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Background: Despite the low spatial resolution of 2D-multisegment late gadolinium enhancement (2D-MSLGE) sequences, it may be useful in uncooperative patients instead of standard 2D single segmented inversion recovery gradient echo late gadolinium enhancement sequences (2D-SSLGE). The aim of the study is to assess the feasibility and comparison of 2D-MSLGE reconstructed with artificial intelligence reconstruction deep learning noise reduction (NR) algorithm compared to standard 2D-SSLGE in consecutive patients with ischemic cardiomyopathy (ICM). Methods: Fifty-seven patients with known ICM referred for a clinically indicated CMR were enrolled in this study. 2D-MSLGE were reconstructed using a growing level of NR (0%,25%,50%,75%and 100%). Subjective image quality, signal to noise ratio (SNR) and contrast to noise ratio (CNR) were evaluated in each dataset and compared to standard 2D-SSLGE. Moreover, diagnostic accuracy, LGE mass and scan time were compared between 2D-MSLGE with NR and 2D-SSLGE. Results: The application of NR reconstruction ≥50% to 2D-MSLGE provided better subjective image quality, CNR and SNR compared to 2D-SSLGE (p < 0.01). The best compromise in terms of subjective and objective image quality was observed for values of 2D-MSLGE 75%, while no differences were found in terms of LGE quantification between 2D-MSLGE versus 2D-SSLGE, regardless the NR applied. The sensitivity, specificity, negative predictive value, positive predictive value and accuracy of 2D-MSLGE NR 75% were 87.77%,96.27%,96.13%,88.16% and 94.22%, respectively. Time of acquisition of 2D-MSLGE was significantly shorter compared to 2D-SSLGE (p < 0.01). Conclusion: When compared to standard 2D-SSLGE, the application of NR reconstruction to 2D-MSLGE provides superior image quality with similar diagnostic accuracy.

Background Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca2+) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. Methods and results ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. Conclusions Altogether, our results extend the knowledge of Ca2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.

Myocardial aging increases the cardiovascular risk in the elderly. The Receptor for Advanced Glycation End-products (RAGE) is involved in age-related disorders. The soluble isoform (sRAGE) acts as a scavenger blocking the membrane-bound receptor activation. This study aims at investigating RAGE contribution to age-related cardiac remodeling. We analyzed the cardiac function of three different age groups of female Rage-/- and C57BL/6N (WT) mice: 2.5- (Young), 12- (Middle-age, MA) and 21-months (Old) old. While aging, Rage-/- mice displayed an increase in left ventricle (LV) dimensions compared to age-matched WT animals, with the main differences observed in the MA groups. Rage-/- mice showed higher fibrosis and a larger number of α-Smooth Muscle Actin (SMA)+ cells with age, along with increased expression of pro-fibrotic Transforming Growth Factor (TGF)-β1 pathway components. RAGE isoforms were undetectable in LV of WT mice, nevertheless, circulating sRAGE declined with aging and inversely associated with LV diastolic dimensions. Human cardiac fibroblasts stimulated with sRAGE exhibited a reduction in proliferation, pro-fibrotic proteins and TGF-beta Receptor 1 (TGFbR1) expression and Smad2-3 activation. Finally, sRAGE administration to MA WT animals reduced cardiac fibrosis. Hence, our work shows that RAGE associates with age-dependent myocardial changes and indicates sRAGE as an inhibitor of cardiac fibroblasts differentiation and age-dependent cardiac fibrosis.

Background: Graft occlusion after coronary artery bypass graft surgery (CABG) has been associated with native coronary artery competitive flow. Objectives: The present study aims to characterize the functional progression of coronary artery disease (CAD) in native vessels after CABG, and to assess the relationship between preoperative FFR as derived from angiography and graft occlusion. Methods: Multicenter study of consecutive patients undergoing CABG between 2013 and 2018, in whom a follow-up angiogram had been performed. Serial vessel-fractional flow reserve (vFFR) analyses were obtained in each major native coronary vessel before and after CABG, excluding post-anastomotic segments and graft conduits. Results: In 73 patients, serial angiograms were suitable for vFFR analysis, including 118 grafted (86 arterial and 32 saphenous grafts) and 64 non-grafted vessels. The median time between CABG and follow-up angiography was 2.4 years [IQR 1.5, 3.3]. Functional CAD progression, by means of decline in vFFR, was observed in grafted but not in non-grafted vessels (delta vFFR in grafted vessels 0.10 [IQR 0.05, 0.18] vs. 0.01 [IQR -0.01, 0.03], in non-grafted vessels, p < 0.001). Preoperative vFFR predicted graft occlusion (AUC: 0.66, 95% CI 0.52 to 0.80, p = 0.031). Conclusions: In patients undergoing CABG, preoperative vFFR derived from conventional angiograms without use of pressure wire was able to predict graft occlusion. Graft occlusion was more frequent in vessels with high vFFR values. Grafted native coronary vessels exhibited accelerated functional CAD progression, whereas in non-grafted native coronaries the functional status remained unchanged.

Background Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function. Methods In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation, CXCR4/SDF-1α axis activity and metabolic imbalance from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9–39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. Conclusion We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro-fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB-3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB-3modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Rationale: In the exploratory Phase II STEM-AMI (Stem Cells Mobilization in Acute Myocardial Infarction) trial, we reported that early administration of G-CSF (granulocyte colony-stimulating factor), in patients with anterior ST-segment–elevation myocardial infarction and left ventricular (LV) dysfunction after successful percutaneous coronary intervention, had the potential to significantly attenuate LV adverse remodeling in the long-term. Objective: The STEM-AMI OUTCOME CMR (Stem Cells Mobilization in Acute Myocardial Infarction Outcome Cardiac Magnetic Resonance) Substudy was adequately powered to evaluate, in a population showing LV ejection fraction ≤45% after percutaneous coronary intervention for extensive ST-segment–elevation myocardial infarction, the effects of early administration of G-CSF in terms of LV remodeling and function, infarct size assessed by late gadolinium enhancement, and myocardial strain. Methods and Results: Within the Italian, multicenter, prospective, randomized, Phase III STEM-AMI OUTCOME trial, 161 ST-segment–elevation myocardial infarction patients were enrolled in the CMR Substudy and assigned to standard of care (SOC) plus G-CSF or SOC alone. In 119 patients (61 G-CSF and 58 SOC, respectively), CMR was available at baseline and 6-month follow-up. Paired imaging data were independently analyzed by 2 blinded experts in a core CMR lab. The 2 groups were similar for clinical characteristics, cardiovascular risk factors, and pharmacological treatment, except for a trend towards a larger infarct size and longer symptom-to-balloon time in G-CSF patients. ANCOVA showed that the improvement of LV ejection fraction from baseline to 6 months was 5.1% higher in G-CSF patients versus SOC ( P =0.01); concurrently, there was a significant between-group difference of 6.7 mL/m 2 in the change of indexed LV end-systolic volume in favor of G-CSF group ( P =0.02). Indexed late gadolinium enhancement significantly decreased in G-CSF group only ( P =0.04). Moreover, over time improvement of global longitudinal strain was 2.4% higher in G-CSF patients versus SOC ( P =0.04). Global circumferential strain significantly improved in G-CSF group only ( P =0.006). Conclusions: Early administration of G-CSF exerted a beneficial effect on top of SOC in patients with LV dysfunction after extensive ST-segment–elevation myocardial infarction in terms of global systolic function, adverse remodeling, scar size, and myocardial strain. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01969890.

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.

(1)Background: Chronic heart failure (CHF) contributes to the overall burden of cardiovascular disease. Early identification of at-risk individuals may facilitate the targeting of precision therapies. Plasma microRNAs are promising circulating biomarkers for their implications with cardiac pathologies. In this pilot study, we investigate the possible exploitability of circulating micro-RNAs (miRNAs) to track chronic heart failure (CHF) occurrence, and progression from NYHA class I to IV. (2)Methods: We screened 367 microRNAs using TaqMan microRNA Arrays in plasma samples from healthy controls (HC) and CHF NYHA-class I-to-IV patients (5/group). Validation was performed by singleplex assays on 10 HC and 61 CHF subjects. Differences in the expression of validated microRNAs were evaluated through analysis of covariance (ANCOVA). Associations between N-terminal pro-BNP (NT-proBNP), left ventricular end-diastolic volume (LVEDV) or peak oxygen uptake (VO2 peak) and plasma microRNA were assessed by multivariable linear regression analysis. (3)Results: Twelve microRNAs showed higher expression in CHF patients vs. HC. Seven microRNAs were associated with NT-proBNP concentration, of these, miR-423-5p was also an independent predictor of LVEDV. Moreover, miR-499-5p was a predictor of the VO2 peak. Finally, a cluster of 5 miRNAs discriminated New York Heart Association (NYHA) class-I from HC subjects. (4)Conclusions: Our data suggest that circulating miRNAs have the potential to serve as pathophysiology-based markers of HF status and progression, and as indicators of pre-symptomatic individuals.

Coronavirus disease 2019 (COVID-19) has become a rapid worldwide pandemic. While COVID-19 primarily manifests as an interstitial pneumonia and severe acute respiratory distress syndrome, severe involvement of other organs has been documented. In this article, we will review the role of non-contrast chest computed tomography in the diagnosis, follow-up and prognosis of patients affected by COVID-19 pneumonia with a detailed description of the imaging findings that may be encountered. Given that patients with COVID-19 may also suffer from coagulopathy, we will discuss the role of CT pulmonary angiography in the detection of acute pulmonary embolism. Finally, we will describe more advanced applications of CT in the differential diagnosis of myocardial injury with an emphasis on ruling out acute coronary syndrome and myocarditis., Graphical abstract Central Illustration. CT guided diagnostic-work up of COVID-19 patients with elevated troponin. Cardiac CT is reserved to patients with low and intermediate probability of CAD. Timing the acquisition for the simultaneous evaluation of pulmonary and coronary arteries allows the ruling in/out of both pulmonary embolism and CAD. In case of obstructive CAD the patient will be referred to invasive coronary angiography. Conversely, if obstructive CAD is excluded, an additional delayed acquisition might be obtained for the detection of potential myocardial damage. Alternatively to late iodine enhancement imaging, pre and post-contrast CT phase can be analysed to calculate the ECV. Abbreviations: ACS: acute coronary syndrome; CAD: coronary artery disease; CT: computed tomography; ECG: electrocardiogram; ECV: extracellular volume; ICA: invasive coronary angiography; PE: pulmonary embolism; STEMI: ST elevation myocardial infarction.Image 1

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+handling machinery, focusing on the available data supporting this hypothesis. The Ca2+toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease.

“The senescence status of somatic stem/progenitor cells contributes to ageing process”, and “an individual is as old as old are its stem cells”. These quotes represent the concepts, which are actually object of investigations of researchers involved in ageing studies.

Communication between cardiomyocytes depends upon gap junctions (GJ). Previous studies have demonstrated that electrical stimulation induces GJ remodeling and modifies histone acetylase (HAT) and deacetylase (HDAC) activities, although these two results have not been linked. The aim of this work was to establish whether electrical stimulation modulates GJ-mediated cardiac cell-cell communication by acetylation-dependent mechanisms. Field stimulation of HL-1 cardiomyocytes at 0.5. Hz for 24. h significantly reduced connexin43 (Cx43) expression and cell-cell communication. HDAC activity was down-regulated whereas HAT activity was not modified resulting in increased acetylation of Cx43. Consistent with a post-translational mechanism, we did not observe a reduction in Cx43 mRNA in electrically stimulated cells, while the proteasomal inhibitor MG132 maintained Cx43 expression. Further, the treatment of paced cells with the HAT inhibitor Anacardic Acid maintained both the levels of Cx43 and cell-cell communication. Finally, we observed increased acetylation of Cx43 in the left ventricles of dogs subjected to chronic tachypacing as a model of abnormal ventricular activation.In conclusion, our findings suggest that altered electrical activity can regulate cardiomyocyte communication by influencing the acetylation status of Cx43.

According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133+cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 106of CD133+cells (range 2.85 × 106–30.84 × 106), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133+cells of 90,60% (range 81,40%–96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 106cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial).

Arterial aging is a major risk factor for the occurrence of cardiovascular diseases. The aged artery is characterized by endothelial dysfunction and vascular smooth muscle cells altered physiology together with low-grade chronic inflammation. MicroRNA-34a (miR-34a) has been recently implicated in cardiac, endothelial, and endothelial progenitor cell senescence; however, its contribution to aging-associated vascular smooth muscle cells phenotype has not been explored so far. We found that miR-34a was highly expressed in aortas isolated from old mice. Moreover, its well-known target, the longevity-associated protein SIRT1, was significantly downregulated during aging in both endothelial cells and vascular smooth muscle cells. Increased miR-34a as well as decreased SIRT1 expression was also observed in replicative-senescent human aortic smooth muscle cells. miR-34a overexpression in proliferative human aortic smooth muscle cells caused cell cycle arrest along with enhanced p21 protein levels and evidence of cell senescence. Furthermore, miR-34a ectopic expression induced pro-inflammatory senescence-associated secretory phenotype molecules. Finally, SIRT1 protein significantly decreased upon miR-34a overexpression and restoration of its levels rescued miR-34a-dependent human aortic smooth muscle cells senescence, but not senescence-associated secretory phenotype factors upregulation. Taken together, our findings suggest that aging-associated increase of miR-34a expression levels, by promoting vascular smooth muscle cells senescence and inflammation through SIRT1 downregulation and senescence-associated secretory phenotype factors induction, respectively, may lead to arterial dysfunctions.

Aims The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit+ cells. Methods and results Acidic preconditioning was achieved by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca2+]i mobilization and on nitric oxide (NO), as determined by [Ca2+]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit+ cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. Conclusion Acidic preconditioning represents a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression. © The Author 2013.

AimsThe heart contains c-kit+ progenitors that maintain cardiac homeostasis. Cardiac c-kit+ cells are multipotent and give rise to myocardial, endothelial and smooth muscle cells, both in vitro and in vivo. C-kit+ cells have been thoroughly investigated for their stem cell activity, susceptibility to stress conditions and ageing, as well as for their ability to repair the infarcted heart. Recently, expression of mesenchymal stem cell (MSC) markers and MSC differentiation potency have been reported in cardiac progenitor cells. Based on this evidence, we hypothesized that c-kit + cells may have phenotypic and functional features in common with cardiac MSCs. Methods and resultsCulture of cells obtained from enzymatic dissociation of heart auricle fragments produced a fast-growing fibroblast-like population expressing mesenchymal markers. C-kit+ cells co-expressing MSC markers were identified in this population, sorted by flow cytometry and cultured in the presence or the absence of unselected cardiac cells from the same patients. Subsets of c-kit+ cells also co-expressed MSCs markers in vivo, as detected by immunofluorescence analysis of auricle tissue. Ex vivo expanded c-kit+ cells produced osteoblasts and adipocytes, although less preferentially than bone marrow-derived MSCs, possessed vascular smooth muscle cell features and were induced to differentiate into endothelium-like and cardiac-like cells. ConclusionIn line with previous findings, our results indicate that c-kit+ cardiac progenitors are primitive stem cells endowed with multilineage differentiation ability. They further suggest a possible relationship between these cells and a heart-specific MSC population with cardiovascular commitment potential. © 2010 The Author.

Preclinical studies performed in cell culture and animal systems have shown the outstanding ability of stem cells to repair ischemic heart and lower limbs by promoting the formation of new blood vessels and new myocytes. In contrast, clinical studies of stem cell administration in patients with myocardial ischemia have revealed only modest, although promising, results. Basic investigations have shown the feasibility of adult cells reprogramming into pluripotent cells by defined factors, thus opening the way to the devise of protocols to ex vivo derive virtually unexhausted cellular pools. In contrast, cellular and molecular studies have indicated that risk factors limit adult-derived stem cell survival, proliferation and engraftment in ischemic tissues. The use of fully reprogrammed cells raises safety concerns; therefore, adult cells remain a primary option for clinicians interested in therapeutic cardiovascular repair. Pharmacologic approaches have been devised to restore the cardiovascular repair ability of failing progenitors from patients at risk. In the present contribution, the most advanced pharmacologic approaches to (re)program, boost, and condition endothelial and cardiac progenitor cells to enhance cardiovascular regeneration are discussed. © 2010 Elsevier Inc. All rights reserved.