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New Findings What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload., What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia-reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction., The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload-induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia. [ABSTRACT FROM AUTHOR]

Background Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin-2 (Ang-2) acts as its natural inhibitor. Objective We aimed to determine the levels of angiopoietins in sputum supernatants of patients with optimally treated asthma and to investigate whether smoking represents a significant covariate on the above possible processes. Methods Eighty-seven patients with asthma (42 smokers) and 28 healthy subjects (14 smokers) were studied. All subjects underwent lung function tests, bronchial hyper-responsiveness assessment and sputum induction for cell count identification and measurement of Ang-1, Ang-2, vascular endothelial growth factor, TGF-β1, MMP-2, IL-13, Eosinophilic cationic protein and IL-8 in supernatants. Airway vascular permeability (AVP) index was also assessed. Results Ang-1 (ng/mL) levels were significantly higher in patients with asthma compared to normal subjects. Smoking significantly increased Ang-1 levels [median, interquartile ranges 24 (13-37) in smoking asthmatics vs 10 (7-14) in nonsmoking asthmatics vs 5.3 (3.7-6.5) and 4.6 (3.8-5.7) in healthy smokers and nonsmokers, respectively, P < 0.001]. Similar results were observed for Ang-2 (pg/mL) [168 (132-203) vs 124 (82-152) vs 94 (78-113) vs 100 (96-108), respectively, P < 0.001]. Regression analysis in the whole study population showed a significant negative association for Ang-1, with AVP index, and MMP-2. Smoking was a significant covariate for both Ang-1 and Ang-2 in asthmatic patients. Conclusions Ang-1 and Ang-2 levels are upregulated in patients with optimally treated asthma. Our data support a possible role for smoking in the angiogenetic process in asthma. [ABSTRACT FROM AUTHOR]

Controversy surrounds the identity, origin, and physiologic role of endogenous cardiomyocyte progenitors in adult mammals. Using an inducible genetic labeling approach to identify small non-myocyte cells expressing cardiac markers, we find that activated endogenous cardioblasts are rarely evident in the normal adult mouse heart. However, myocardial infarction results in significant cardioblast activation at the site of injury. Genetically labeled isolated cardioblasts express cardiac transcription factors and sarcomeric proteins, exhibit spontaneous contractions, and form mature cardiomyocytes in vivo after injection into unlabeled recipient hearts. The activated cardioblasts do not arise from hematogenous seeding, cardiomyocyte dedifferentiation, or mere expansion of a preformed progenitor pool. Cell therapy with cardiosphere-derived cells amplifies innate cardioblast-mediated tissue regeneration, in part through the secretion of stromal cell-derived factor 1 by transplanted cells. Thus, stimulation of endogenous cardioblasts by exogenous cells mediates therapeutic regeneration of injured myocardium. [ABSTRACT FROM AUTHOR]

Cardiosphere-derived cells (CDCs) have been shown to regenerate infarcted myocardium in patients after myocardial infarction (MI). However, whether the cells of the newly formed myocardium originate from the proliferation of adult cardiomyocytes or from the differentiation of endogenous stem cells remains unknown. Using genetic fate mapping to mark resident myocytes in combination with long-term BrdU pulsing, we investigated the origins of postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mammalian heart. In the normal mouse heart, cardiomyocyte turnover occurs predominantly through proliferation of resident cardiomyocytes at a rate of ∼1.3-4%/year. After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes. Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium. The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair. Thus, CDCs induce myocardial regeneration by differentially upregulating two mechanisms of endogenous cell proliferation. →See accompanying article [ABSTRACT FROM AUTHOR]

Aims Chronic heart failure (CHF) is associated with increased risk of osteoporosis. We investigated the relationship between severity of CHF and bone loss, underlying pathophysiological mechanisms, and the prognostic significance of bone mass changes in heart failure. Methods and results Total body (TB) and femoral (F) bone mineral density (BMD), and T- and Z-scores in the femur were measured in 60 men with CHF (56 ± 11 years) and 13 age-matched men free from CHF. The composite study endpoint was death, implantation of a left ventricular assist device (LVAD), or inotrope dependency during a median 2-year follow-up. Parathyroid hormone (PTH) and vitamin D were measured in all subjects. TBBMD, FBMD, T-score, and Z-score were significantly lower in men with CHF. Their PTH levels were also significantly increased (111 ± 59 vs. 39 ± 14; P < 0.001). Patients in New York Heart Association classes III–IV compared with those in classes I–II demonstrated significantly lower TBBMD, FBMD, T-score, and Z-score, and higher PTH (136 ± 69 vs. 86 ± 31; P= 0.001). Increased PTH levels were correlated with reduced TBBMD (P = 0.003), FBMD (P = 0.002), and femur T-score (P = 0.001), reduced cardiac index (P = 0.01) and VO2 peak (P < 0.0001), and increased wedge pressure (P = 0.001). Low TBBMD [hazard ratio (HR) 0.003, 95% confidence interval (CI) 0.00–0.58; P = 0.03] and Z-score (HR 0.56, 95% CI 0.35–0.90; P = 0.017) were associated with adverse outcome. Conclusions Secondary hyperparathyroidism and reduction in bone density occur in CHF patients and are associated with disease severity. Increased bone mass loss in CHF has prognostic significance. [ABSTRACT FROM PUBLISHER]

Background: Chronotropic response to exercise and heart rate recovery immediately after exercise (HRR1) are valid prognostic markers in patients with chronic heart failure (CHF). The aim of this study was to evaluate heart rate profile during and after exercise in CHF patients early after left ventricular assist device (LVAD) implantation. Methods: We enrolled seven stable consecutive CHF patients (five males, mean age: 45 ± 16 years) after 1 month of LVAD (HeartMate II; Thoratec Corp, Pleasanton, CA, USA) implantation, seven healthy subjects, and 14 patients with advanced HF (HF control group) who performed an incremental symptom-limited cardiopulmonary exercise testing (CPET). CHF patients performed CPET at 1 and 3 months after LVAD. HRR1 was defined as the HR difference from peak to 1 minute after exercise and chronotropic response to exercise as the chronotropic reserve ([CR, %]=[peak HR-resting HR/220-age-resting HR]× 100). Results: LVAD patients 3 months after implantation had a significantly different HR profile during exercise compared to healthy controls, with significantly lower CR (57 ± 31 vs 90 ± 14, %, P < 0.001) and HRR1 (14 ± 6 vs 28 ± 8, bpm, P < 0.01). HR profile during exercise did not significantly change 1 and 3 months after LVAD implantation. There was no statistical difference compared to HF control group and LVAD group regarding cardiopulmonary parameters. Conclusions: LVAD patients present an impaired CR and an abnormal HRR1 after implantation, indicating significant cardiac autonomic abnormalities. These alterations seem to remain unaltered 3 months after LVAD implantation. (PACE 2011; 34:1607-1614) [ABSTRACT FROM AUTHOR]

Newts can regenerate amputated limbs and cardiac tissue, unlike mammals which lack broad regenerative capacity. Several signaling pathways involved in cell proliferation, differentiation and survival during newt tissue regeneration have been elucidated, however the factors that coordinate signaling between cells, as well as the conservation of these factors in other animals, are not well defined. Here we report that media conditioned by newt limb explant cells (A1 cells) protect mammalian cardiomyocytes from oxidative stress-induced apoptosis. The cytoprotective effect of A1-conditioned media was negated by exposing A1 cells to GW4869, which suppresses the generation of extracellular vesicles (EVs). A1-EVs are similar in diameter (~100-150 nm), structure, and share several membrane surface and cargo proteins with mammalian exosomes. However, isolated A1-EVs contain significantly higher levels of both RNA and protein per particle than mammalian EVs. Additionally, numerous cargo RNAs and proteins are unique to A1-EVs. Of particular note, A1-EVs contain numerous mRNAs encoding nuclear receptors, membrane ligands, as well as transcription factors. Mammalian cardiomyocytes treated with A1-EVs showed increased expression of genes in the PI3K/AKT pathway, a pivotal player in survival signaling. We conclude that newt cells secrete EVs with diverse, distinctive RNA and protein contents. Despite ~300 million years of evolutionary divergence between newts and mammals, newt EVs confer cytoprotective effects on mammalian cardiomyocytes. [ABSTRACT FROM AUTHOR]