Ricardo Sanz-Ruiz

Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial.

AIMS Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. METHODS AND RESULTS Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. CONCLUSION Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Early Translation of Adipose-Derived Cell Therapy for Cardiovascular Disease

Over the past decade, cell therapy has emerged as a new approach to reversing myocardial ischemia. Several types of adult stem cells have been studied in both preclinical and clinical conditions for this purpose: bone marrow cells, circulating cells, and myoblasts. Nevertheless, the quest for the ideal “anti-ischemic” cell is still ongoing. Recently, the existence of a population of stem cells located in adipose tissue (adipose-derived stem cells) has been observed. These are able to differentiate into multiple cell lineages including cardiomyocytic differentiation. In this review we discuss the basic principles of adipose-derived stem cells (types and characteristics, harvesting, and expansion), the initial experimental studies, and the currently ongoing clinical trials.

Global position paper on cardiovascular regenerative medicine

Authors/Task Force Members. Chairpersons: Francisco Fern andez-Avilés (Spain), Andre Terzic (USA); Basic Research Subcommittee: Lina Badimon (Spain), Kathleen Broughton (USA), Darcy L. DiFede (USA), Stefanie Dimmeler (Germany), Rosalinda Madonna (Italy), Marc S. Penn (USA), Mark A. Sussman (USA), Joost P.G. Sluijter (The Netherlands), Kai C. Wollert (Germany); Translational Research Subcommittee: Wayne Balkan (USA), Roberto Bolli (USA), Steven Chamuleau (The Netherlands), Dominique Charron (France),

Validation of Noninvasive Indices of Global Systolic Function in Patients With Normal and Abnormal Loading Conditions A Simultaneous Echocardiography Pressure-Volume Catheterization Study

Background—Noninvasive indices based on Doppler echocardiography are increasingly used in clinical cardiovascular research to evaluate left ventricular global systolic chamber function. Our objectives were to clinically validate ultrasound-based methods of global systolic chamber function to account for differences between patients in conditions of abnormal load, and to assess their sensitivity to load confounders. Methods and Results—Twenty-seven patients (8 dilated cardiomyopathy, 10 normal ejection fraction, and 9 end-stage liver disease) underwent simultaneous echocardiography and left heart catheterization with pressure-conductance instrumentation. The reference index, maximal elastance (Emax), was calculated from pressure–volume loop data obtained during acute inferior vena cava occlusion. A wide range of values were observed for left ventricular systolic chamber function (Emax: 2.8±1.0 mm Hg/mL), preload, and afterload. Among the noninvasive indices tested, the peak ejection intraventricular pressure difference showed the best correlation with Emax (R=0.75). A significant but weaker correlation with Emax was observed for ejection fraction (R=0.41), midwall fractional shortening (R=0.51), global circumferential strain (R=−0.53), and strain rate (R=−0.46). Longitudinal strain and strain rate failed to correlate with Emax, as did noninvasive single-beat estimations of this index. Principal component and multiple regression analyses demonstrated that peak ejection intraventricular pressure difference was less sensitive to load, whereas ejection fraction and longitudinal strain and strain rate were heavily influenced by afterload. Conclusions—Current ultrasound methods have limited accuracy to characterize global left ventricular systolic chamber function in a given patient. The Doppler-derived peak ejection intraventricular pressure difference should be preferred for this purpose because it best correlates with the reference index and is more robust in conditions of abnormal load.

Cultured and freshly isolated adipose tissue-derived cells: fat years for cardiac stem cell therapy

As understanding has grown about what happens when heart muscle cells die en masse after a heart attack, so has the development of treatments aimed at avoiding the loss or failure of cardiovascular function. These treatments include stem cell transplantation. The first pre-clinical and clinical experiences in stem cell transplantation were reported around a decade ago.1,2 However, and although the field has moved quickly in these years, the most important questions—the ‘cell product’ to be used, delivery method, outcome measurement, organizational problems, and funding—remain unanswered. The quest for the best cell type has been wheeled around from bedside to bench and back again.3 The ideal cell type should be capable of differentiating into functional cardiomyocytes and forming new vessels. Cell types from several different sources have already been tested in animal models, and bone marrow-derived cells and skeletal myoblasts have already been used in clinical trials. Each subtype has its advantages and disadvantages, but one important issue is the time needed for their preparation: time-consuming protocols hinder easy implementation in the acute clinical setting and carry a risk of culture contamination and/or genetic modification. Furthermore, whether the beneficial effect is mediated by one specific cell type or many cell types in concert remains unknown. It is obviously of great scientific interest to test all possible combinations of progenitor types, numbers of cells, times of injection after damage, frequencies of injection, mechanisms of action, as well as homing/grafting and survival, all through different routes in animal models and then in man. The report by Bai et al. 4 is significant for different reasons. First, it demonstrates that freshly isolated adipose tissue-derived stem cells (ASCs) transplanted into ischaemic hearts after acute myocardial infarction promote cardiac function as well as do cultured ASCs. Secondly, it indicates that transplanted cells … *Corresponding author. Tel: +34 91 426 5880, Fax: +34 91 586 8276, Email: faviles{at}secardiologia.es

Direct injury to right coronary artery in patients undergoing tricuspid annuloplasty.

BACKGROUND Direct injury to the right coronary artery as a result of reparative operation on the tricuspid valve is a rare, probably underdiagnosed, but serious complication, which often involves dramatic clinical consequences. So far, only five cases have been described in the literature. METHODS We describe our single-center experience of this complication, and review and analyze relevant clinical and anatomic considerations related to this entity. Cases previously reported in the literature were also reviewed. RESULTS We describe four cases of direct injury to the right coronary artery in patients undergoing tricuspid annuloplasty (DeVega annuloplasty, 3; ring annuloplasty, 1) in our institution since 2005. All patients had right ventricular dilatation and severely dilated tricuspid annulus. Right coronary artery occlusion always occurred between the right marginal artery and the crux of the heart. Patients presented with hemodynamic or electrical instability. Coronary flow could be restored in 2 patients (percutaneously 1; surgically 1), both of whom finally survived, while it was not technically possible in the other 2 (1 died). CONCLUSIONS Occlusion of the right coronary artery in patients undergoing tricuspid annuloplasty is a rare complication that may occur if great annulus dilatation is present, thus altering both normal annular geometry and the relationship between the right coronary artery and the tricuspid annulus, particularly when DeVega annuloplasty is performed. Such an entity should be considered in the immediate postoperative period in an unstable patient, especially when complementary tests support this diagnosis. Prompt recognition and treatment can positively affect the patients outcome, most often by means of an emergency revascularization strategy.

Comparative healing response after sirolimus- and paclitaxel-eluting stent implantation in a pig model of restenosis.

We compared local vessel healing and inflammatory responses associated with nonoverlapping sirolimus‐eluting stents (SES) and paclitaxel‐eluting stents (PES).

Two-year follow up after surgical versus percutaneous paravalvular leak closure: A non-randomized analysis

Percutaneous closure of paravalvular leak (PVL) has emerged as an alternative treatment. Predictors of survival and procedural success are unknown.

Adipose Tissue-derived Stem Cells: The Friendly Side of a Classic Cardiovascular Foe

Recently, the existence of a population of stem cells located in the adipose tissue has been observed. Adipose-derived stem cells are able to differentiate into multiple cell lineages including cardiac myocytes. Hence, adipose-derived cells are emerging as a new source of adult stem cells for cardiovascular repair. In this review, we discuss the basic principles of adipose-derived stem cells (types and characteristics, obtention processes, immunophenotypic characterization, and cell potency), the initial experimental studies, and the currently ongoing clinical trials.