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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological limitations to cardiac regenerative growth create a clinical need to promote more efficient cardiac repair. Experimental studies and early-phase clinical trials indicate that progenitor cells may be useful as a therapeutic tool to improve heart function after myocardial ischaemia. This paper will summarize experimental studies to determine (1) the mechanisms underlying progenitor cell homing to ischaemic tissue and (2) to define transcription factors involved in endothelial maturation of progenitor cells. Homing seems to be assisted by a proteolytic enzyme, cathepsin L, which degrades the extracellular matrix. In an in vitro assay, a cathepsin inhibitor prevented different progenitor cell populations from passing through a matrigel layer. In vivo, progenitor cells lacking cathepsin L had an impaired capacity to promote neovascularization in ischaemic mouse limbs compared with normal, wild-type cells. Differentiation of progenitor cells towards the endothelial phenotype involves a member of the homeobox gene family, HoxA9. HoxA9 regulates endothelial gene expression (eNOS, KDR, VE-cadherin). Moreover, HoxA9-deficient mice have a severe impairment of neovascularization capacity after ischaemia. In the second part of the paper, we describe clinical studies using bone marrow or the peripheral blood-derived cells for functional recovery of patients with acute and chronic heart failure (TOPCARE-AMI, TOPCARE-CHF). Whereas blood-derived and bone marrow-derived progenitor cells were equally effective in patients with acute myocardial infarction, bone marrow-derived cells were significantly better than blood-derived progenitor cells in patients with chronic ischaemic heart disease.
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PMID:Restoration of cardiac function with progenitor cells. 1701 14

Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a time when overt mitochondrial defects are not yet apparent. In the present study, hypertrophic remodeling was induced by means of an aorto-caval fistula (ACF) in WKHA rats and experiments were performed 12 weeks post surgery. At this time, ACF animals displayed normal contractile function, tissue oxidative capacity as well as mitochondrial membrane potential and respiratory function. However, compared to sham, mitochondria from ACF animals were more vulnerable to anoxia-reoxygenation injury in vitro as indicated by a greater impairment of oxidative phosphorylation and a greater dependence of respiration on exogenous NADH. Addition of the PTP inhibitor CsA restored respiratory function to the level observed in mitochondria from sham animals. Likewise, mitochondria from ACF displayed a greater sensitivity to Ca(2+)-induced PTP opening in vitro compared to their sham counterparts. In addition to the greater vulnerability of mitochondria in vitro, mitochondrial PTP opening measured in situ in perfused hearts was greater following ischemia-reperfusion in ACF animals than in their sham counterparts. This was associated with a more impaired functional recovery and greater tissue damage during reperfusion in hearts from ACF vs sham. Taken together, these results indicate that, in response to volume overload, mitochondria may display increased vulnerability in the absence of any sign of dysfunction under baseline unstressed conditions, at a time when adverse ventricular remodelling is observed but systolic dysfunction and decompensation have not occurred yet.
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PMID:Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress. 1706 27

Heart transplant is considered to be an extremely severe ischemia-reperfusion sequence. Post-ischemic dysfunction triggers multiple processes especially oxidative stress, but the mechanisms remain unclear. Free radical interactions lead to peroxynitrite generation, which seems to be involved in early post-transplant heart failure. The aim of this study was to evaluate the potential impact of a peroxynitrite decomposition catalyst: FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-fer[III]) and pyruvate on myocardial functional recovery after cardioplegic arrest using an experimental protocol in rat hearts. Isolated working rat hearts were subjected to ischemia (4 h at 4 degrees C in cardioplegic solutions), followed by 45 min of reperfusion. Four groups were constituted: control, pyruvate: (2 mm) added to cardioplegic and Ringer-lactate solutions, FeTPPS: (10 microm) perfused during the reperfusion, and a combination of both treatments. Lactate dehydrogenase (LDH) activity was assessed during the reperfusion to evaluate the level of cardiac injury. Oxidative stress was evaluated on heart slices using a fluorescent probe: dihydroethidium, and the collagen content was assessed using picro-Sirius coloration. Global post-ischemic recovery in the control group was about 35% of pre-ischemic values. Results showed that addition of pyruvate led to an increase in myocardial function and to a decrease in LDH activity released during the reperfusion. FeTPPS protected against injury after cardioplegic arrest during reperfusion. No additive effect of the two treatments (pyruvate + FeTPPS) was observed. The collagen content was better preserved in the FeTPPS group than in the control and pyruvate groups. In conclusion, this study shows that peroxynitrite plays an important role in the functional and cellular alterations associated with cardiac ischemia-reperfusion sequences and confirms that pyruvate helped to preserve myocardial function. The use of the peroxynitrite decomposition catalyst (FeTPPS) may help to improve myocardial preservation during a prolonged ischemia sequence.
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PMID:A peroxynitrite decomposition catalyst: FeTPPS confers cardioprotection during reperfusion after cardioplegic arrest in a working isolated rat heart model. 1739 Dec 90

The role of ventricular-assist devices in the management of end-stage heart failure is growing. Initially developed as a 'bridge to transplantation', they are now implanted permanently in patients who need cardiac replacement but are not candidates for cardiac transplantation ('destination therapy'). Furthermore, observations from expert centers indicate that a significant proportion of patients under long-term mechanical assistance can be weaned from mechanical circulatory support after significant functional recovery of their native heart ('bridge to recovery'). This review discusses the emerging roles of mechanical circulatory support and their direct implications in clinical practice. Evolution of devices, important aspects of candidate selection, challenging issues in the management of ventricular-assist device patients (infection, device malfunction, anticoagulation-thromboembolic complications, psychosocial issues and cost) and ongoing research targeting sustained myocardial recovery are discussed.
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PMID:Ventricular-assist devices for the treatment of chronic heart failure. 1748 79

1. Several mouse strains have been prepared in which different subtypes of the alpha1-adrenoceptor (AR) are overexpressed or deleted. The phenotypes of the animals generated vary depending on whether the receptors are expressed specifically in heart or generally throughout the animal, but some overall conclusions can be drawn. 2. Heightened activity of alpha1B-AR by overexpressing the receptors leads to depressed contractile responses to beta-AR activation, which may be related to activation of the inhibitory G-protein Gi. In contrast, alpha1A-AR cause substantially heightened contractility when overexpressed in heart. 3. Overexpressed alpha1B-AR predispose hearts to hypertrophy and worsen heart failure caused by pressure overload, whereas increased alpha1A-AR expression does not influence hypertrophic responses and, furthermore, improves outcomes after pressure overload or myocardial infarction. 4. Alpha1A-adrenoceptors mediate a preconditioning action to improve functional recovery after acute ischaemic insult, whereas alpha1B-AR are ineffective. Both subtypes appear to protect from inositol 1,4,5-trisphosphate generation and arrhythmogenesis in early postischaemic reperfusion. 5. Although some of the protective effects of heightened alpha1A-AR drive may be related to the enhanced contractility, it is also possible that alpha1A-AR protect from cardiomyocyte apoptotic responses.
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PMID:Roles of alpha1A- and alpha1B-adrenoceptors in heart: insights from studies of genetically modified mice. 1764 35

A significant proportion of patients placed on long-term mechanical circulatory support for end-stage heart failure can be weaned from mechanical assistance after functional recovery of their native heart ("bridge to recovery"). The pathophysiological mechanisms implicated in reverse remodeling that cause a sustained functional myocardial recovery have recently become the subject of intensive research, expected to provide information with a view to accurately identify reliable prognostic indicators of recovery. In addition, this kind of information will enable changes in the strategy of myocardial recovery by modifying the duration and scale of the unloading regimen or by combining it with other treatments that promote reverse remodeling.
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PMID:Reverse remodeling during long-term mechanical unloading of the left ventricle. 1765 51

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.
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PMID:Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart. 1819 89

Despite state-of-the-art therapy, clinical outcome remains poor in myocardial infarction (MI) patients with reduced left ventricular (LV) function with yearly mortality rates of approximately 15% and rehospitalization rates for heart failure or recurrent infarction within the first year exceeding 20%. Progenitor cell-mediated repair of the damaged heart is a promising new development in cardiovascular medicine. Progenitor cells residing in bone marrow and presumably also in the heart are capable of improving LV function in preclinical MI models but underlying mechanisms remain incompletely understood. Recent placebo-controlled, randomized bone marrow cell transfer trials in MI patients have shown augmented recovery of global LV function of variable magnitude. The observed changes were associated with a favourable effect on myocardial perfusion, with greater infarct size reduction, or with enhanced regional contraction in the infarct border zones. There is now growing consensus that these beneficial effects of bone marrow-derived progenitor cell transfer, as applied in post-MI patients thus far, occur independent of cardiomyocyte formation. At the same time, we have recognized that insufficient homing and survival of transplanted cells into the ischaemic milieu limits the full potential of cell-based cardiac repair. A better understanding of underlying molecular mechanisms of these critical steps in cell-based repair will, however, facilitate the development of improved clinical strategies to enhance functional recovery after myocardial infarction in the years to come.
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PMID:Stem cell therapy in acute myocardial infarction. 1822 69

Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.
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PMID:Phospholamban phosphorylation by CaMKII under pathophysiological conditions. 1850 37

Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow-derived or circulating blood-derived progenitor cells is safe and provides beneficial effects. However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors, or a combination thereof may provide useful approaches for enhancement of cell therapy for cardiovascular diseases.
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PMID:Aging and disease as modifiers of efficacy of cell therapy. 1853 69


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