Update on cardiac stem cell therapy in heart failure.

PURPOSE OF REVIEW: Presentation of the current status of cardiac stem cell therapy for the treatment of ischaemic heart failure by highlighting recent clinical results and introducing ongoing trials. Furthermore, necessary upcoming procedural adjustments are discussed. RECENT FINDINGS: During the last decade, stem cell application in the setting of ischaemic heart failure has been evaluated in phase I and II clinical trials, proving safety and feasibility of this approach. Functional results gained so far indicate moderate benefits. However, conclusive evaluation of cell therapy will not be possible before completion of ongoing phase III multicentre trials. Moreover, questions regarding the optimal cell population for treatment in a chronic setting and the favourable time-point of cell delivery have not been ultimately answered. SUMMARY: Cell therapy for the treatment of ischaemic heart failure needs to be evaluated separately from the setting of acute myocardial infarction. In parallel with upcoming clinical evaluation in large-scale trials, further optimization of the 'cell product' regarding the favourable cell type and periprocedural processing, as well as route and time-point of application, is mandatory.

Accumulation of VEGFR-2+/CD133+ cells and decreased number and impaired functionality of CD34+/VEGFR-2+ cells in patients with SLE.

OBJECTIVE: Inflammation and atherosclerosis are the major causes of cardiovascular disease (CVD) in SLE. Both traditional and disease-specific risk factors contribute to the formation of endothelial dysfunction. Endothelial progenitor cells (EPCs) have the ability to restore endothelial integrity. The aim of this study was to determine whether the number and function of EPCs are altered in SLE. METHODS: Nineteen patients with SLE and 19 controls were analysed. VEGF receptor-2 (VEGFR-2)(+)/CD133(+) and CD34(+)/VEGFR-2(+) cells were quantified by flow cytometry. EPC differentiation was measured by DiI-acLDL/Lectin I staining. Furthermore, apoptosis, proliferation capacity, migration capacity and clonogenic ability of EPCs were determined. RESULTS: VEGFR-2(+)/CD133(+) cells were enhanced in SLE [215 (37) vs 122 (11) cells/1 x 10(6) lymphocytes; P = 0.029], whereas the number [106 (13) vs 215 (27) cells/1 x 10(6) lymphocytes; P = 0.002] and the proliferation rate [96% (6%) vs 143% (19%); P = 0.008] of CD34(+)/VEGFR-2(+) cells were decreased compared with controls. Additionally, EPCs in SLE showed an increased apoptosis [7% (1.4%) vs 3% (0.4%); P = 0.004], an impaired differentiation [36 (5) vs 121 (20) cells/mm(2); P < 0.001] and a reduced migratory capacity [116% (4%) vs 139% (4%); P = 0.001]. CONCLUSIONS: Our results suggest that the mobilization of progenitor cells is unaffected in SLE, but the diminished number and the altered functionality of circulating CD34(+)/VEGFR-2(+) cells reduce the ability to repair vascular damage and thus may trigger the development of atherosclerosis in SLE.

Ivabradine as an alternative therapeutic trial in the therapy of inappropriate sinus tachycardia: a case report.

Inappropriate sinus tachycardia is a disease which is relatively rarely found and sometimes difficult to treat. Up to now it has been mostly treated with a beta-blocker or verapamil. If this did not work sinus node modulation was considered. Since the relatively new selective IF-stream blocker ivabradine has been approved for the therapy of chronic stable angina pectoris, a new therapeutic option is available. As ivabradine is well tolerated and only few side effects are known, it may become a new therapeutic step between medication and the invasive sinus node modulation. We report the case of a young female patient with inappropriate sinus tachycardia where a sustained therapeutic success was achieved with ivabradine medication as an alternative therapeutic trial after various ineffective medications.

Evidence for in vivo transport of bioactive nitric oxide in human plasma.

Although hitherto considered as a strictly locally acting vasodilator, results from recent clinical studies with inhaled nitric oxide (NO) indicate that NO can exert effects beyond the pulmonary circulation. We therefore sought to investigate potential remote vascular effects of intra-arterially applied aqueous NO solution and to identify the mechanisms involved. On bolus application of NO into the brachial artery of 32 healthy volunteers, both diameter of the downstream radial artery and forearm blood flow increased in a dose-dependent manner. Maximum dilator responses were comparable to those after stimulation of endogenous NO formation with acetylcholine and bradykinin. Response kinetics and pattern of NO decomposition suggested that despite the presence of hemoglobin-containing erythrocytes, a significant portion of NO was transported in its unbound form. Infusion of NO (36 micromol/min) into the brachial artery increased levels of plasma nitroso species, nitrite, and nitrate in the draining antecubital vein (by < 2-fold, 30-fold, and 4-fold, respectively), indicative of oxidative and nitrosative chemistry. Infused N-oxides were inactive as vasodilators whereas S-nitrosoglutathione dilated conduit and resistance arteries. Our results suggest that NO can be transported in bioactive form for significant distances along the vascular bed. Both free NO and plasma nitroso species contribute to the dilation of the downstream vasculature.

Sudden death is associated with a widened paced QRS complex in noncoronary cardiac disease.

INTRODUCTION: Recent experimental and clinical trials have provided evidence that increased duration of right ventricular electrogram in response to premature extrastimuli correlates with the risk of ventricular fibrillation in noncoronary heart disease. The aim of the present study was to investigate the duration of the surface QRS complex at short coupling intervals of extrastimuli as a new indicator for major arrhythmic events. METHODS: 32 patients all with nonischemic heart diseases and well preserved left ventricular function in sinusrhythm were included into the study. Fifteen had witnessed sudden death due to ventricular fibrillation or polymorphic ventricular tachycardia (VF/VT group). The control group comprised seventeen patients without a history of ventricular arrhythmias (control group). All subjects underwent programmed ventricular stimulation and QRS-durations S1-S2-S3 directly above the ventricular refractory period were analyzed. RESULTS: Both groups had a comparable basic QRS complex of 85 +/- 9 (VF/VT) vs. 87 +/- 13 ms (control), p = 0.83. The stimulated QRS complex S3 was significantly wider in the VF/VT group compared to the control group at pacing rates of 500 and 430 ms (500 ms: 256 +/- 22 vs. 235 +/- 32 ms, p = 0.04; 430 ms: 258 +/- 23 vs. 226 +/- 27 ms, p = 0.001). No differences with regard to the ventricular effective refractory period and the ventriculoatrial conduction could be observed beween the groups. CONCLUSIONS: Our results indicate that the duration of the paced QRS complex may be a valuable parameter to predict arrhythmic risk in patients with nonischemic heart disease. Further prospective studies in larger trials are necessary to corroborate this investigation.

Autologous mononuclear stem cell transplantation in patients with peripheral occlusive arterial disease.

UNLABELLED: Patients with chronic peripheral occlusive arterial disease often are not candidates for conventional revascularization procedures. Preclinical trials have shown that the transplantation of autologous bone marrow cells induces and increases the collateral vessel formation. We analyzed the clinical benefit of combined intraarterial and intramuscular transplantation of adult autologous mononuclear bone marrow stem cells in patients with lower-limb peripheral occlusive arterial disease. METHODS: Patients with severe peripheral occlusive arterial disease and a reduced walking distance (Fontaine stage II or III) were included. Bone marrow was harvested from the hip under local anesthesia and mononuclear cells were transplanted intramuscularly and intraarterially into the ischemic limb after isolation under good manufacturing practice conditions. RESULTS: After 2 months, pain-free walking distance increased 3.7-fold. Furthermore, the ankle-brachial index was significantly improved at rest and after exercise. Similar improvements could be documented by capillary-venous oxygen saturation and venous occlusion plethysmography. No side effects or complications were detected during transplantation and during time of follow-up. CONCLUSIONS: Combined intraarterial and intramuscular transplantation of autologous mononuclear bone marrow stem cells is a clinically feasible and minimally invasive therapeutic option for patients with severe, chronic peripheral occlusive arterial disease.

[Chronic inflammatory bowel disease and cardiovascular complications]. / Kardiovaskuläre Manifestationen bei chronisch-entzündlichen Darmerkrankungen.

The most common extraintestinal manifestations of Crohn's disease and ulcerative colitis are iritis and uveitis, primary sclerosing cholangitis (PSC) and nodal erythema and pyoderma gangrenosum. Complications within the cardiovascular system seem to be uncommon, but there are no systematic investigations concerning the epidemiology of these manifestations. There are more than 100 cases reported about pericarditis and perimyocarditis in patients with inflammatory bowel disease. Other patients with Crohn's disease or ulcerative colitis suffer from vasculitis, representing a further mechanism of inflammatory diseases of the cardiovascular system. There are several case reports showing a combination of Takayasu's arteritis and Crohn's disease, and cross-reacting antibodies against gut mucosa and aortic tissue were found. Some patients developed thrombotic complications by activating the coagulation system, which can result in atrial thrombi, embolism of the pulmonary arteries, myocardial infarction and disseminated intravascular coagulopathy (DIC). Furthermore, a few case were reported about atrio ventricular blocks, amyloidosis of the heart, dilative cardiomyopathy and endomyocardial fibrosis in patients with chronic inflammatory bowel disease. Here, a 27-year-old patient with known ulcerative colitis for 2 years is reported, who presented in the authors' department with unstable angina pectoris. Coronary angiographic examination was immediately performed and diffuse intracoronary thrombi were found, which could be removed by the catheter procedure. A myocardial infarction did not develop. Because of positive anti neutrophil cytoplasmic antibodies (p-ANCA) a p-ANCA-positive arteritis of the coronary vessels with intracoronary thromboembolism due to ulcerative colitis was diagnosed. Systematic studies or investigations concerning the epidemiology of the cardiovascular complications are still lacking, so that an overview about the published data is given.

[Therapy of acute decompensated heart failure with levosimendan]. / Akute hämodynamische und klinische Effekte von Levosimendan in der Therapie des kardiogenen Schocks.

PURPOSE: To determine the short-term hemodynamic and clinical effects of levosimendan, a calcium-sensitizing agent, in patients with decompensated heart failure. PATIENTS AND METHODS: Seven patients with cardiogenic shock requiring catecholamines (two patients with acute myocardial infarction, two patients with decompensated hypertensive heart disease, one patient with low cardiac output with ischemic cardiomyopathy, two patients with dilated cardiomyopathy [ethyl-toxic, polymyositis] with a cardiac index < or = 2.5 ) 1 x min(-1) x m(-2) and a pulmonary wedge pressure > or = 15 mmHg received levosimendan with an initial loading dose of 12 microg/kg over 10 min followed by a continuous infusion of 0.1 microg/kg/min for 24 h. RESULTS: During levosimendan infusion an increase in cardiac index (30% after 6 h and 24 h), a decrease in heart rate (4% after 6 h and 10% after 24 h, respectively), and a decrease in systemic vascular resistance (27% after 6 h and 41% after 24 h, respectively) appeared. In combination with volume resuscitation the pulmonary capillary wedge pressure increased. Under therapy with levosimendan no relevant adverse events occurred; there was no increase in severe cardiac arrhythmias and QT interval duration. CONCLUSION: Levosimendan causes rapid improvement in hemodynamic function in patients with cardiogenic shock. These hemodynamic effects are not associated with relevant adverse events. Levosimendan may be of value in the short-term management of patients with cardiogenic shock.

HFE mutations in idiopathic dilated cardiomyopathy.

BACKGROUND AND PURPOSE: Dilated cardiomyopathy is a typical complication of hereditary hemochromatosis (HH). The present study investigated, whether mutations of the hemochromatosis (HFE) gene might be etiologic and disease-modifying factors in idiopathic dilated cardiomyopathy PATIENTS AND METHODS: Clinical and biochemical assessment and HFE gene analysis were perfomed in 46 patients with IDCM and 350 healthy controls. Cardiomyopathy was angiographically defined according to the criteria of the Collaborative Research Group of the European Human and Capital Mobility Project of Familial Dilated Cardiomyopathy. RESULTS: A higher prevalence of C282Y homozygosity was found among patients with IDCM compared to healthy subjects (4.3% vs. 0.6%; p < 0.02). A total of 6.5% of the patients with IDCM were either C282Y homozygotes or C282Y/H63D compound heterozygotes. The C282Y allele frequency was somewhat higher among patients with IDCM (8.7%) compared to healthy controls (5.4%; p < 0.2), whereas the H63D allele frequency was not increased. No significant differences of serum iron, ferritin or transferrin saturation, cardiac iron loading, NYHA classification, Lown's classification, the history of cardiopulmonary resuscitation, LVEDD (left ventricular end-diastolic diameter), EF (ejection fraction), LADD (left atrial end-diastolic diameter) and CI (cardiac index) were seen between HFE carriers and noncarriers. CONCLUSION: The present study indicates that it is worth screening patients with IDCM for iron parameters given the increased prevalence of disease-predisposing HFE constellations. It remains unclear, to what extent iron or immune-mediated processes contribute to the pathomechanism of IDCM.

[Transplantation of autologous adult bone marrow stem cells in patients with severe peripheral arterial occlusion disease]. / Transplantation von autologen adulten Knochenmarkstammzellen bei Patienten mit schwerer peripherer arterieller Verschlusskrankheit.

BACKGROUND: For many patients with severe peripheral arterial occlusion disease (PAOD) an interventional or surgical treatment is not feasible. The regenerative potential of adult autologous mononuclear stem cells could contribute to neoangiogenesis. PATIENTS AND METHODS: Ten patients with severe PAOD were included. The walking distance was < 200 m and no interventional or surgical treatment was possible. After harvesting of 80 ml of bone marrow the mononuclear cell fraction was separated. Thereafter, intraarterial (10 ml into the common femoral artery) and intramuscular (5 ml into the muscles of the thigh and the lower leg) transplantation of the cell suspension was performed. RESULTS: After 2 months the walking distance was enhanced significantly in all patients. Furthermore, a significant improvement of ankle-brachial index at rest, capillary-venous oxygen saturation and parameters of venous occlusion plethysmography was seen. No complications or side effects could be monitored. CONCLUSION: These results demonstrate, that the combined intraarterial and intramuscular transplantation of autologous adult bone marrow stem cells leads to a significant improvement of perfusion indices in patients with severe PAOD.

[Effects of exercise training on mobilization of BM-CPCs and migratory capacity as well as LVEF after AMI]. / Die Effekte von körperlichem Training auf die Mobilisation und funktionelle Aktivität zirkulierender Progenitorzellen aus dem Knochenmark sowie die LVEF nach akutem Myokardinfarkt.

BACKGROUND AND PURPOSE: Bone marrow-derived circulating progenitor cells (BM-CPCs) are mobilized in adult peripheral blood (PB) during the acute myocardial infarction (AMI) period and contribute to the regeneration of infarcted myocardium. In this study, the influence of physical training on the mobilization and the migratory activity of the BM-CPCs as well as on the left ventricular function (LVEF) after AMI was examined. PATIENTS AND METHODS: 26 patients with AMI were analyzed in two groups. The first group comprised 17 patients with standardized exercise training for 3 weeks 14 +/- 4 days after AMI, the second group nine control subjects without exercise training. PB concentrations of CD34/45+ and CD133/45+ were measured by FACS. The migratory activity of BM-CPCs was analyzed by migration assay. B-type natriuretic peptide (BNP) in PB and the functional investigations spiroergometry (VO2 and PaO2) and stress echocardiography (LVEF) were determined in both groups. RESULTS: A significant increase in both concentrations, CD34/45+ and CD133/45+, as well as in migratory capacity of BM-CPCs was found after 3 weeks of exercise training, which was significantly decreased 3 months after completion of exercise training. No significant difference was observed in the control group without exercise training. In the functional investigations a significant increase in VO2 as well as PaO2 was shown spiroergometrically after exercise training. There was no difference in stress echocardiographic LVEF at rest in both groups. On the other hand, interestingly, the findings showed that the increase of LVEF at peak stress was significantly higher after exercise training as compared to the control group. Moreover, a significant decrease in BNP values was found after exercise training as well as 3 months after AMI. No difference was found in the control group. CONCLUSION: This study demonstrates that exercise training for 3 weeks after AMI leads to a significant mobilization as well as increase of functional activation of BM-CPCs in humans. Moreover, regular exercise training might contribute to the positive effects on the regenerative potency after AMI.

[Rapid healing of a therapy-refractory diabetic foot after transplantation of autologous bone marrow stem cells]. / Schnelle Abheilung eines therapierefraktären diabetischen Fusses nach autologer Knochenmarkstammzelltransplantation.

BACKGROUND: The diabetic foot mainly depends on painless pressure lesions, which are based on diabetic polyneuropathy and microangiopathy. In these cases the regenerative potential of adult autologous mononuclear stem cells could serve as causal therapy. HISTORY AND CLINICAL FINDINGS: A 63-year-old patient with long-lasting type 2 diabetes mellitus suffers from a reduced walking distance of 200 m and a therapy-refractory ulcer at the right ball of the great toe. Therefore, the authors have decided to perform a combined intraarterial and intramuscular transplantation of stem cells into the right limb for the first time on this disease. THERAPY AND RESULTS: After harvesting of bone marrow the mononuclear cell fraction was separated (157 x 10(6) cells). Thereafter, the fractional intraarterial and intramuscular transplantation of the cell suspension was performed (10 ml each). Already 8 weeks later, the ulcer healed completely, after 6 months the walking distance increased by > 100%, on venous occlusion plethysmography the arterial blood circulation at rest increased by 23% and the reactive hyperemia by 56%. CONCLUSION: The combined intraarterial and intramuscular transplantation of autologous bone marrow stem cells could constitute a novel, clinically feasible and safe therapy for patients with diabetic foot syndrome. The success of this approach may be ascribed to microangiogenesis and to an anti-inflammatory effect of the transplanted stem cells.

A prospective study on incidence and risk factors of arteriovenous fistulae following transfemoral cardiac catheterization.

BACKGROUND: A potentially harmful complication of cardiac catheterization is the arteriovenous fistula. Precise knowledge of possible factors predisposing for acquisition of iatrogenic AV-fistulae could enable cardiologists to perform a risk stratification for cardiac patients prior to catheterization. METHODS: Over a period of 2 years, 10,271 consecutive patients who underwent cardiac catheterization were included in this study. Auscultation of a new femoral bruit was followed by a duplex scan to confirm the suspected diagnosis of an AVF. Every patient was investigated on the day after catheterization. RESULTS: The incidence of iatrogenic AVF was 0.86%. A multivariate regression analysis revealed five significant and independent risk factors: (1) procedural heparin dosage >or=12,500 IU (Odds Ratio (OR)=2.88), (2) coumadin therapy (OR=2.34), (3) puncture of the left groin (OR=2.21), (4) arterial hypertension (OR=1.86) and (5) female gender (OR=1.84). Coronary angioplasty (instead of diagnostic procedure), size and number of sheaths, age and body mass index did not significantly affect the incidence of AVF. CONCLUSIONS: The overall incidence of AV-fistulae following cardiac catheterization approximates 1%. Determination of significant risk factors will facilitate identification of patients at risk for iatrogenic arteriovenous fistulae prior to cardiac catheterization and thus help to develop strategies to reduce the incidence of AV-fistulae.

[The current status of noninvasive cardiac diagnosis in women with suspected coronary heart disease]. / Stellenwert der nichtinvasiven kardialen Diagnostik bei Frauen mit Verdacht auf koronare Herzkrankheit.

BACKGROUND AND OBJECTIVE: Coronary artery disease is the leading cause of mortality among women in the industrial countries. Unfortunately, the routinely available noninvasive tests used to screen the presence of coronary artery disease have been relatively insensitive and nonspecific for women. The aim of this study was to evaluate the importance of pretest coronary artery disease probability and to determine whether the evaluation of left ventricular diastolic parameters is a relevant diagnostic tool in women with suspected coronary artery disease. PATIENTS AND METHODS: Electrocardiography at rest and during exercise, echocardiography at rest with evaluation of systolic and diastolic functional parameters, dobutamine stress echocardiography, exercise thallium myocardial scintigraphy, and coronary angiography were performed in 180 consecutive patients with suspected coronary artery disease. RESULTS: Coronary angiography revealed significant coronary artery disease in 104 patients. Angina pectoris, resting and exercise electrocardiography had a very low pretest probability in women. Dobutamine stress echocardiography, myocardial scintigraphy and the evaluation of left ventricular diastolic function showed less relevant gender-related differences and had a significantly better pretest probability. CONCLUSION: Dobutamine stress echocardiography and exercise thallium myocardial scintigraphy are reliable methods of diagnosing coronary artery disease in women. Echocardiographic assessment of diastolic left ventricular function represents another screening test for the evaluation of suspected coronary artery disease in women. All three methods, however, are not able to discriminate between coronary macro- or microangiopathy.

10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice.

Intracoronary and intramyocardial stem cell therapy aim at the repair of compromised myocardium thereby--as a causal treatment--preventing ventricular remodeling and improving overall performance. Since the first-in-human use of bone marrow stem cells (BMCs) after acute myocardial infarction in 2001, a large number of clinical studies have demonstrated their clinical benefit: BMC therapy can be performed with usual cardiac catheterization techniques in the conscious patient as well as also easily during cardiosurgical interventions. New York Heart Association severity degree of patients as well as physical activity improve in addition to ("on top" of) all other therapeutic regimens. Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous BMC therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials.

The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study.

AIMS: Despite accumulated evidence that intracoronary bone marrow cell (BMC) therapy may be beneficial in acute myocardial infarction, there are only limited data available on the effectiveness of BMC's in chronic heart failure. The aim of this study was to quantitatively investigate ventricular haemodynamics, geometry, and contractility as well as the long-term clinical outcome of BMC treated patients with reduced left ventricular ejection fraction (LVEF) due to chronic ischaemic cardiomyopathy. METHODS AND RESULTS: Patients with chronic heart failure (n = 391 LVEF

Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion.

BACKGROUND: Obstructive sleep apnea (OSA) is thought to act as a coronary risk factor. There is emerging evidence that intermittent phases of hypoxia might contribute to alterations of the cardiovascular system. We hypothesized that OSA syndrome (OSAS) might be accompanied by an increased coronary collateral vessel (CCV) development in patients with total coronary occlusion. METHODS: Thirty-four patients with total coronary occlusions were classified according to the apnea-hypopnea index (AHI) (OSAS: AHI > 10/h; non-OSAS: AHI < 10/h). CCVs were scored by visual analysis and were analyzed according to the Cohen and Rentrop grading system. RESULTS: There was no significant discrepancy between the groups concerning the prevalence of age, gender, the presence of hypertension, smoking, or diabetes mellitus. There was no difference in left ventricular systolic function (ejection fraction 53% +/- 20% vs 61% +/- 20%, P = .29) or left ventricular end-diastolic pressure (22.6 +/- 8.5 mm Hg vs 18.5 +/- 7.7 mm Hg, P = .41). OSAS showed a higher Rentrop score compared with non-OSAS (1.61 +/- 1.2 vs 2.4 +/- 0.7, P = .02). CONCLUSIONS: These findings suggest that CCV development is augmented in patients with OSA.

The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction.

OBJECTIVES: The aim of this study was to investigate the quantitative amount of improvement of ventricular hemodynamic status, geometry, and contractility as well as the long-term clinical outcome of cell-treated patients after acute myocardial infarction (AMI). BACKGROUND: Animal experiments as well as clinical studies have demonstrated that autologous bone marrow cell (BMC) transplantation might improve ventricular function and prevent remodeling. METHODS: Sixty-two patients underwent intracoronary autologous BMC transplantation 7 +/- 2 days after AMI. Cells were infused directly into the infarct-related artery. The control group consisted of 62 patients with comparable left ventricular (LV) ejection fraction (EF) and diagnosis. All patients had several examinations (e.g., coronary angiography, right heart catheterization, biplane left ventriculography, electrocardiogram [ECG] at rest and exercise, echocardiography, late potential [LP], heart rate variability [HRV], and 24-h Holter ECG). The therapeutic follow-up was performed 3, 12, and 60 months after BMC therapy. RESULTS: Three months after BMC therapy there was significant improvement of EF and stroke volume index. The infarct size was significantly reduced by 8%. Contraction velocities (lengths/second, volumes/second) increased significantly and the slope of the ventricular function curve (systolic pressure/end-systolic volume) became steeper. There was significant improvement of contractility in the infarct zone, as evidenced by a 31% increase of LV velocity of shortening (VCF), preferably in the border zone of the infarct zone. In contrast, the noninfarcted area showed no difference in VCF before and after BMC therapy. Furthermore, decreases of abnormal HRV, LP, and ectopic beats were documented after BMC therapy. Twelve and 60 months after BMC therapy the parameters of contractility, hemodynamic status, and geometry of the LV were stable. The exercise capacity of treated patients was significantly augmented, and the mortality was significantly reduced in comparison with the control group. CONCLUSIONS: BMC therapy leads to significant and longstanding improvements of LV performance as well as quality of life and mortality of patients after AMI. After BMC therapy, no side effects were observed, showing that BMC therapy is safe.

Enhanced mobilization of CD34(+) progenitor cells expressing cell adhesion molecules in patients with STEMI.

BACKGROUND: Adult stem cells can contribute to myocardial regeneration after ischemic injury. The aim of the study was to determine (1) the amount of mobilized CD34(+)/CD117(+), CD34(+)/KDR(+) cells into peripheral blood (PB) in relation to inflammatory and haematopoietic cytokines, (2) the presence of circulating CD34(+) cells, expressing cell adhesion molecules (CAM), in patients with ST-segment elevation myocardial infarction (STEMI) in comparison to patients with coronary artery disease (CAD). MATERIALS AND METHODS: Twenty-three patients with STEMI (<12 h), 24 patients with CAD and 15 control subjects were enrolled in this study. The patients were matched in age, 2-CAD, ejection fraction (45%) and end-diastolic volume index (70 ml/m(2)). The number of stem cells and the expression of adhesion molecules were quantified by use of flow cytometry. Inflammatory cytokines [interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor] and chemotactic factors as stromal cell-derived factor-1 (SDF-1), hepatocyte growth factor (HGF) were determined by ELISA. RESULTS: The amount of circulating progenitor cells including CD34(+)/CD117(+) and CD34(+)/KDR(+) cells was significantly higher in patients with STEMI than in patients with CAD (CD34(+)/CD117(+) 433 +/- 128 vs. 100 +/- 17, P = 0.012; CD34(+)/KDR(+) 253 +/- 41 vs. 128 +/- 24, P = 0.02). The mobilization of CD34(+) progenitor cells expressing CXCR4-receptor, lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and ICAM-1 into PB was significantly higher in patients with STEMI compared to CAD (CD34(+)/CXCR4(+) 740 +/- 327 vs. 136 +/- 23, P = 0.006; CD34(+)/LFA-1 976 +/- 227 vs. 329 +/- 41, P = 0.025; CD34(+)/VLA4(+) 830 +/- 161 vs. 330 +/- 31, P = 0.007; CD34(+)/ICAM(+) 387 +/- 66 vs. 144 +/- 26, P < 0.001). Additionally, the cytokines G-CFS, IL-6 and HGF were upregulated and significantly increase in the STEMI group compared with controls and CAD (G-CSF 50.6 +/- 6.8 vs. 23 +/- 3 vs. 23.8 +/- 2, P (Co vs. STEMI) < 0.001, P (Co vs. CAD) = n.s., P (STEMI vs. CAD) < 0.001; IL-6 8.4 +/- 0.6 vs. 3.8 +/- 1.9 vs. 2.6 +/- 1, P (Co vs. STEMI) < 0.001, P (Co vs. CAD) = n.s., P (STEMI vs. CAD) < 0.001; HGF 4,502 +/- 461 vs. 686 +/- 195 vs. 1,746 +/- 461, P (Co vs. STEMI) < 0.001, P (Co vs. CAD) = n.s., P (STEMI vs. CAD) < 0.001), while the level of SDF-1 was increased in patients with CAD compared to controls and patients with STEMI (3,035 +/- 286 vs. 2,028 +/- 76 vs. 2,154 +/- 234, P (Co vs. STEMI) = n.s., P (Co vs. CAD) = n.s., P (STEMI vs. CAD) = 0.005). CONCLUSIONS: The study demonstrates in patients with STEMI an increased mobilization of progenitor cells like CD34(+)/CD117(+) and CD34(+)/KDR(+) compared to CAD. Furthermore, we could shown that in patients with STEMI the mobilization of CD34(+) progenitor cells with expressed CAM was increased. It is to speculate that an enhanced expression of adhesion molecules may increase the transmigration and implantation of progenitor cells into ischemic myocardium for myocardial repair.