M. Brehm

Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction

Autologous bone marrow cell transplantation (BMCs‐Tx) is a promising novel option for treatment of cardiovascular disease. We analysed in a randomized controlled study the influence of the intracoronary autologous freshly isolated BMCs‐Tx on the mobilization of bone marrow–derived circulating progenitor cells (BM‐CPCs) in patients with acute myocardial infarction (AMI). Sixty‐two patients with AMI were randomized to either freshly isolated BMCs‐Tx or to a control group without cell therapy. Peripheral blood (PB) concentrations of CD34/45+‐ and CD133/45+‐circulating progenitor cells were measured by flow cytometry in 42 AMI patients with cell therapy as well as in 20 AMI patients without cell therapy as a control group on days 1, 3, 5, 7, 8 and 3, 6 as well as 12 months after AMI. Global ejection fraction (EF) and the size of infarct area were determined by left ventriculography. We observed in patients with freshly isolated BMCs‐Tx at 3 and 12 months follow up a significant reduction of infarct size and increase of global EF as well as infarct wall movement velocity. The mobilization of CD34/45+ and CD133/45+ BM‐CPCs significantly increased with a peak on day 7 as compared to baseline after AMI in both groups (CD34/45+: P < 0.001, CD133/45+: P < 0.001). Moreover, this significant mobilization of BM‐CPCs existed 3, 6 and 12 months after cell therapy compared to day 1 after AMI. In control group, there were no significant differences of CD34/45+ and CD133/45+ BM‐CPCs mobilization between day 1 and 3, 6 and 12 months after AMI. Intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system in patients with AMI may enhance and prolong the mobilization of CD34/45+ and CD133/45+ BM‐CPCs in PB and this might increase the regenerative potency after AMI.

Factors influencing spontaneous mobilization of CD34+ and CD133+ progenitor cells after myocardial infarction.

Background  Bone marrow‐derived circulating progenitor cells (BM‐CPCs) are mobilized into adult peripheral blood (PB) during acute myocardial infarction (AMI) and may contribute to the regeneration of infarcted myocardium. The purpose of the present study is to determine whether mobilization of BM‐CPCs into PB depends on cardiovascular risk factors (CVRFs), age of patients, infarct associated inflammatory markers, and left ventricular function after AMI.

The therapeutic potential of stem cells in heart disease.

Abstract.  Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non‐ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart disease.

EFFECTS OF EXERCISE TRAINING ON MOBILIZATION AND FUNCTIONAL ACTIVITY OF BLOOD-DERIVED PROGENITOR CELLS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

BackgroundThe aim of the present study was to determine whether regular exercise training (ET) is effective at promoting the mobilization of CPCs and improving their functional activity in patients with recently acquired myocardial infarction(STEMI). Regular physical training has been shown to improve myocardial perfusion and cardiovascular function. This mayberelatedin part to a mobilization of bonemarrow-derived circulating progenitor cells (CPCs) as well as an enhanced vascularisation.Methods37 patients with STEMI were randomly assigned to an ET group or a non-ET group(controls). Two weeks after STEMI, three weeks after regular ET and three months after ET, BNP levels, exercise echocardiography and exercise spiroergometry were evaluated. The number of CD34+/CD45+ and CD133+/CD45+CPCs was measured by flow cytometry analysis. The migration capacity of the CPCs was determined with a boyden chamber and the clonogenic capacity by CFU-assay.ResultsIn the ET-group the number and migration capacity of CPCs increased significantly after regular exercise training. The BNP level decreased significantly from 121 ± 94 to 75 ± 47 pg/ml (p < 0.001) after the ET period, the left ventricular rejection fraction raised in parallel at peak exercise, and the cardiorespiratory condition improved as demonstrated by an increase of VO2max (from 1641 ± 522 to 1842 ± 724 ml/min, p < 0.02). These three effects persist till three months after the ET period.ConclusionsRegular physical activity appears to predispose the mobilization and enhanced functional activity of CPCs, a phenomenon which might lead to an improved cardiac function in patients with recently acquired acute myocardial infarction.

Improved Mobilization of the CD34+ and CD133+ Bone Marrow-Derived Circulating Progenitor Cells by Freshly Isolated Intracoronary Bone Marrow Cell Transplantation in Patients with Ischemic Heart Disease

Cell therapy is a promising novel option for treatment of cardiovascular disease. Because the role of bone marrow-derived circulating progenitor cells (BM-CPCs) after cell therapy is less clear, we analyzed in this randomized, controlled study the influence of intracoronary autologous freshly isolated bone marrow cell transplantation (BMC-Tx) by using a point-of-care system on cardiac function and on the mobilization of BM-CPCs in patients with ischemic heart disease (IHD). Fifty-six patients with IHD were randomized to either receive freshly isolated BMC-Tx or a control group that did not receive cell therapy. Peripheral blood concentrations of CD34/45(+) and CD133/45(+) CPCs were measured by flow cytometry pre-, immediately post-, and at 3, 6, and 12 months postprocedure in both groups. Global ejection fraction and the size of infarct area were determined by left ventriculography. We observed in patients with IHD after intracoronary transplantation of autologous freshly isolated BMCs-Tx at 3 and 12 months follow-up a significant reduction of the size of infarct area and increase of global ejection fraction as well as infarct wall movement velocity. The mobilization of CD34/45(+) and CD133/45(+) BM-CPCs significantly increased at 3, 6, and 12 months after cell therapy when compared with baseline in patients with IHD, although no significant changes were observed between pre- and immediately postintracoronary cell therapy administration. In the control group without cell therapy, there was no significant difference of CD34/45(+) and CD133/45(+) BM-CPCs mobilization between pre- and at 3, 6, and 12 months postcoronary angiography. Intracoronary transplantation of autologous freshly isolated BMCs by using a point-of-care system in patients with IHD may enhance and prolong the mobilization of CD34/45(+) and CD133/45(+) BM-CPCs in peripheral blood and this might increase the regenerative potency in IHD.

Stem cell therapy in acute myocardial infarction

ZusammenfassungDie therapeutischen Erfolge auf dem Gebiet der Stammzellforschung eröffnen einer Vielzahl an kardiovaskulären Erkrankungen neue Behandlungsmöglichkeiten, insbesondere mit dem Ziel, die Entwicklung einer Herzinsuffizienz auf dem Boden eines akuten Myokardinfarkts oder einer chronisch ischämischen koronaren Herzkrankheit zu verhindern. Derzeit wird intensiv die Anwendung von Stammzellen (Knochenmarkstammzellen) und Progenitorzellen (endotheliale Progenitorzellen) zur funktionellen Restitution der Herzfunktion nach Infarkt bzw. bei myokardialer Ischämie untersucht, wobei unterschiedliche Applikationswege wie die intrakoronare, transendokardiale und intramyokardiale Injektion angewendet werden. In klinischen Studien konnte sich das Konzept der Myokardregeneration nach Anwendung autologer Stammzellen bzw. Progenitorzellen nach akutem Myokardinfarkt umsetzen lassen. Die Mehrzahl der kontrollierten und randomisierten Studien sowie mehrere Metaanalysen bestätigen die klinisch-therapeutische Relevanz der intrakoronaren Stammzellapplikation nach Herzinfarkt mit positiven Einfluss der adulten Stammzellen oder Progenitorzellen auf Mortalität und Morbidität der Patienten mit eingeschränkter Herzleistung nach akutem Herzinfarkt.AbstractTherapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.Therapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.

Inflammatory cardiac diseases by primary extracardial diseases

ZusammenfassungAllgemeininternistische Erkrankungen aus der Gastroenterologie, Rheumatologie und Infektiologie können als immunologische Systemerkrankungen neben dem Darm, dem Bewegungsapparat und dem Immunsystem auch das Herz in Mitleidenschaft ziehen. Am Herzen können dabei sämtliche Strukturen und Funktionen betroffen sein, vornehmlich aber Perikard und Myokard. Die Perikarditis bei Lupus erythematodes bzw. chronisch entzündlicher Darmerkrankung, die Myokarditis bei HIV-Infektion bzw. Lyme-Erkrankung sind Beispiele kardialer Beteiligungen allgemeininternistischer Systemerkrankungen. Die pathogenetischen Ursachen sind vielfältig von direkter zytotoxischer Wirkung bei HIV- und Borrelia-burgdorferi-Infektion, von induzierter Vaskulitis bis hin zur Aktivierung von lokalen Gerinnungsfaktoren bei Lupus erythematodes und chronisch entzündlicher Darmerkrankung. Aufgrund der zunehmend besseren Behandlungsmöglichkeiten allgemeininternistischer Erkrankungen und den daraus resultierenden Langzeitverläufen werden krankheitsbedingte und therapiebedingte kardiovaskuläre Sekundärkomplikationen wie die Perikarditis und Myokarditis zunehmend klinische Bedeutung gewinnen.AbstractAs systemic immunological disorders, internal diseases in gastroenterology, rheumatology and infectiology can, in addition to the bowels, potentially involve the musculo-skeletal system, the immunological system and heart structures. All structures and functions of the heart can be affected. Pericarditis in lupus erythematosus and chronic inflammatory bowel disease, myocarditis in HIV infection and lyme disease are examples of cardiac manifestations of internal diseases. The pathogenetic causes can be manifold, such as direct cytotoxic effects in HIV or Borrelia burgdorferi infections, induced vasculitis and local activation of coagulation factors as in lupus erythematosus or chronic inflammatory bowel disease. Improved treatment options have led to more long-lasting courses of internal diseases, such as in infectious diseases, lupus erythematosus and chronic inflammatory bowel disease, thus cardiovascular complications such as pericarditis and myocarditis gain increasing importance as a consequence of chronic disease and therapy-related damage.As systemic immunological disorders, internal diseases in gastroenterology, rheumatology and infectiology can, in addition to the bowels, potentially involve the musculo-skeletal system, the immunological system and heart structures. All structures and functions of the heart can be affected. Pericarditis in lupus erythematosus and chronic inflammatory bowel disease, myocarditis in HIV infection and lyme disease are examples of cardiac manifestations of internal diseases. The pathogenetic causes can be manifold, such as direct cytotoxic effects in HIV or Borrelia burgdorferi infections, induced vasculitis and local activation of coagulation factors as in lupus erythematosus or chronic inflammatory bowel disease. Improved treatment options have led to more long-lasting courses of internal diseases, such as in infectious diseases, lupus erythematosus and chronic inflammatory bowel disease, thus cardiovascular complications such as pericarditis and myocarditis gain increasing importance as a consequence of chronic disease and therapy-related damage.

Stammzelltherapie nach akutem Myokardinfarkt

ZusammenfassungDie therapeutischen Erfolge auf dem Gebiet der Stammzellforschung eröffnen einer Vielzahl an kardiovaskulären Erkrankungen neue Behandlungsmöglichkeiten, insbesondere mit dem Ziel, die Entwicklung einer Herzinsuffizienz auf dem Boden eines akuten Myokardinfarkts oder einer chronisch ischämischen koronaren Herzkrankheit zu verhindern. Derzeit wird intensiv die Anwendung von Stammzellen (Knochenmarkstammzellen) und Progenitorzellen (endotheliale Progenitorzellen) zur funktionellen Restitution der Herzfunktion nach Infarkt bzw. bei myokardialer Ischämie untersucht, wobei unterschiedliche Applikationswege wie die intrakoronare, transendokardiale und intramyokardiale Injektion angewendet werden. In klinischen Studien konnte sich das Konzept der Myokardregeneration nach Anwendung autologer Stammzellen bzw. Progenitorzellen nach akutem Myokardinfarkt umsetzen lassen. Die Mehrzahl der kontrollierten und randomisierten Studien sowie mehrere Metaanalysen bestätigen die klinisch-therapeutische Relevanz der intrakoronaren Stammzellapplikation nach Herzinfarkt mit positiven Einfluss der adulten Stammzellen oder Progenitorzellen auf Mortalität und Morbidität der Patienten mit eingeschränkter Herzleistung nach akutem Herzinfarkt.AbstractTherapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.Therapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.

Therapie mit adulten Stammzellen beim Herzinfarkt

Zum ThemaDie Therapie des akuten Herzinfarktes basiert überwiegend auf Maßnahmen, die das Ziel haben, die Infarktzone zu begrenzen, eine Ausdehnung des Infarktareals zu verhindern, die Infarktkomplikationen zu vermeiden (u. a. Herzrhythmusstörungen, Herzinsuffizienz) und dem “Remodeling”, d. h. den für die Ventrikeldynamik und Herzfunktion ungünstigen strukturellen Umbauvorgängen vorzubeugen. Dazu sind medikamentöse (Thrombozytenhemmung, Antikoagulation, Thrombolyse, herzentlastende Medikamente etc.) sowie mechanische Therapieverfahren (Ballon, Stent u. a.) verfügbar. Den Untergang von Myokardzellen beim Herzinfarkt können diese Therapieverfahren jedoch nur eingrenzen, eine Rückbildung der Nekrose ist nicht möglich. Dieses Ziel verfolgt die Stammzelltherapie des Myokardinfarktes, die im folgenden Beitrag mit ersten Ergebnissen vorgestellt werden soll.

Stammzelltherapie nach akutem Myokardinfarkt@@@Stem cell therapy in acute myocardial infarction

ZusammenfassungDie therapeutischen Erfolge auf dem Gebiet der Stammzellforschung eröffnen einer Vielzahl an kardiovaskulären Erkrankungen neue Behandlungsmöglichkeiten, insbesondere mit dem Ziel, die Entwicklung einer Herzinsuffizienz auf dem Boden eines akuten Myokardinfarkts oder einer chronisch ischämischen koronaren Herzkrankheit zu verhindern. Derzeit wird intensiv die Anwendung von Stammzellen (Knochenmarkstammzellen) und Progenitorzellen (endotheliale Progenitorzellen) zur funktionellen Restitution der Herzfunktion nach Infarkt bzw. bei myokardialer Ischämie untersucht, wobei unterschiedliche Applikationswege wie die intrakoronare, transendokardiale und intramyokardiale Injektion angewendet werden. In klinischen Studien konnte sich das Konzept der Myokardregeneration nach Anwendung autologer Stammzellen bzw. Progenitorzellen nach akutem Myokardinfarkt umsetzen lassen. Die Mehrzahl der kontrollierten und randomisierten Studien sowie mehrere Metaanalysen bestätigen die klinisch-therapeutische Relevanz der intrakoronaren Stammzellapplikation nach Herzinfarkt mit positiven Einfluss der adulten Stammzellen oder Progenitorzellen auf Mortalität und Morbidität der Patienten mit eingeschränkter Herzleistung nach akutem Herzinfarkt.AbstractTherapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.Therapeutic successes in the area of stem cell research have opened up many new avenues for treating cardiovascular diseases, especially with respect to the prevention of the development of cardiac failure due to acute myocardial infarction or chronic coronary artery disease. Currently, the delivery of bone marrow-derived stem cells and circulating progenitor cells via the coronary artery, intravenous, the left ventricle (transendocardial) as well as directly into the heart muscle during cardiac bypass surgery (intramyocardial) is being investigated intensively for the treatment of acute myocardial infarction and chronic coronary artery disease. All application modes pursue the same objective of regenerating damaged myocardium. In clinical studies, the concept of myocardial regeneration by injection of adult autologous stem cells or circulating progenitor cells has been transferred. In the majority of controlled and randomised trials as well as in several meta-analysis the therapeutic impact of intracoronary stem cell application in myocardial infarction is affirmed by a beneficial effect of stem cells or progenitor cells on mortality and morbidity in patients with reduced cardiac function after acute myocardial infarction.