed an enhanced migration of CXCR4⁺ BMCs associated with an increased expression level of the corresponding growth factor SDF-1α in ischemic myocardium. In contrast, plasma SDF-1α expression was significantly decreased after PTH treatment.Conclusion: This is the first study demonstrating the suitability of triple headed pinhole SPECT system for repetitive infarct size measurement in mice. In this context, we showed that PTH administration significantly reduced LV perfusion defects associated with SDF-1 driven homing of regenerative CXCR4⁺ BMCs.
Abstract 13391: Comparison of G-CSF and Parathyroid Hormone Treatment After Myocardial Infarction on Cardiac Perfusion Quantified by Pinhole Spect and Stem Cell Homing
- Bruno C Huber,
- Rebekka Fischer,
- Stefan Brunner,
- Michael Groebner,
- Christoph Rischpler,
- Tim Wollenweber,
- Marcus Hacker and
- Wolfgang-Michael Franz
Circulation Volume 122, Issue suppl_2123 November 2010

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Aims: Mobilization of stem cells by G-CSF was shown to have protective effects after myocardial infarction (MI) however clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularisation and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were non-invasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by flow cytometry.Methods: Mice (C57BL/6J) were infarcted by LAD ligation. PTH (80 μg/kg) and G-CSF (100 μg/kg) were injected for 5 days. After injection of 370 MBq [99mTc]-sestamibi, the extent of left ventricular perfusion defects was determined with a triple headed pinhole clinical SPECT system. Imaging was performed at day 6 and day 30 after LAD occlusion. Defect size was indicated as percentage of left ventricular myocardium. Number of BMCs characterized by Lin-/Sca-1+/c-kit+ cells in peripheral blood and heart was analyzed by FACS.Results: In contrast to G-CSF-treated and control mice, administration of PTH and the combination of G-CSF and PTH resulted in a significant decrease in absolute infarct size after 30 days. Evaluating change of defect size from day 6 (baseline) to day 30 after MI we found a relative reduction of infarct sizes after cytokine therapy, whereas an increase in perfusion defects (+1.36%) was only found in controls. PTH treatment (−2.64%) and the combination of G-CSF + PTH (−2.80%) showed more pronounced effects in comparison to single G-CSF treatment (−1.41%). Contrary to G-CSF and controls, PTH and the combination showed significant homing of BMCs into ischemic myocardium.Conclusions: This is the first study, demonstrating the suitability of SPECT as a non-invasive imaging technique for cardiovascular stem cell therapy monitoring in mice. In this context, we showed that PTH administration in contrast to G-CSF significantly reduced LV perfusion defects associated with an enhanced homing of BMCs to the ischemic myocardium.

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