Structural and Functional Support by Left Atrial Appendage Transplant to the Left Ventricle after a Myocardial Infarction.

The left atrial appendage (LAA) of the adult heart has been shown to contain cardiac and myeloid progenitor cells. The resident myeloid progenitor population expresses an array of pro-regenerative paracrine factors. Cardiac constructs have been shown to inhibit deleterious remodeling of the heart using physical support. Due to these aspects, LAA holds promise as a regenerative transplant. LAAs from adult mT/mG mice were transplanted to the recipient 129X1-SvJ mice simultaneously as myocardial infarction (MI) was performed. A decellularized LAA patch was implanted in the control group. Two weeks after MI, the LAA patch had integrated to the ventricular wall, and migrated cells were seen in the MI area. The cells had two main phenotypes: small F4/80+ cells and large troponin C+ cells. After follow-up at 8 weeks, the LAA patch remained viable, and the functional status of the heart improved. Cardiac echo demonstrated that, after 6 weeks, the mice in the LAA-patch-treated group showed an increasing and statistically significant improvement in cardiac performance when compared to the MI and MI + decellularized patch controls. Physical patch-support (LAA and decellularized LAA patch) had an equal effect on the inhibition of deleterious remodeling, but only the LAA patch inhibited the hypertrophic response. Our study demonstrates that the LAA transplantation has the potential for use as a treatment for myocardial infarction. This method can putatively combine cell therapy (regenerative effect) and physical support (inhibition of deleterious remodeling).

Left atrial appendages from adult hearts contain a reservoir of diverse cardiac progenitor cells.

AIMS: There is strong evidence supporting the claim that endogenous cardiac progenitor cells (CPCs) are key players in cardiac regeneration, but the anatomic source and phenotype of the master cardiac progenitors remains uncertain. Our aim was to investigate the different cardiac stem cell populations in the left atrial appendage (LAA) and their fates. METHODS AND RESULTS: We investigated the CPC content and profile of adult murine LAAs using immunohistochemistry and flow cytometry. We demonstrate that the LAA contains a large number of CPCs relative to other areas of the heart, representing over 20% of the total cell number. We grew two distinct CPC populations from the LAA by varying the degree of proteolysis. These differed by their histological location, surface marker profiles and growth dynamics. Specifically, CD45(pos) cells grew with milder proteolysis, while CD45(neg) cells grew mainly with more intense proteolysis. Both cell types could be induced to differentiate into cells with cardiomyocyte markers and organelles, albeit by different protocols. Many CD45(pos) cells expressed CD45 initially and rapidly lost its expression while differentiating. CONCLUSIONS: Our results demonstrate that the left atrial appendage plays a role as a reservoir of multiple types of progenitor cells in murine adult hearts. Two different types of CPCs were isolated, differing in their epicardial-myocardial localization. Considering studies demonstrating layer-specific origins of different cardiac progenitor cells, our findings may shed light on possible pathways to study and utilize the diversity of endogenous progenitor cells in the adult heart.

Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage.

Cardiotoxicity associated with doxorubicin (DOX) treatment limits the therapeutic efficiency of this drug against cancer. 2-Chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective agonist of A(3) adenosine receptor (A(3)R), reduces DOX toxicity in newborn rat cultured cardiomyocytes. The study's aim was to determine whether the protection demonstrated by Cl-IB-MECA attenuates cardiac depression in vivo. In addition, we wished to examine whether this protective pathway affects the sarcoplasmic reticulum (SR) calcium uptake and release, as well as intramitochondrial Ca(2+) accumulation induced by DOX. Rats were injected every alternate day (6 times) with (1) saline, (2) 2.5mg/kg i.p. DOX, (3) 33 microg/kg i.v. Cl-IB-MECA, (4) DOX+Cl-IB-MECA. Left ventricular functions were assessed by invasive (pressure) and non-invasive (echocardiography) techniques at the end of the injection period and 4 weeks later. Cytosolic and intramitochondrial calcium levels were measured with indo-1 and rhod-2 probes. SR Ca(2+) content was determined by exposing cultured rat cardiomyocytes to caffeine. Echocardiography data demonstrate left ventricular wall thinning (23%), an increase in the end systolic dimension (170%) and decreased fractional shortening (35+/-5% vs. 54+/-5%, p<0.01) in DOX-treated animals, compared to the control group. DOX increased Ca(2+) levels in the cytosol and in mitochondria by diminishing the SR Ca(2+) uptake. Pretreatment with Cl-IB-MECA attenuated left ventricular dysfunction, improved SR calcium storage capacity and prevented mitochondrial Ca(2+) overload. We conclude that the adenosine A(3) receptor agonist is effective in vivo against DOX cardiotoxicity via the restoration of Ca(2+) homeostasis and prevention of mitochondrial damage that occurs as a result of Ca(2+) overload.