Resident cardiac stem cells

The introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathologic heart and opens new options for the treatment of cardiovascular diseases. The feasibility of adult bone marrow autologous and allogenic cell therapy of ischemic cardiomyopathies has been demonstrated in humans. However, many unresolved questions remain to link experimental with clinical observations. The demonstration that the heart is a self-renewing organ and that its cell turnover is regulated by myocardial progenitor cells offers novel pathogenetic mechanisms underlying cardiac diseases and raises the possibility to regenerate the damaged heart. Indeed, cardiac stem progenitor cells (CSPCs) have recently been isolated from the human heart by several laboratories although differences in methodology and phenotypic profile have been described. The present review points to the potential role of CSPCs in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors.     

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test

Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val^108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val^108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val^108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val^108/158Met on cognitive performance.     

The effect of phenobarbital on the methylation level of the p16 promoter region in rat liver

It has been suggested that non-genotoxic carcinogens (NGCs) may cause modification of the DNA methylation status. We studied the effects of phenobarbital (PB) -- a non-genotoxic rodent liver carcinogen -- on the methylation level of the promoter region of the p16 suppressor gene, as well as on hepatomegaly, DNA synthesis, and DNA-methyltransferase (DNMTs) activity in the rat liver. Male Wistar rats received PB in 1, 3 or 14 daily oral doses (at 24-h intervals), each equivalent to 1/10 of the LD(50) value. The study showed that PB has caused persistent elevation in relative liver weight (RLW) as well as a transient increase in DNA synthesis. This suggests that the PB-induced increase in RLW was due to a combination of both hyperplasia and hypertrophy of liver cells. The effect of PB on DNA synthesis corresponded to an increase in the methylation pattern of the p16 promoter sequence. Methylation of cytosine in the analyzed CpG sites of the p16 gene was found after short exposure of the animals to PB. Treatment of rats with PB for 1 and 3 days also produced an increase in nuclear DNMTs activity. After prolonged administration (14 days), DNA synthesis declined, returning to the control level. No changes in methylation of the p16 gene nor in DNMTs activity were observed. The reversibility of early induced changes in target tissues is a mark characteristic of tumor promoters. Thus, transient changes in methylation of the p16 gene, although their direct role in the mechanisms of PB toxicity, including its carcinogenic action, remains doubtful, may therefore be a significant element of such processes.     

Zur Kenntnis der mykotischen und rheumatischen Aneurysmen der Lungenschlagader

Zusammenfassung Die Tabelle I gibt eine Ubersicht über die Fälle von mykotischen und rheumatischen Aneurysmen der Lungenschlagader, so weit wir sie in dem uns zugänglichen Schrifttum finden konnten. Aus dieser Zusammenstellung geht hervor, daß von den 25 einschlägigen Fällen das weibliche Geschlecht bei weitem überwiegt, stehen doch 17 Fälle weiblichen Geschlechtes 7 Fällen männlichen Geschlechtes gegenüber. (Bei einem Fall ist das Geschlecht nicht angegeben.)Was das Alter der einzelnen Fälle anlangt, so betrifft die jüngste Beobachtung, die Lellis, ein 12jähriges Individuum, der älteste Fall eines Lungenschlagaderaneurysmas wurde bei einer 70 jährigen Frau von Chiari erhoben.Als Durchschnittsalter errechneten wir beim Mann 26 Jahre, bei der Frau 341/2 Jahre, also wird die mittlere Altersstufe bevorzugt.Von den 23 Fällen, in denen eine mykotische Genese für die Aneurysmaentstehung entweder allein oder zumindest als wesentlich mitbeteiligter Faktor anzunehmen ist, war der Ductus Botalli zwölfmal offen, daraus erhellt die beträchtliche Bedeutung dieser Anomalie bei der Entstehung des Lungenschlagaderaneurysmas.Ätiologisch fanden sich bei 8 Fällen endokarditische Veränderungen der Pulmonalklappen, von diesen in 2 Fällen auch Mitbeteiligung der Pulmonalarterie. Bei 5 Fällen konnten allein nicht spezifische arteriitische Veränderungen der Pulmonalis gefunden werden. 3 Fällen liegt nach Annahme der Autoren eine rheumatische Wanderkrankung als Ursache der Entstehung der Aneurysmen zugrunde.Bei den sonstigen Fällen fand sich Endokarditis an den übrigen Klappen. Besonders hervorzuheben ist noch der Fall von Salzer, bei dem sich eine Atherosklerose der Pulmonalarterie vorfand und außerdem eine hämorrhagische, aszendierende Zystopyelonephritis. Im Falle Reiches handelte es sich um ein Traktionsaneurysma als dessen Ursache ein aktinomykotisches Granulationsgewebe in der Nachbarschaft des Aneurysma gefunden wurde.Bei einem eigenen Fall handelt es sich um ein Arrosionsaneurysma, ausgehend von einer vereiterten Lobärpneumonie.Mit 8 Abbildungen.Auszugsweise vorgetragen in der Sitzung der Wiener medizinischen Gesellschaft, Fachgruppe Pathologische Anatomie, am 26. Januar 1943.     

Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan

Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerase-competent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan.     

Risk factors of atrial fibrillation in patients with Wolff-Parkinson-White syndrome

BACKGROUND: Atrial fibrillation (AF) in patients with WPW syndrome may be a life-threatening arrhythmia. AIM: To identify risk factors of AF and their prognostic significance in patients with WPW syndrome. METHODS: Clinical and electrophysiological parameters of 239 patients with WPW syndrome, who underwent successful RF ablation, were analysed using logistic regression and multivariate analysis. One hundred eight patients had no history of AF whereas the remaining 81 patients had previous spontaneous AF episodes. Long-term follow-up data (mean 29+/-23 months, range 1-99 months) were available in 136 patients (87 without AF and 49 with AF). RESULTS: Patients with AF were significantly older, more frequently of male gender and had more often a history of syncope than patients without AF. There were two peaks of AF occurrence - in the third and in the fifth decade of life. Fourteen patients had a history of ventricular fibrillation - 11 patients with AF vs 3 patients without AF (p=0.0016). Patients with a history of AF were more prone to AF induced during electrophysiological study and had less frequently concealed accessory pathways. CONCLUSIONS: Age, gender and a history of syncope are the independent risk factors of AF in patients with WPW syndrome. Anterograde conduction via accessory pathway is of major importance in the development of AF. RF ablation of an accessory pathway should be performed early because the risk of the procedure is small and there is an increasing risk of AF with ageing.     

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-c-Met and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas alpha-sarcomeric actin, cardiac myosin heavy chain, troponin I, and alpha-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.     

Cardiac stem cells and myocardial disease

Recent data indicate that the heart is a self-renewing organ and contains a pool of progenitor cells (PCs). According to the new paradigm, this resident population of multipotent undifferentiated cells gives rise to myocytes, endothelial cells, smooth muscle cells and fibroblasts. Understanding the function of cardiac PCs is critical for the implementation of these cells in the treatment of the diseased human heart. However, cardiac repair is an extremely complex phenomenon. Efficient myocardial regeneration requires restoration of segmental and focal areas of myocardial scarring, replacement of damaged coronary arteries, arterioles and capillaries, and substitution of hypertrophied poorly contracting myocytes with smaller better functioning parenchymal cells. To achieve these goals, the acquisition of a more profound knowledge of the biology of cardiac PCs cells and their fate following pathologic insults represents an essential need.     

Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function

Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of approximately 42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.     

Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression

To determine whether cellular aging leads to a cardiomyopathy and heart failure, markers of cellular senescence, cell death, telomerase activity, telomere integrity, and cell regeneration were measured in myocytes of aging wild-type mice (WT). These parameters were similarly studied in insulin-like growth factor-1 (IGF-1) transgenic mice (TG) because IGF-1 promotes cell growth and survival and may delay cellular aging. Importantly, the consequences of aging on cardiac stem cell (CSC) growth and senescence were evaluated. Gene products implicated in growth arrest and senescence, such as p27Kip1, p53, p16INK4a, and p19ARF, were detected in myocytes of young WT mice, and their expression increased with age. IGF-1 attenuated the levels of these proteins at all ages. Telomerase activity decreased in aging WT myocytes but increased in TG, paralleling the changes in Akt phosphorylation. Reduction in nuclear phospho-Akt and telomerase resulted in telomere shortening and uncapping in WT myocytes. Senescence and death of CSCs increased with age in WT impairing the growth and turnover of cells in the heart. DNA damage and myocyte death exceeded cell formation in old WT, leading to a decreased number of myocytes and heart failure. This did not occur in TG in which CSC-mediated myocyte regeneration compensated for the extent of cell death preventing ventricular dysfunction. IGF-1 enhanced nuclear phospho-Akt and telomerase delaying cellular aging and death. The differential response of TG mice to chronological age may result from preservation of functional CSCs undergoing myocyte commitment. In conclusion, senescence of CSCs and myocytes conditions the development of an aging myopathy.