Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy

It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of myocyte hypertrophy and hyperplasia. Intense new myocyte formation results from the differentiation of stem-like cells committed to the myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and myocyte precursors, as well as very primitive myocytes that turn into terminally differentiated myocytes, provides a link between cardiac stem cells and myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the myocyte lineage in response to increased workload. Their presence is consistent with the notion that myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling myocytes

Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus (DM) has multifactorial detrimental effects on myocardial tissue. Recently, carbonic anhydrases (CAs) have been shown to play a major role in diabetic microangiopathy but their role in the diabetic cardiomyopathy is still unknown. METHODS AND RESULTS: We obtained left ventricular samples from patients with DM type 2 (DM-T2) and nondiabetic (NDM) patients with postinfarct heart failure who were undergoing surgical coronary revascularization. Myocardial levels of CA-I and CA-II were 6- and 11-fold higher, respectively, in DM-T2 versus NDM patients. Elevated CA-I expression was mainly localized in the cardiac interstitium and endothelial cells. CA-I induced by high glucose levels hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro. Accordingly, capillary density was significantly lower in the DM-T2 myocardial samples (mean±SE=2152±146 versus 4545±211/mm(2)). On the other hand, CA-II was mainly upregulated in cardiomyocytes. The latter was associated with sodium-hydrogen exchanger-1 hyperphosphorylation, exaggerated myocyte hypertrophy (cross-sectional area 565±34 versus 412±27 μm(2)), and apoptotic death (830±54 versus 470±34 per 10(6) myocytes) in DM-T2 versus NDM patients. CA-II is activated by high glucose levels and directly induces cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium-hydrogen exchanger-1 inhibition. CA-II was shown to be a direct target for repression by microRNA-23b, which was downregulated in myocardial samples from DM-T2 patients. MicroRNA-23b is regulated by p38 mitogen-activated protein kinase, and it modulates high-glucose CA-II-dependent effects on cardiomyocyte survival in vitro. CONCLUSIONS: Myocardial CA activation is significantly elevated in human diabetic ischemic cardiomyopathy. These data may open new avenues for targeted treatment of diabetic heart failure

Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining

Intensity‐controlled (relative to VO2max) treadmill exercise training in adult rats results in the activation and ensuing differentiation of endogenous c‐kitpos cardiac stem/progenitor cells (eCSCs) into newly formed cardiomyocytes and capillaries. Whether these training‐induced adaptations persist following detraining is undetermined. Twelve male Wistar rats (~230 g) were exercised at 80–85% of their VO2max for 30 min day−1, 4 days week−1 for 4 weeks (TR; n = 6), followed by 4 weeks of detraining (DTR; n = 6). Twelve untrained rats acted as controls (CTRL). Exercise training significantly enhanced VO2max (11.34 mL kg−1 min−1) and wet heart weight (29%) above CTRL (P < 0.05). Echocardiography revealed that exercise training increased LV mass (~32%), posterior and septal wall thickness (~15%), ejection fraction and fractional shortening (~10%) compared to CTRL (P < 0.05). Cardiomyocyte diameter (17.9 ± 0.1 μm vs. 14.9 ± 0.6 μm), newly formed (BrdUpos/Ki67pos) cardiomyocytes (7.2 ± 1.3%/1.9 ± 0.7% vs. 0.2 ± 0.1%/0.1 ± 0.1%), total cardiomyocyte number (45.6 ± 0.6 × 106 vs. 42.5 ± 0.4 × 106), c‐kitpos eCSC number (884 ± 112 per 106 cardiomyocytes vs. 482 ± 132 per 106 cardiomyocytes), and capillary density (4123 ± 227 per mm2 vs. 2117 ± 118 per mm2) were significantly greater in the LV of trained animals (P < 0.05) than CTRL. Detraining removed the stimulus for c‐kitpos eCSC activation (640 ± 98 per 106 cardiomyocytes) and resultant cardiomyocyte hyperplasia (0.4 ± 0.3% BrdUpos/0.2 ± 0.2% Ki67pos cardiomyocytes). Capillary density (3673 ± 374 per mm2) and total myocyte number (44.7 ± 0.5 × 106) remained elevated following detraining, but cardiomyocyte hypertrophy (15.0 ± 0.4 μm) was lost, resulting in a reduction of anatomical (wall thickness ~4%; LV mass ~10% and cardiac mass ~8%, above CTRL) and functional (EF & FS ~2% above CTRL) parameters gained through exercise training. These findings demonstrate that cardiac adaptations, produced by 4 weeks of intensity‐controlled exercise training are lost after a similar period of detraining

Migration of a stent from left main and its retrieval from femoral artery: A case report

Rationale:Embolization of a deployed stent is a rare complication and its mechanism remains unclear in most cases.Patient concerns:A 52-year-old man underwent coronary angiography for effort angina, revealing an 80% stenosis of the proximal left anterior descending (LAD) involving the distal left main (LM). After luminal sizing with intravascular ultrasound two drug-eluting stents were deployed (5.0 × 12 mm and 3.5 × 15 mm) to cover the LM-LAD lesion. After postdilatation, the proximal stent had disappeared from the LM.Diagnoses:The missing stent was found in the right deep femoral artery.Interventions:A new 5.0 × 15 mm stent was deployed onto the LM-LAD ostium, in overlapping with the previously implanted. Then, the stent migrated to the deep femoral artery was successfully retieved through the contralateral femoral artery.Outcomes:The patient was discharged 2 days later, after an uneventful hospital stay.Lessons:Stent deformation after postdilation is a possible causes of stent migration

Regulating working families in the European Union: a history of disjointed strategies

Families in market economies worldwide have long been confronted with the demands of participating in paid work and providing care for their dependent members. The social, economic and political contexts within which families do so differ from country to country but an increasing number of governments are being asked to engage, or better engage, with this important area of public policy. What seems like a relatively simple goal – to enable families to better balance care-giving and paid employment – has raised several difficulties and dilemmas for policy makers which have been approached in different ways. This paper aims to identify and critique the nature and development of the means by which legal engagement with work-family reconciliation has, historically, been framed in the European Union. In doing so, and with reference to specific cohorts of workers, we demonstrate how disjointed the strategies are in relation to working carers and argue that the EU is unlikely to provide the legal framework necessary to bring about effective change in this fundamentally important area of social policy

Clinical and procedural outcomes of 5-French versus 6-French sheaths in transradial coronary interventions

The radial artery has been increasingly used for its favorable safety profile. However, no conclusive data are available on the optimal sheath size. In particular, it is seemingly difficult to weight both advantages and disadvantages of narrower versus larger sheaths size. Despite several studies were performed to compare the use of 6-Fr to the smaller 5-Fr sheaths, these were mostly small, single center-studies, yielding various results. We performed a comprehensive meta-analysis of all available studies comparing the use of 5-Fr versus 6-Fr sheaths in coronary procedures through the TRA. Studies comparing a 5-Fr versus a 6-Fr sheaths were searched for in PubMed, the Cochrane Library, and ISI Web of Knowledge databases. Studies were deemed eligible if they only included patients undergoing transradial cardiac catheterization with 5-Fr or 6-Fr system and reported at least one of these parameters: contrast dye volume, procedural success, procedural time, access complications, radial artery occlusion, and bleedings. Odds ratio (OR) and the mean difference (MD) were respectively used for dichotomous and continuous variables as summary measures. Both the random-effects model and the fixed effect models were used for computation of meta-analyses. Heterogeneity was assessed by means of the Cochrane Q test. Metaregression was calculated using the unrestricted maximal likelihood random effects model. The use of a 5-Fr system is associated with a significant lower contrast medium administration (MD=-22.20 [-36.43 to-7.96], P<0.01) and significantly reduces bleedings (OR=0.58 [0.38- 0.90], P=0.02), without compromising procedural success (OR=0.95 [0.53-1.69], P=0.86) or procedure length (OR=0.55 [-2.58 to 3.69], P=0.73), compared to the 6-Fr system. Despite no significant difference was observed between the groups (OR=0.88 [0.50-1.56], P=0.67), at metaregression RAO incidence in the 5-Fr group was increasingly lower as the percentage of women included into the study increased (P=0.02). Some potentially interesting technical details, such as sheath length, hydrophilic coating, or periprocedural anticoagulation, were not homogeneously reported in individual studies. Results of the present meta-analysis confirm the excellent safety profile of transradial procedures both with 5-Fr and 6-Fr system. A 5-Fr system could be preferred in patients with a higher bleeding propensity or kidney injury

The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation

Aims It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored. Methods and results In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kitpos eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kitpos eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5pos) or capillary (Ets-1pos) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kitpos eCSC proliferation and commitment in vitro, pointing to a similar role in vivo. Conclusion Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kitpos eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries)