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Regenerative therapies with cardiac and vascular applications represent one of the most promising options in the fight against cardiovascular failure. Since 2004, the International Symposium on Cell Therapy and Cardiovascular Innovations (TECAM, www.cardiovascularcelltherapy.com) has been held in Spain on a yearly basis to gather the most important research groups of clinicians and scientists worldwide and to discuss the progress and hurdles of Cardiovascular Regenerative Medicine (CRM) in an open forum. The latest edition of the TECAM conference took place in Madrid on June the 15th and the 16th. Recent breakthroughs and future steps were debated during the meeting, with a special focus on the most recent achievements of the Transnational AllianCe for regenerative Therapies In Cardiovascular Syndromes (TACTICS, www.tacticsalliance.org) group and are summarized in this article. The opening session started with a keynote conference delivered by Dr Michael Laflamme, who reflected on the difficulties for obtaining real cardiac regeneration with old types of stem cells. He therefore focused his talk on pluripotent stem cells, the one cell type that has demonstrated robust differentiation into cardiomyocytes. After presenting the important functional benefits of human embryonic stem cell (ESC)–derived cardiomyocytes in murine models and recognizing safety concerns (ie, ventricular arrhythmias) in primates and swine models of myocardial scar, he concluded that large-scale remuscularization is possible using this type of human-derived cells. In the second talk, Dr Juan Carlos Izpisua presented the latest approaches to manipulate the genome in cells that do not divide. After describing how CRISPR/Cas9 can be used to induce double-strand breaks and nonhomologous end joining-based repair on the DNA, he explained the Homology Independent Targeted Integration technology that has been designed by his group. This novel tool for gene editing has been used to correct mutations in nondividing cells such as neurons and cardiomyocytes, with impressive …

More than 20 years after the introduction of stem cells as a potential tool for cardiovascular regenerative medicine (CRM), the possibility of modulating cardiac regeneration in humans is still considered the most promising alternative to overcome the limitations of existent treatments for cardiovascular failure. However, CRM has not yet showed clear improvements over standard therapies in terms of clinical outcomes. Therefore, there is a compelling need and willingness among clinicians and scientists to discuss progress and hurdles of CRM in an open forum. This has been the aim of the International Symposium on Cell Therapy and Cardiovascular Innovations (TECAM, http://www.cardiovascularcelltherapy.com) since its inception 14 years ago. The latest edition of the TECAM conference was held in Madrid last May 12th and 13th. During the meeting, recent breakthroughs, open questions, and future steps were debated by the main experts worldwide and are summarized in this article. The opening session started with a keynote conference delivered by Dr Olaf Bergmann who updated his results about the turnover of cardiac cells throughout human life by means of elegant analysis of nuclear bomb test-derived 14C DNA integration. These recent results corroborate the capacity of adult human hearts to generate new cardiac cells that could counteract the loss of cardiomyocytes due to varying causes. One of the more heated debates of the conference was led by Dr Piero Anversa and Dr Bergmann , since their respective results regarding new cardiomyocyte generation rates differ from 1% to 25% per year. Despite those discrepancies in the specific numbers, to be clarified in future years, the most important message is the unquestionable evidence that supports the existence of a conserved mechanism of novel cardiomyocyte generation in humans. The open question remains: which are the best strategies to potentiate this phenomenon, especially in damaged hearts? In line with …

Previous clinical trials of stem cell therapy have demonstrated that the technique can promote the recovery of heart muscle after the acute phase of myocardial infarction and can improve cardiac function in chronic ischemic heart disease. However, some studies have produced conflicting results, and there are still questions about underlying mechanisms of action and about the best treatment strategy for optimizing cardiac repair. This article contains a review of recent findings in translational cardiovascular research and of the results and limitations of phase-I and -II clinical trials, discusses key issues in the design of future trials, and summarizes new areas for investigation in this fascinating field.

Barge-Caballero, E., Segovia-Cubero, J., Gonzalez-Vilchez, F., Delgado-Jimenez, J., Perez-Villa, F., Almenar-Bonet, L., Arizon-Del Prado, J.L., Lage-Galle, E., De La Fuente-Galan, L., Manito-Lorite, N., Sanz-Julve, M., Villa-Arranz, A., Lambert Rodriguez, J.L., Brossa-Loidi, V., Pascual-Figal, D., Muniz-Garcia, J., Crespo-Leiro, M.

[Abstract] Objectives. We sought to investigate the potential impact of preoperative short-term mechanical circulatory support (MCS) with extracorporeal devices on postoperative outcomes after emergency heart transplantation (HT). Methods. We conducted an observational study of 669 patients who underwent emergency HT in 15 Spanish hospitals between 2000 and 2009. Postoperative outcomes of patients bridged to HT on short-term MCS (n = 101) were compared with those of the rest of the cohort (n = 568). Short-term MCS included veno-arterial extracorporeal membrane oxygenators (VA-ECMOs, n = 23), and both pulsatile-flow (n = 53) and continuous-flow (n = 25) extracorporeal ventricular assist devices (VADs). No patient underwent HT on intracorporeal VADs. Results. Preoperative short-term MCS was independently associated with increased in-hospital postoperative mortality (adjusted odds-ratio 1.75, 95% CI 1.05–2.91) and overall post-transplant mortality (adjusted hazard-ratio 1.60, 95% CI 1.15–2.23). Rates of major surgical bleeding, cardiac reoperation, postoperative infection and primary graft failure were also significantly higher among MCS patients. Causes of death and survival after hospital discharge were similar in MCS and non-MCS candidates. Increased risk of post-transplant mortality affected patients bridged on pulsatile-flow extracorporeal VADs (adjusted hazard-ratio 2.21, 95% CI 1.48–3.30) and continuous-flow extracorporeal VADs (adjusted hazard-ratio 2.24, 95% CI 1.20–4.19), but not those bridged on VA-ECMO (adjusted hazard-ratio 0.51, 95% CI 0.21–1.25). Conclusions. Patients bridged to emergency HT on short-term MCS are exposed to an increased risk of postoperative complications and mortality. In our series, preoperative bridging with VA-ECMO resulted in comparable post-transplant outcomes to those of patients transplanted on conventional support.

Background— Postoperative outcomes of patients with advanced heart failure undergoing ventricular assist device implantation are strongly influenced by their preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles. We sought to investigate whether a similar association exists in patients undergoing emergency heart transplantation. Methods and Results— By means of the Spanish National Heart Transplant Registry database, we identified 704 adult patients treated with emergency heart transplantation in 15 Spanish centers between 2000 and 2009. Post-transplant outcomes were analyzed pertaining to patient preoperative INTERMACS profiles, which were retrospectively assigned by 2 blinded cardiologists. Before transplantation, INTERMACS profile 1 (critical cardiogenic shock) was present in 207 patients, INTERMACS profile 2 (progressive decline) in 291, INTERMACS profile 3 (inotropic dependence) in 176, and INTERMACS profile 4 (resting symptoms) was present in 30 patients. In-hospital postoperative mortality rates were, respectively, 43%, 26.8%, and 18% in patients with profiles 1, 2, and 3 to 4 ( P P =0.03) and postoperative need for dialysis (1: 33.2%, 2: 18.9%, 3–4: 21.5%; P Conclusions— Preoperative INTERMACS profiles determine outcomes after emergency heart transplantation. Results call for a change in policies related to the management of heart transplant candidates presenting with INTERMACS profiles 1 and 2.

Recent advances in reperfusion strategies have dramatically reduced early mortality after acute myocardial infarction (AMI), but as a result there is a higher incidence of heart failure among survivors. Optimal medical therapy and device implantation can improve the prognosis and the quality of life of these patients. Nevertheless, mortality and rehospitalization rates are still high and entail an overwhelming cost. The field of cardiac cell therapy has emerged as a new alternative in this situation, and has made rapid progress. Its final goal is to repair the damaged myocardium and to restore cardiac function. Nevertheless, this goal is hindered by the massive loss of cardiomyocytes after an AMI (in the order of 1 billion cells) and because ischemic myocardium loses cellular and extracellular signals which guide stem cells to the cardiac lineage or to the secretion of paracrine factors (Wollert & Drexler, 2010). Studies evaluating this new approach during the last 15 years have overall succeeded to a greater or lesser extent, and evidence available so far is encouraging. Phase I and II randomized clinical trials (RCT) indicate that cell therapy is a safe treatment which can improve cardiac function after AMI and in the chronic phase of coronary artery disease (CAD). Trial results are not uniform, however, probably due 1) to a lack of standardization of cell isolation and delivery procedures, 2) to the absence of a universally accepted nomenclature, and 3) to the large number of stem cell types under investigation in different clinical settings. Nevertheless, these inconsistencies can be avoided or reduced if classical scientific methodology is followed. Although considered a relatively new field of research, stem cell experimentation must invariably walk on the path of the scientific method. Since Aristotle s time, scientific method has been used as a way to ask and answer scientific questions by making observations and doing experiments. It includes a series of steps, i.e. 1) asking a question, 2) doing background research, 3) constructing a hypothesis, 4) testing the hypothesis by doing an experiment, 5) analyzing the data and drawing a conclusion, and 6) communicating the results.

[Abstract] In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan–Meier 2−year survival to 70% versus 16% among inoperable patients.

First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field.

[Abstract] Introduction. Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). Methods. We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. Results. Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n = 97; 25.9%); gastrointestinal tract (n = 52; 13.9%); prostate gland (n = 47; 12.5%; 14.0% of men), bladder (n = 32; 8.5%), liver (n = 14; 3.7%), and pharynx (n = 14; 3.7%), as well as Kaposi's sarcoma (n = 11; 2.9%). The corresponding Kaplan-Meier survival curves differed significantly (P < .0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. Conclusion. Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%–85% at 5 years), and lowest for prostate cancer (23%).

Background: For many years, high-emergency cardiac re-transplantation (HE-CR) has been considered as the choice therapeutic option for patients with irreversible primary graft failure during the early postoperative period of a previous heart transplantation (HT). HE-CR is also occasionally considered for HT patients in a critical clinical condition due to late graft failure secondary to chronic rejection. Aims: To describe the early postoperative and long-term outcomes of patients undergoing HE-CR and to compare them with those of patients undergoing a first heart transplantation under a high-emergency status (FHT-HE). Methods: Multicenter registry including 711 patients aged >18 who underwent high-emergency HT between January 1, 2000 and December 31, 2009 in fifteen out of the sixteen hospitals provided with an adult HT program. All patients suffered from severe cardiac failure depending on intravenous inotropes or mechanical circulatory support, or complicated with refractory arrythmic storm. Data were collected from the National Heart Transplant Registry database and clinical records. Early postoperative outcomes and long-term survival of HE-CR and FHT-HE patients were compared. Data on patients' vital status were available as for October 31, 2010. Kaplan-Meier post-transplant long-term survival curves were estimated, and then compared by means of the log-rank test. Results: 31 (4.5%) patients underwent HE-CR and 680 patients underwent FHT-HE. Mean age was 50 years, and 20% were women. No significant differences regarding basal clinical characteristics of recipients or donors were observed between the two groups, with the exception that HE-CR patients showed a higher mean serum creatinin (1.7±0.7 versus 1.3±0.7 mg/dl, p=0.01). The proportion of patients supported on a short-term VAD was 26% in the HE-CR group and 15% in the HE-FHT group (p=0.09). During the early postoperative period, the HE-CR group presented significantly higher rates of major surgical bleeding (48% versus 24%, p=0.02), primary graft failure (52% versus 24%, p