Effects of exercise training on mobilization and functional activity of blood-derived progenitor cells in patients with acute myocardial infarction.

BACKGROUND: The 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 may be related in part to a mobilization of bone marrow-derived circulating progenitor cells (CPCs) as well as an enhanced vascularisation. METHODS: 37 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. RESULTS: In 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 ejection 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. CONCLUSIONS: Regular 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.

[Pathophysiology of the right ventricle in lung diseases]. / Pathophysiologie des rechten Ventrikels bei Lungenerkrankungen.

The thin-walled right heart is characterized by a low mass-volume-relation. Right ventricular function is influenced basically by loading conditions (afterload and preload), myocardial perfusion, contractility and heart rate. Afterload is determined by intrathoracal and pulmonary vascular pressure/resistance. Morphologic adaptions of the right ventricle affect right ventricular function in cor pulmonale. So the normal, not hypertrophied right ventricle is extremely sensitive to increasing pulmonary artery pressure. Otherwise, minor reductions in afterload lead to a substantial decrease of right ventricular wall stress, myocardial oxygen demand and likely the risk of arrhythmia. Therefore clinical consequences and complications of pulmonary hypertension are substantially dependent on right ventricular dynamics.

Therapeutic potentials of stem cells in cardiac diseases.

Coronary heart disease and chronic heart failure are common diseases 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 impair quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies carried out in the past few years have 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, leukemic 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 (dilatative cardiomyopathy) and heart failure due to hypertensive heart disease.

Therapeutic potential of stem cells in elderly patients with cardiovascular disease.

The success of treatment for acute myocardial infarction and chronic myocardial ischemia has improved general medical care in Europe, resulting in an increasing population of patients with chronic and congestive heart failure. By applying currently available therapeutic options the quality of life and lifespan of these patients have both increased. However, amongst patients -- predominantly the elderly -- who remain symptomatic despite intensive medical treatment, autologous bone marrow-derived mononuclear cells may trigger attempts to repopulate lost tissues directly as a novel therapeutic option. In this concised paper the current understanding of stem cell therapy and early clinical experiences are discussed and related to the application of stem cells in elderly patients with myocardial ischemia.

[Stem cell therapy in acute myocardial infarction]. / Stammzelltherapie nach akutem Myokardinfarkt.

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.

Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax.

BACKGROUND: The Düsseldorf-based cardiologist Professor Strauer was the first to present a therapeutic concept for the repair of acute infarcted myocardium in 2001: the autologous intracoronary transplantation of unfractionated human bone marrow (BM) mononuclear cells (MNC). The Division of Cardiology, Pneumology and Angiology, University of Duesseldorf Medical School, Duesseldorf, Germany, was also able to show the regenerative potential of BM stem cell transplantation in patients with chronic heart disease (CHD) and peripheral arterial disease (PAD). In the mean time, several clinical trials have been set up worldwide, predominantly by using MNC isolated manually from BM aspirates via density-gradient centrifugation; 374 patients have been treated here with unselected BM MNC since 2001. Altogether 217 BM aspirates have been processed manually. In order to maintain the high standards required for cellular therapeutics, the Sepax cell-separation system was implemented into routine BM processing in 2006. The closed Sepax system provides a reproducible MNC isolation method, and 157 BM samples have been processed with the Sepax device. The results of manual MNC isolation were compared with the Sepax-mediated MNC isolation. METHODS: The manual Ficoll separation method was compared with the Sepax density gradient-based separation (DGBS) protocol using Ficoll with the kit CS-900 and the Sepax S-100 main processing unit from Biosafe. RESULTS: Nucleated cell and MNC recovery were significantly higher after Sepax processing (P<0.0001) whereas no significance was found for red blood cell depletion. DISCUSSION: The Sepax cell-separation system is a time-saving method providing clinical-grade MNC isolated automatically from human BM by Ficoll density centrifugation.

[Value of cardiovascular magnetic resonance in acute myocarditis]. / Wertigkeit der kardialen Magnetresonanztomografie bei akuter Myokarditis.

Cardiovascular magnetic resonance imaging (MRI) demonstrates location, activity and extent of inflammation in acute myocarditis. A combined approach, using different imaging modalities (T2-IR-weighted imaging, early and late gadolinium enhancement) provides high diagnostic accuracy. The type of myocardial virus infection (PVB19, HHV6) may be related to the pattern of inflammation demonstrated by cardiovascular MRI and the clinical course. Whether specific patterns of late gadolinium enhancement in myocarditis are associated with poor prognosis remains a subject for further investigation. Cardiovascular MRI in myocarditis is believed to become a significant imaging tool in identifying patients at risk for heart failure and ventricular arrhythmias. These patients may need specific treatment, such as antiviral or immunosuppressive medication, dependent on the result of endomyocardial biopsy.

The therapeutic potential of stem cells in heart disease.

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.

[Inflammatory cardiac diseases by primary extracardial diseases]. / Entzündliche Herzerkrankungen bei primär extrakardialen Erkrankungen.

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.

Cardiac chemoreflex sensitivity in critically ill patients.

Chemoreflexes are important mechanisms for regulating ventilatory and cardiovascular function. The aim of this study was to determine the meaning of autonomic dysfunction for the pathophysiology and outcome in critical ill patients. For the determination of the chemoreflex sensitivity (ChRS), the ratio of the RR interval shift and the shift of oxygen partial pressure during a 5-min inhalation of oxygen with a nose mask was formed. Pathological chemoreflex sensitivity was predefined as a ChRS below 3.0 ms/mmHg. Out of the 27 critical ill patients included into the study, 17 had a sepsis and 10 a cardiogenic shock. In these patients, chemoreflex sensitivity was significantly reduced compared with a control group (sepsis: 2.1 +/- 1.68, cardiogenic shock: 0.4 +/- 0.27, controls: 5.0 +/- 2.8 ms/mmHg; P<0.05 vs. sepsis or cardiogenic shock). There was a significant negative correlation (r=-0.6; P<0.01) between the chemoreflex sensitivity and the severity of illness described by the SOFA-score. We conclude that cardiac reflex mechanisms are changed toward increased sympathetic activity reflected by reduced chemoreflex sensitivity in critical ill patients. Moreover, there is a close negative correlation between the ChRS and the SOFA-score.

Obstructive sleep apnea in heart failure patients: evidence for persistent conduction disturbances or sinus node dysfunction.

Bradycardia is a common finding in patients with obstructive sleep apnea and might be pronounced in heart failure patients. The aim of the present study was to determine the relationship between nocturnal hypoxemia, apnea-hypopnea index, and electrophysiological parameters of sinus node and atrioventricular conduction properties. Electrophysiological studies were performed in 12 patients with heart failure. Polygraphic studies were done in all of the patients. Patients with an AHI >10/h were classified as sleep apnea patients. Mild sleep apnea was diagnosed in 50% of the patients (AHI 17.8 +/- 4.4 vs. 5.1 +/- 3.6/h). There were no differences with respect to the resting heart rate, PQ interval, or QRS duration between the two groups. Sinus node recovery time was normal in all of the patients (993 +/-291 vs. 1099 +/-62 ms, P=0.45). There was no abnormal atrioventricular conduction. Nevertheless, sleep apnea patients showed decreased atrioventricular conduction time (AH) intervals (134 +/- 42 vs. 102 +/- 25 ms, P=0.1) and infranodal conduction time (HV) intervals (59 +/- 9 vs. 43 +/- 7 ms, P=0.01). We conclude that mild sleep apnea was not associated with abnormal findings in sinus node function or AV conduction properties in patients with heart failure. Decreased AH/HV intervals might be a consequence of apnea associated sympathetic activation.

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. MATERIALS AND METHODS: Peripheral blood concentrations of CD34/45(+) and CD133/45(+) BM-CPCs were measured by flow cytometry in 44 patients after AMI and in 16 subjects with atypical chest pain acting as controls. RESULTS: Mobilization of CD34/45(+) and CD133/45(+) BM-CPCs on day 1 after AMI showed significant negative correlation with age, the number of CVRFs, infarct size, creatine phosphokinase peak in bivariate as well as in multivariate analyses. We additionally found a positive correlation of CD34/45(+) and CD133/45(+) BM-CPCs mobilization on day 1 after AMI with global ejection fraction (EF) in bivariate analysis but could not confirm this in multivariate analysis. Elevated of C-reactive protein (CRP) and leukocyte levels on day 1 after AMI were significantly associated with decreased concentrations of CD34/45(+) BM-CPCs. The concentrations of CD34/45(+) and CD133/45(+) BM-CPCs significantly increased in AMI patients, with the peak on day 7 as compared to the control group. CONCLUSIONS: The mobilization of CD34/45(+) and CD133/45(+) BM-CPCs into the PB depends on many factors, i.e. the number of CVRFs, age, infarct size and inflammatory markers of patients. Most importantly, the severity of the circulatory dysfunction and the amount of necrotic myocardial tissue are the main determinants. Moreover, this spontaneous mobilization of BM-CPCs may serve as a very important surrogate for infarct size as well as for global EF and it may determine the regenerative potency after AMI.