Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague-Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH.

Outcome predictors in dilated cardiomyopathy or myocarditis.

BACKGROUND: The objective of this study was to identify parameters of prognostic relevance in patients presenting with chronic left ventricular dysfunction who underwent endomyocardial biopsy. MATERIALS AND METHODS: A total of 351 consecutive patients (age 47·7 ± 12·6 years, 281 male) with a chronic left ventricular dysfunction were enrolled. Endomyocardial biopsies were analysed by histopathology according to Dallas criteria and immunohistological WHO criteria. Virus genome was detected by polymerase chain reaction. The combined end point was time to death or heart transplantation. RESULTS: About 19% of patients (n = 67) showed positive Dallas criteria and 39% (n = 118) immunohistochemical signs of inflammation. Viral genome was present in 58% (n = 155). During follow-up, 25% (n = 89; 76 death, 13 HTx) reached the end point. Dallas-positive histopathology (hazard ratio: 0·42; 95% CI: 0·29-0·84, P = 0·031), ejection fraction (hazard ratio: 0·97; 95% CI: 0·94-0·99, P = 0·019) and ß-blocker therapy (hazard ratio: 0·41; 95% CI: 0·23-0·69, P = 0·003) were independent outcome predictors. For patients under ß-blocker therapy, Dallas-positive histopathology (hazard ratio: 0·37; 95% CI: 0·25-0·76, P = 0·009) and NYHA class III and class IV (hazard ratio: 2·11; 95% CI: 1·04-3·12, P = 0·006) were independent predictors. CONCLUSIONS: For patients with a chronic left ventricular dysfunction, Dallas-positive histopathology, ß-blocker therapy and left ventricular ejection fraction are the most striking parameters for outcome prediction.

Serum levels of tenascin-C variants in congestive heart failure patients: comparative analysis of ischemic, dilated, and hypertensive cardiomyopathy.

BACKGROUND: Tissue remodelling in ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertensive heart disease (HHD) is accompanied by the re-occurrence of fetal tenascin-C (Tn-C) variants. The study was aimed to comparatively analyze the serum levels of Tn-C containing the FNIIIB (B+ Tn-C) or FNIIIC (C+ Tn-C) domain in heart failure patients due to ICM, DCM, and HHD. METHODS: 119 male patients with congestive heart failure (45 with ICM, 43 with DCM, 31 with HHD) were included. Measurement of serum levels of B+ and C+ Tn-C was performed using Enzyme Linked Immunosorbent Assay (ELISA). Results were correlated to clinical, laboratory, echocardiographic, and spiroergometric parameters. RESULTS: Analysis of Tn-C concentrations according to heart failure etiology revealed no significant differences. There was an association of C+ Tn-C serum levels to enlargement of the left atrium in DCM (p < 0.01) and the left ventricle in HHD (p < 0.05). In patients with ICM, C+ Tn-C showed a strong negative correlation to the stress test performance (p = 0.002, R2: -0.691). Most strikingly, there was a strong correlation between BNP and B+ Tn-C (p = 0.038, R2: 0.466) as well as C+ Tn-C (p = 0.001, R2: 0.814) in DCM patients. CONCLUSIONS: The present study highlights the impact of Tn-C variants as biomarkers reflecting the extent of cardiac remodeling in heart failure patients. Furthermore, B+ Tn-C can be suggested as an additional tool to estimate ICM performance in patients. Especially in combination with BNP, analysis of Tn-C might pave the way for a more precise evaluation of heart failure patients.

Positive effect of eplerenone treatment on endothelial progenitor cells in patients with chronic heart failure.

BACKGROUND: Endothelial progenitor cells (EPCs) are known to play a significant role in reendothelialization and vascular repair. Recently, a mineralocorticoid receptor was demonstrated to be expressed by EPCs. The study aimed to evaluate a potential influence of eplerenone treatment on the total number of EPCs in patients with chronic heart failure. METHODS: Eighty-seven male patients with chronic heart failure were included (age: 23-83 years; body mass index 29.1 ± 5.1 kg/m²; New York Heart failure classification (NYHA) I: 29 patients, NYHA II: 32 patients, NYHA III: 26 patients). Numbers of circulating EPCs were quantified immediately using flow cytometry. Twenty-eight patients received therapy with eplerenone. Patients were further characterized by echocardiography, spirometry and laboratory markers. RESULTS: Patients with ongoing eplerenone administration showed higher levels of circulating cells expressing CD34+ (p<0.05) and CD34+KDR+ (p<0.05) and CD34+CD133+KDR+ cells (p<0.05). The effects of eplerenone treatment could be shown to be independent of NYHA status, genesis of the underlying cardiovascular morbidity, left ventricular function and co-medication. CONCLUSION: Patients with chronic heart failure treated with eplerenone show higher numbers of EPCs. The clinical benefit for treatment with eplerenone has been demonstrated even for patients with mild heart failure and might be partially mediated by EPCs.

Prognostic relevance of heart rate at rest for survival and the quality of life in patients with dilated cardiomyopathy.

OBJECTIVES: Reduction of resting heart rate (HR) has been suggested as a novel therapeutic approach in patients with chronic heart failure because it has been shown to prolong survival and also to improve health-related quality of life (Hr-QoL). The purpose of this analysis was to assess the prognostic impact of resting HR in patients with dilated cardiomyopathy (DCM). METHODS: 217 patients with DCM confirmed by endomyocardial biopsy were investigated (age 49 ± 11 years, 20.7 % were female). The study population was divided into two groups according to the median of the resting HR. After a median follow-up time of 7.4 years overall survival and health-related quality of life (Hr-QoL) were compared in both groups. Survival was compared using Kaplan-Meier method and Hr-QoL was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). RESULTS: Elevated resting HR was associated with poor 1-year survival (p = 0.03). In contrast, long-term survival was not affected by HR (p = 0.20). Patients with lower HR at rest scored significantly lower on the MLHFQ (20 vs. 36, p = 0.03), indicating that higher resting HR is associated with an impairment of Hr-QoL. CONCLUSIONS: Increased HR might be used as a diagnostic tool to identify patients at risk. Reduction of resting HR in patients with DCM might be a therapeutic option to improve Hr-QoL and therefore merits further investigation in future studies.

Impact of diabetes mellitus on quality of life in patients with congestive heart failure.

OBJECTIVES: Congestive heart failure (CHF) and diabetes mellitus (DM) are increasing in prevalence. There are conflicting data regarding the crosstalk of DM and CHF with respect to the prognostic impact for the patients. Health-related quality of life (Hr-QoL) has been reported to be useful for risk stratification. The purpose of this study was to investigate the impact of DM on Hr-QoL in a CHF population. METHODS: 325 consecutive patients with CHF were retrospectively analyzed (age 49 ± 12 years, 74.2% male, 18% had diabetes). After a median follow-up time of 7.4 years, we compared Hr-QoL of patients with and without DM. Hr-QoL was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Kaplan-Meier curves were used to compare survival. RESULTS: The presence of DM reduced Hr-QoL in patients with CHF, indicated by a higher overall MLHFQ score (43.5 vs. 21, P = 0.013). Kaplan-Meier survival curves showed a significant survival difference (P = 0.024). Survival rates of both groups differed significantly after 3 (P = 0.031), 5 (P = 0.006), and 10 years (P = 0.047) favoring the group without DM. CONCLUSIONS: In patients with CHF, the coexistence of DM is associated with a reduced Hr-QoL and a particularly poor long-term survival. Our results indicate that CHF patients with DM are at increased risk.

An unusual case of progressive shock and highly elevated procalcitonin level.

A 21-year-old man with signs and symptoms of rapidly progressive shock was admitted to the intensive care unit for treatment of suspected sepsis. Levels of inflammatory markers (including procalcitonin) were highly elevated, but no obvious focus of infection was apparent. Initial sepsis therapy included administration of broad-spectrum antibiotics, vasoconstrictors, and drotrecogin alfa. Cultures of blood, sputum, and urine showed no growth, and no viruses were detected. The random (no stimulation with corticotropin) cortisol level at admission was less than 25 nmol/L. Assays for autoantibodies to the adrenal cortex were strongly positive and confirmed the diagnosis of adrenal failure caused by Addison disease. After initiation of steroid therapy, the patient fully recovered. Although increased procalcitonin levels are considered a reliable and specific indicator of severe generalized infections and bacterial sepsis, elevated procalcitonin levels cannot be relied on when trying to differentiate between addisonian crisis and septic shock.

Prevalence of parvovirus B19 and human bocavirus DNA in the heart of patients with no evidence of dilated cardiomyopathy or myocarditis.

BACKGROUND: Although the DNA of parvovirus B19 (B19V) is frequently detected in patients with dilated cardiomyopathy or myocarditis, whether the parvovirus causes disease is questionable, since even in healthy individuals the virus persists in various tissues. The same question applies to human bocavirus (HBoV). We have determined the prevalence and quantity of B19V and HBoV DNA in heart tissue of patients who were not experiencing virus-related heart diseases and analyzed whether the seroprevalence corresponded to DNA prevalence in the heart. METHODS: Samples of left-atrium heart tissue and serum were obtained from 100 patients who underwent open-heart surgery. Serum immunoglobulin (Ig) G and IgM against proteins encoded by B19V and HBoV were detected by enzyme-linked immunoabsorption assay and immunoblotting. B19V and HBoV DNA concentrations were determined by quantitative real-time polymerase chain reaction (PCR) in heart tissue and serum samples. Nested PCRs for VP1, K71, and GT3 identified the B19V genotypes. RESULTS: The prevalences of serum IgG specific for B19V and HBoV were 85% and 96%, respectively. Of all the patients, 85% had B19V DNA detected in heart tissues, and 4% displayed low-level B19V viremia, whereas only 5% of heart tissue samples and none of the serum samples demonstrated HBoV DNA. The sensitivity of B19V serological testing for B19V DNA in heart samples was 0.96 (95% confidence interval, 0.92-1.0). Specificity was 0.8 (95% confidence interval, 0.6-1.0), and the positive predictive value was 0.96 (95% confidence interval, 0.92-1.0). B19V genotypes 1 and 2 were present in 11% and 89% of heart tissues samples, respectively. B19V genotype 3 was not detected in any of the samples. CONCLUSIONS: Our data suggest that B19V but not HBoV demonstrates a lifelong persistence in the heart. The detection of B19V DNA in heart tissue showed no correlation with clinical symptoms. We strongly recommend that serological testing become a standardized procedure for future studies, to obtain representative data concerning the prevalence of B19V in the heart.

Treatment of a patient with shock complicating severe falciparum malaria: a case report.

INTRODUCTION: Malaria is a potentially life-threatening disease, especially when complicated by a septic shock. When patients present in such a critical condition, the currently available literature allows a dilemma to develop as to which the correct treatment strategy is concerning fluid resuscitation. CASE PRESENTATION: A 55-year-old Caucasian man was admitted to the intensive care unit with the clinical picture of severe malaria, brought by a Plasmodium falciparum infection. On admission, the patient was confused, had high fever up to 40 degrees C, and his blood analysis revealed a severe thrombocytopenia, a parasitemia of 25.5%, and biochemical features indicative of severe malaria. The patient received quinine and underwent two automated red cell exchanges by use of a centrifuge-driven cell separator. Two days after admission, the patient developed a septic shock. He received an "early-goal" treatment, according to the surviving sepsis campaign guidelines, which propose fluid resuscitation. The existing recommendations concerning the treatment of severe malaria that favour a restrictive fluid administration were disregarded. Fluid therapy was guided by regular measurements of the central venous pressure, blood pressure and monitoring of the hemodynamic status. The patient survived the shock and the subsequent multiorgan failure, which required mechanical ventilation and dialysis. After 12 days in the intensive care unit and an additional three weeks of hospitalization, the patient was discharged to rehabilitation. CONCLUSION: The authors believe that in patients with severe malaria complicated by septic shock, the treatment of sepsis and septic shock should be the one of first priority.

Cardiotrophin-1 induces interleukin-6 synthesis in human monocytes.

BACKGROUND: Patients with congestive heart failure (CHF) show increased serum concentrations of cytokines like interleukin-6 (IL-6) and cardiotrophin-1 (CT-1). Additionally, monocyte function is modulated in CHF. The aim of this study was to examine if CT-1 is able to induce IL-6 in human monocytes and to investigate the underlying pathway. METHODS: Separated peripheral blood monocytes of healthy volunteers were cultured with increasing concentrations of CT-1 for different periods. IL-6 mRNA was determined by RT-PCR or real-time PCR and IL-6 protein concentration in the supernatant by ELISA. Phosphorylation of signal transducer and activation of transcription (STAT) 3 was analyzed by western blot or by FACS analysis. To clarify the signalling pathway of CT-1 induced IL-6 expression various inhibitors of possible signal transducing molecules were used. RESULTS: CT-1 induced IL-6 mRNA in monocytes in a time- and concentration-dependent manner. Maximal mRNA induction was detectable after 6h with 100 ng/ml CT-1. IL-6 protein also increased in a time- and concentration-dependent manner with a maximum after 48 h with 100 ng/ml CT-1. AG490 as well as SB 203580 and parthenolide blocked CT-1 induced IL-6 expression completely. AG 490 was able to inhibit STAT3 phosphorylation in western blot analysis completely. This indicates that JAK2/STAT3, p38 and nuclear factor kappaB (NFkappaB) are involved in this pathway. To exclude a possible influence of plastic adherence of monocytes on CT-1 induced IL-6 expression, we determined intracellular STAT3 phosphorylation in whole blood samples by FACS analysis and observed independently of culture conditions a CT-1 concentration-dependent STAT3 phosphorylation. CONCLUSION: CT-1 induces IL-6 mRNA and protein expression in a time- and concentration-dependent manner. The underlying pathway is Janus kinase (JAK)2/STAT3, p38 and NFkappaB dependent. These data may explain increased IL-6 serum concentrations and altered monocyte function found in patients with CHF. Modulation of the CT-1 pathway might be a interesting strategy in the treatment of CHF.

Detection of viral genome in the myocardium: lack of prognostic and functional relevance in patients with acute dilated cardiomyopathy.

BACKGROUND: The presence of viral genome in the myocardium of patients with dilated cardiomyopathy (DCM) has been suggested as causative for the underlying cardiac disease. Nevertheless, the results of present studies are conflicting regarding the natural course of heart diseases associated with detection of viral genome. This study was undertaken to determine if the detection of viral genome in the myocardium of patients with DCM is of functional and prognostic relevance under modern treatment strategies of heart insufficiency. METHODS: In 197 patients with DCM, left ventricular endomyocardial biopsies were performed. Analysis for genome of adenovirus, enterovirus (EV), and parvovirus B19 as well as enteroviral replication and immunohistology was performed. RESULTS: The increase in ejection fraction (EF) was 14.5 +/- 12.4% in the EV-positive group compared with 11.1 +/- 14.2 in the EV-negative group (P = not significant [NS]) after a mean follow-up (FU) of 19.5 and 17.6 months. The increase in EF in the virus-positive group (positive for EV, adenovirus, or parvovirus B19) was 15.3 +/- 13.3% compared with 12.3 +/- 11.9% in the virus-negative group (P = NS) after a mean FU of 17.6 and 11.5 months. There was no significant difference in the change of EF between the EV-positive and virus-negative groups. Detection of enteroviral RNA replication (detection of EV minus-strand RNA) did not result in a deterioration of left ventricular function compared with the virus-negative group (P = NS) after mean FU of 11.2 and 12.0 months. The transplantation-free survival of the patients was not influenced by detection of viral genome. CONCLUSIONS: Our results favor the view that the presence of viral genome in the myocardium of patients with DCM is of no functional and prognostic relevance.

Immunopathogenesis of dilated cardiomyopathy. Evidence for the role of TH2-type CD4+T lymphocytes and association with myocardial HLA-DR expression.

BACKGROUND: An immunological pathogenesis underlying dilated cardiomyopathy and myocarditis has been suggested on the basis of the subtype of lymphocyte infiltrates and the degree of HLA expression in cardiac tissue. In the present study, we investigated the relation between the peripheral CD4+T-cell subset and the degree of HLA expression in the heart. METHODS: Fifty-four patients with heart insufficiency included in the study were biopsied after coronary heart disease had been excluded. Immunohistological staining of the left ventricular tissue were performed employing anti-CD3, -CD4, -CD8, -CD14, and HLA-DR monoclonal antibodies. Intracellular expression of IL-2, IL-4, IL-5, IFN-gamma, and TNF-alpha in peripheral CD4+T lymphocytes was determined using flow cytometry. The severity of heart insufficiency was determined by measurement of brain natriuretic peptide (BNP) and the NYHA class. On the basis of HLA expression in the heart, the patients were divided into three groups: Group I (mild-to-none), Group II (moderate), and Group III (strong-to-very strong). RESULTS: Of the 54 patients included in this study, 33 (61%) patients were diagnosed as having idiopathic dilated cardiomyopathy and 10 (18.5%) borderline or healing myocarditis according to the Dallas criteria. Both patient groups were found in all three HLA-DR groups. There was no difference in BNP level or NYHA class between the three groups. However, a significant difference in the proportion of CD4+T lymphocytes producing IL-2 (39.2 versus 21.8%), IFN-gamma (19.5 versus 7.8%), and TNF-alpha (35.8 versus 16.1%) between Groups I and III could be detected, whereas the distribution of IL-4 and IL-5 producing CD4+T lymphocytes was similar. The myocardium of Group III patients exhibited a significant higher number of CD3+T cells (11.4 versus 4.3 per mm2) and CD4+T cells (4.7 versus 0.8 per mm2) compared to Group I patients, while no difference existed with respect to CD8+T cells. CONCLUSION: High myocardial expression of the HLA-DR antigen is associated with an increase of peripheral-blood CD4+T lymphocytes expressing cytokines of the TH2 subset. The degree of HLA-DR expression is not associated with the degree of heart insufficiency or underlying diagnosis, but correlates with an increase of activated T cells in the myocardium. The data suggest that CD4+T lymphocytes infiltrating cardiac tissue may play a pathogenic role in dilated cardiomyopathy.

Cardiotrophin-1 induces monocyte chemoattractant protein-1 synthesis in human umbilical vein endothelial cells.

In chronic heart failure (CHF) cardiotrophin-1 (CT-1) and monocyte chemoattractant protein-1 (MCP-1) plasma concentrations are elevated. CT-1 is a cytokine of the interleukin-6 (IL-6) superfamily. Most members of the IL-6 family are able to activate human umbilical vein endothelial cells (HUVEC) but so far there are no data which demonstrate that CT-1 can activate HUVEC. Because MCP-1-as a marker of endothelial activation-is elevated in CHF we examined whether CT-1 will induce MCP-1 production in HUVEC. MCP-1 mRNA levels were determined by real time PCR, RT-PCR and northern blot analysis and MCP-1 protein concentrations in the supernatant by ELISA. Signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (pSTAT3) were investigated by western blot analysis. Incubation of HUVEC with different CT-1 concentrations for various time periods induced time and concentration dependent MCP-1 mRNA. Maximal MCP-1 mRNA was reached after 6h. After 24h CT-1 caused a significant induction of MCP-1 protein in the supernatant compared to control. CT-1 induced concentration dependent phosphorylation of STAT3 without any change in total-STAT3 concentration. Piceatannol-a specific blocker of STAT3 phosphorylation-inhibited CT-1 induced MCP-1 induction completely. AG490-a blocker of the JAK2 pathway-was also able to inhibit CT-1 induced MCP-1 upregulation, indicating that the JAK2 pathway is also necessary for MCP-1 induction. Parthenolide-a blocker of NFkappaB-inhibited CT-1 induced MCP-1 expression, completely. Our data show that CT-1 induces in a concentration and time dependent manner MCP-1 mRNA and protein in HUVEC. STAT3 phosphorylation, the activation of JAK2 and NF-kappaB are involved in this pathway. In CHF, CT-1 may be able to induce MCP-1 which might be responsible for progression of heart failure either by recruiting inflammatory cells within the myocardium or by a direct modulation of myocyte function.

Cardiotrophin-1 induces interleukin-6 synthesis in human umbilical vein endothelial cells.

In patients with chronic heart failure (CHF) increased plasma concentrations of proinflammatory cytokines are found. For example, the plasma interleukin-6 (IL-6) concentration correlates with disease severity. Beside IL-6 cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is also increased in CHF. We examined whether CT-1 is able to induce IL-6 in human umbilical vein endothelial cells (HUVEC) and characterised the underlying pathway. IL-6 mRNA was determined by real-time PCR and by RT-PCR in HUVEC which were stimulated with different CT-1 concentrations and for different time periods. IL-6 concentration in the supernatant was determined by ELISA. For the pathway determination following inhibitors were used: piceatannol (signal transducer and activation of transcription (STAT)3 phosphorylation), wortmannin (phosphatiylinositol 3-kinase (PI3K)), SB203580 (p38 mitogen-activated protein kinase (MAPK)), AG490 (Janus kinase (JAK)2), PD98059 (mitogen-activated protein kinase kinase (MEK) 1/2), parthenolide (nuclear factor kappaB) and cycloheximide (protein biosynthesis). CT-1 caused a concentration- and time-dependent increase in IL-6 mRNA in HUVEC with a maximal induction seen after 6 h (2-fold compared to control) with 100 ng/ml CT-1. In the supernatant of HUVEC a concentration- and time-dependent increase of IL-6 protein was found. A maximum effect with 100 ng/ml CT-1 was found after 24 h (11-fold compared to control). AG490, SB203580, piceatannol, parthenolide and cycloheximide inhibit CT-1 induced IL-6 mRNA and protein expression whereas wortmannin and PD98059 did not inhibit IL-6 expression. CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in HUVEC. The underlying pathway includes activation of JAK2, STAT3, p38 and NFkappaB. CT-1 induced IL-6 expression and requires protein synthesis and IL-6 is not stored intracellularly. We speculate that in CHF CT-1 might be in part responsible for increased IL-6 plasma concentrations. Modulation of the CT-1 pathway may be a further strategy in CHF treatment.

Treatment with granulocyte colony-stimulating factor for mobilization of bone marrow cells in patients with acute myocardial infarction.

BACKGROUND: This study was undertaken to evaluate the hypothesis that treatment with granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow cells (BMCs) is feasible and safe and promotes neovascularization and myocardial function in patients with acute myocardial infarction. METHODS: Fourteen patients in the treatment group and 9 patients in the control group were enrolled in this prospective, nonrandomized, open-label study. Forty-eight hours after successful recanalization and stent implantation, the patients of the treatment group received 10 microg/kg body weight per day G-CSF subcutaneously for mean treatment duration of 7.0 +/- 1.0 days. Nine patients fulfilled the entry criteria but refused participation and served therefore as control group. In both groups, regional wall motion and perfusion was evaluated with electrocardiogram-gated sestamibi single-photon emission computed tomography imaging and ejection fraction with radionuclidventriculography before discharge and after 3 months. RESULTS: No severe side effects of G-CSF treatment were observed. There was a significant improvement of the regional wall motion and perfusion within the treatment group (P < .0001) and between the treatment and control group (P < .05 and P < .01, respectively). Ejection fraction in the treatment group increased from 0.40 +/- 0.11 to 0.48 +/- 0.13 (P < .01), whereas in the control group, ejection fraction increased from 0.40 +/- 0.13 to 0.43 +/- 0.13 (P = .049). A control angiography of the treatment group after 12.4 +/- 6.6 months showed an in-stent restenosis in 1 patient. CONCLUSION: In patients with acute myocardial infarction, treatment with G-CSF to mobilize BMCs is feasible and safe and seems to be effective under clinical conditions. The therapeutic effect might be attributed to BMC-associated promotion of myocardial regeneration and neovascularization.

Autologous intracoronary mononuclear bone marrow cell transplantation in chronic ischemic cardiomyopathy in humans.

BACKGROUND: Recent data suggest that transplantation of autologous bone marrow cells (BMC) may contribute to myocardial repair after acute myocardial infarction. We hypothesized that patients with chronic ischemic cardiomyopathy could also benefit from autologous BMC transplantation in addition to established heart failure therapy. METHODS AND RESULTS: Five patients with chronic ischemic cardiomyopathy caused by anterior myocardial infarction, 1.3+/-0.5 years ago and open infarct artery, received autologous mononuclear BMC transplantation via balloon catheter in the target vessel at the site of previous occlusion. Patients were followed up at 3 months (left heart catheterisation, 2D-echocardiography, dobutamine stress echocardiography, cardiopulmonary exercise testing) and at 12 months (2D-echocardiography, cardiopulmonary exercise testing). Follow-up examination showed no significant improvement neither in global, regional, and microvascular function, nor in physical performance. CONCLUSIONS: In this pilot trial intracoronary transplantation of autologous, mononuclear BMC did not lead to any significant improvement in myocardial function and physical performance of patients with chronic ischemic heart disease.

Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion.

BACKGROUND: A good collateral function in patients with regional myocardial dysfunction may indicate viability with the potential for left ventricular (LV) recovery after revascularization of a chronic total coronary occlusion (CTO). METHODS: A CTO (duration > 2 weeks) was successfully recanalized in 126 patients. During this procedure, the collateral function was assessed before the first balloon inflation by intracoronary Doppler and pressure wires. Collateral function indexes were calculated. Left ventricular function was assessed by the LV ejection fraction (LVEF) and the wall motion severity index (WMSI [SD/chords]). A repeat angiography was available in 119 patients after 4.9 +/- 1.4 m. An improvement of WMSI > or =1 SD/chord was considered significant. RESULTS: Left ventricular function was normal in 42%, regional dysfunction with LVEF > or = 0.60 was observed in 16%, and regional dysfunction with LVEF < 0.60 in 42%. The former had a better collateral function than patients with LV dysfunction. In 39% of patients with LV dysfunction, a significant myocardial recovery was observed at follow-up. The collateral function was similar in patients with and without recovery. However, patients with recovery had a lower peripheral resistance as an indicator of a better preserved microvascular integrity. CONCLUSIONS: Recovery of impaired LV function after revascularization of a CTO is not directly related to the quality of collateral function, as collateral development does not appear to require the presence of viable myocardium. However, a preserved microvascular integrity may be of relevance for myocardial recovery.

Growth factors in the collateral circulation of chronic total coronary occlusions: relation to duration of occlusion and collateral function.

BACKGROUND: Despite extensive animal experimental evidence, there are few data on the relation of growth factors and collateral function in humans. METHODS AND RESULTS: In 104 patients with a chronic total coronary occlusion (CTO; >2 weeks' duration), collateral function was assessed invasively during recanalization by intracoronary Doppler and pressure recordings. A collateral resistance index, R(Coll), was calculated. Blood samples were drawn from the distal coronary bed supplied by the collaterals and from the aortic root to measure basic fibroblast growth factor (bFGF), monocytic chemotactic protein-1 (MCP-1), transforming growth factor-beta (TGF-beta), placenta growth factor (PlGF), and tumor necrosis factor-alpha (TNF-alpha). The bFGF concentration in the collateralized artery was higher than in the aortic root (34+/-20 versus 18+/-14 pg/mL; P<0.001). bFGF was highest in recent occlusions (2 to 12 weeks) with the highest R(Coll). Higher collateral concentrations were also observed for MCP-1, TGF-beta, and PlGF, but without a close relation to the duration of occlusion. TNF-alpha was not increased in collaterals compared with the systemic circulation. MCP-1, PlGF, and TGF-beta were significantly increased in small collaterals with the highest shear stress. Diabetic patients had lower bFGF and higher MCP-1 levels than nondiabetics. CONCLUSIONS: In CTOs, the continuous release of bFGF into collaterals showed a close relation to the duration of occlusion and collateral function, which underscores its therapeutic potential. Other factors influencing growth factor release appeared to be shear stress for MCP-1, TGF-beta, and PlGF and the presence of diabetes.

Lack of regeneration of myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans with large anterior myocardial infarctions.

BACKGROUND: Experimental and preliminary clinical data suggest that transplantation of autologous bone marrow cells (BMC) may contribute to regeneration of the myocardium after acute myocardial infarction. This approach should be tested in patients with large infarctions in whom a positive effect would be most beneficial. METHODS AND RESULTS: After successful recanalization within 5.9 +/- 2.5 h and stent implantation in five patients with a large acute anterior myocardial infarction (AMI), the patients received autologous mononuclear BMCs via a balloon catheter placed into the left anterior descending artery 6.3 +/- 0.4 days after revascularization. At 3-month follow-up, no improvement was observed for left ventricular ejection fraction, regional wall motion in the infarcted zone, contractility index measured via dobutamine stress echocardiography, coronary blood flow reserve and maximal oxygen uptake, respectively. After further follow-up of 12 months, again no change of the left ventricular ejection fraction could be detected. CONCLUSIONS: Intracoronary transplantation of autologous mononuclear BMCs did not improve cardiac function in our patients with large anterior myocardial infarctions after 3 and 12 months.

Angiographic assessment of collateral connections in comparison with invasively determined collateral function in chronic coronary occlusions.

BACKGROUND: The evaluation of new therapeutic modalities to induce collateral growth in coronary artery disease require improved methods of angiographic characterization of collaterals, which should be validated by quantitative assessment of collateral function. METHODS AND RESULTS: In 100 patients with total chronic occlusion of a major coronary artery (duration >2 weeks) collaterals were assessed angiographically by the Rentrop grading, by their anatomic location, and by a new grading of collateral connections (CC grade 0: no continuous connection, CC1: threadlike continuous connection, CC2: side branch-like connection). The interobserver variability was 10%. Collateral function was assessed by Doppler flow (average peak velocity) and pressure recordings distal to the occlusion before recanalization. A collateral resistance index (RColl) was calculated. Recruitable collateral flow was measured during a final balloon inflation >30 minutes after the baseline measurement. The comparison of the anatomic location, the Rentrop, and the collateral connection grade showed only for the latter an independent and significant relation with RColl. CC2 collaterals preserved regional left ventricular function better than did CC1 collaterals and provided a higher collateral flow reserve during adenosine infusion. CC0 collaterals were predominantly observed in recent occlusions of 2 to 4 weeks' duration, with the highest RColl. During balloon reocclusion, recruitable collateral function was best preserved with CC2 and least with CC0. CONCLUSIONS: The angiographic grading of collateral connections in total chronic occlusions could differentiate collaterals according to their functional capacity to preserve regional left ventricular function and was closely associated with invasively determined parameters of collateral hemodynamics.