Randomized, controlled clinical trials have demonstrated that cell therapy can improve the recovery of cardiac function in patients after acute myocardial infarction (AMI). Trial results are ...inconsistent, however, and uncertainty persists regarding the mechanism of action and prospect of cell therapy for patients with heart disease. This Review examines the results from the first-generation trials and discusses procedure-related variables that could have determined treatment outcomes. Obvious issues, including optimal timing of cell transfer, dose, and delivery methods are being investigated in ongoing second-generation trials. These studies aim to refine the protocols and identify the patients who will benefit most from cell therapy. Third-generation trials will address the current limitations of cell therapy, such as cell retention and cell survival after transplantation, and impaired cell functionality in patients with advanced cardiovascular disease. The secretion of factors with paracrine effects by the transplanted cells is an increasingly recognized phenomenon. Identification of these factors, by secretome analyses and bioinformatic approaches, could advance protein-based therapies to promote healing and inhibit pathological remodeling of the heart after AMI. The identification of reliable sources of pluripotent stem cells and their differentiation into mature cardiac cell types could ultimately enable regeneration of the infarcted heart.
Repair of the heart is an old dream of physicians caring for patients with cardiac disease. Experimental studies suggest that cardiac transfer of stem and progenitor cells can have a favorable impact ...on tissue perfusion and contractile performance of the injured heart. Some researchers favor stable stem cell engraftment by fusion or transdifferentiation into cardiomyocyte or vascular cell lineages as likely explanations for these beneficial effects. Others have proposed that transient cell retention may be sufficient to promote functional effects, eg, by release of paracrine mediators. Although the mechanistic underpinnings of stem cell therapy are still intensely debated, the concept of cell therapy has already been introduced into the clinical setting, where a flurry of small, mostly uncontrolled trials indicate that stem cell therapy may be feasible in patients. The overall clinical experience also suggests that stem cell therapy can be safely performed, if the right cell type is used in the right clinical setting. Preliminary efficacy data indicate that stem cells have the potential to enhance myocardial perfusion and/or contractile performance in patients with acute myocardial infarction, advanced coronary artery disease, and chronic heart failure. The field now is rapidly moving toward intermediate-size, double-blinded trials to gather more safety and efficacy data. Ultimately, large outcome trials will have to be conducted. We need to proceed cautiously with carefully designed clinical trials and keep in mind that patient safety must remain the key concern. At the same time, continued basic research to elucidate the underlying mechanism of stem cell therapy is clearly needed.
Blood vessel growth in adult organisms involves the following two fundamental processes: angiogenesis, the proliferation and extension of capillary networks; and arteriogenesis, the growth of ...functional arteries. We provide a protocol for the evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Surgical ligation of the femoral artery at a specific site triggers arteriogenesis of small, pre-existing collateral arteries into functional conduit vessels proximally and ischemic angiogenesis distally. The vascular response to hind-limb ischemia can be readily evaluated by laser Doppler-based perfusion measurements, histological quantification of arteriogenesis and angiogenesis or whole-mount visualization of arteries in limb muscles. Depending on the experimental design, the protocol takes between 4 and 29 d to complete; however, the net working time is about 2 d per mouse. The concurrent and specific analysis of postnatal angiogenesis and arteriogenesis in the same animal is a unique feature of the protocol.
Role of oxidative stress in atherosclerosis Harrison, David; Griendling, Kathy K; Landmesser, Ulf ...
The American journal of cardiology,
02/2003, Letnik:
91, Številka:
3
Journal Article, Conference Proceeding
Recenzirano
The common risk factors for atherosclerosis increase production of reactive oxygen species (ROS) by endothelial, vascular smooth muscle, and adventitial cells. These ROS initiate processes involved ...in atherogenesis through several important enzyme systems, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase. Physical forces also regulate vascular production of ROS. Oscillatory shear, which is present at sites where atherosclerosis develops, seems a particularly potent stimulus of superoxide production. The signaling cascade for activation of the NAD(P)H oxidase by angiotensin II has recently been elucidated and seems to involve a feed-forward mechanism that permits ongoing production of ROS for prolonged periods. Oxidative stress in humans with coronary artery disease is also exacerbated by a reduction of vascular extracellular superoxide dismutase, normally an important protective enzyme against the superoxide anion.
Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of
...stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitior of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.
Prognostic Utility of Growth Differentiation Factor-15 in Patients With Chronic Heart Failure Tibor Kempf, Stephan von Haehling, Timo Peter, Tim Allhoff, Mariantonietta Cicoira, Wolfram Doehner, ...Piotr Ponikowski, Gerasimos S. Filippatos, Piotr Rozentryt, Helmut Drexler, Stefan D. Anker, Kai C. Wollert It was recently shown that patients with chronic heart failure have increased circulating levels of the transforming growth factor-β–related cytokine growth differentiation factor (GDF)-15. The prognostic relevance of GDF-15 in heart failure has never been investigated. Shown here in a cohort of 455 patients with chronic heart failure, the risk of death during follow-up was closely related to the levels of GDF-15 at baseline. Growth differentiation factor 15 emerged as an independent predictor of mortality and added prognostic information to New York Heart Association functional class, left ventricular ejection fraction, and amino-terminal pro–B-type natriuretic peptide. Our study identifies GDF-15 as a new biomarker in chronic heart failure that provides prognostic information beyond established clinical and biochemical markers.
Aims
Acute heart failure (AHF) has a poor prognosis. We evaluated 3- and 12-month mortality in different clinical classes of AHF patients from 30 European countries who were included in the EuroHeart ...Failure Survey (EHFS) II.
Methods and results
Follow-up data were available for 2981 AHF patients, of these 62% had a history of chronic HF. One-year mortality after discharge was lower in patients with de novo AHF when compared with acutely decompensated chronic HF (ADCHF), 16.4 vs. 23.2% (P < 0.001). Cardiogenic shock conferred the highest cumulative 1-year mortality (52.9%) as a result of in-hospital mortality of 39.3%. Long-term prognosis in decompensated AHF was also dismal. Hypertensive HF was associated with the lowest mortality (13.7% at 1 year). Age, prior myocardial infarction, creatinine level, and low plasma sodium were independently associated with mortality during the whole follow-up period. Diabetes, anaemia, and history of chronic HF were associated with worse and hypertension with better long-term survival. History of cerebrovascular disease was associated with worse short-term outcome.
Conclusion
Early and late mortality differ between de novo AHF and ADCHF and between clinical classes of AHF. EHFS II identifies clinical risk markers and demonstrates the importance of a thorough characterization of AHF populations according to history and clinical presentation.
Mice with a cardiomyocyte (CM)-restricted knockout of signal transducer and activator of transcription 3 (STAT3-KO) develop spontaneous heart failure. We investigated the impact of STAT3-mediated ...regulation of microRNAs for pathophysiological alterations in the heart.
MicroRNAchip and qRT-PCR analysis revealed elevated cardiac expression of miR-199a in STAT3-KO mice. Lentiviral shRNA-mediated STAT3-knock-down in neonatal rat CMs markedly increased miR-199a promoter activity and miR-199a levels indicative of a suppressive effect of STAT3 on miR-199a transcription. Up-regulated miR-199a in CM by pre-miR-199a transfection (pre-miR-199a-CM) reduced expression of components of the ubiquitin-proteasome system (UPS), i.e. the ubiquitin-conjugating enzymes Ube2g1 (mRNA and protein) and Ube2i (protein). Pre-miR-199a-CM or CM with siRNA-mediated down-regulation of Ube2i and Ube2g1 (siRNA-Ube2i/2g1-CM) displayed massive down-regulation of α- and β-myosin heavy chain expression associated with disrupted sarcomere structures. In addition, protein arginine methyltransferase I (PRMT-I) expression and asymmetric dimethylarginine (ADMA) synthesis were increased in pre-miR-199a-CM or in siRNA-Ube2i/2g1-CM. Increased ADMA in cell culture supernatant (SN) from pre-miR-199a-CM or siRNA-Ube2i/2g1-CM lowered nitric oxide (NO) bioavailability of rat cardiac endothelial cells while lowering ADMA concentration in CM SNs by the PRMT inhibitor arginine methyltransferase inhibitor 1 (AMI-1) (100 µM) improved NO bioavailability. In STAT3-KO hearts Ube2i and Ube2g1 expression were markedly reduced. Human terminal failing hearts harbouring low STAT3 protein levels displayed increased miR-199a levels and decreased Ube2g1 expression.
This study identifies a novel pathophysiological circuit in the heart between reduced STAT3 protein levels, increased miR-199a expression, and subsequent impairment of the UPS that disrupts CM sarcomere structure and impairs via the release of ADMA endothelial cell function.
In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via ...janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction.
The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) Y(757)F); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y(757)F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y(757)F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction.
Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.
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