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In addition to rejecting the unique biological status conferred on the heart and placing it in the same context as other organs with regenerative capacity, the viewpoint expressed here offers new options for treating processes secondary to the loss of contractile myocardial mass. This is the case because as long as the myocardium was regarded as a tissue without regenerative capacity, the only clinical choice for treating myocyte loss was to maintain or improve the function of the surviving myocytes or to replace the lost mass via cardiac transplantation.

By identifying the regenerative capacity of the myocardium via CSC, which can be isolated and amplified in vitro 35 or stimulated in vivo, 51,52 it became reasonable to investigate methods that would enable us to exploit this potential to induce myocardial regeneration with autologous cells without the need for cellular transplantation. By the mids it was already clear that post-MI chronic heart failure was reaching epidemic proportions and becoming a serious public healthcare problem that could not be solved via cardiac transplantation, due to the shortage of donors, its prohibitive costs, and serious side-effects.

Thus, different cell types, including skeletal myoblasts, fetal cardiomyocytes 58,59 and ESC-derived myocytes 60 were transplanted into the myocardium of experimental animals. Shortly after, and despite the poor results obtained in animals, clinical trials began with skeletal myoblasts. Surprisingly, the results were positive. The transplanted cells not only restored the number of myocytes lost to the infarction, but they improved ventricular function. Despite the interest aroused by these publications, the undeniable fact is that all these studies were both preliminary and incomplete and did not contain the information necessary to justify beginning clinical trials.

To start with, none of these works specifically identified the cell type responsible for the myocardial regeneration. Thus, when other researchers were unable to replicate the results, it was impossible to determine whether the cause of the discrepancy was technical or biological. Furthermore, none of these works established a dose-effect relationship, guidelines or methods for optimal administration or the long-term effect and fate of the transplanted cells.

In addition, none of these publications investigated the mechanism responsible for the transplanted cells differentiating into myocardium. The lack of solid information on the identity of the regenerative cells and on the biological process itself was compounded by a series of important practical questions that needed to be answered to be able to plan a stringent clinical trial that would not unnecessarily endanger the patients.

Among the unknowns pending solution was determining whether the methods that seemed effective in regenerating mouse myocardium were directly applicable to organisms thousands of times larger, like humans, regardless of whether the biological process involved was similar or identical. Mouse ventricular myocardium weighs around 70 mg and is approximately 1 mm thick.

This task is times bigger and qualitatively more complex than regeneration in mouse. Thus, the many unknowns which the mouse experiments had left unresolved foresaw a long period of experimental work before cellular therapy with bone-marrow cells, either through transplantation or mobilization with cytokines, was in a position where clinical trials could begin. Contrary to this prediction, and despite the shortcomings regarding the animal data, the first clinical trial of myocardial transplantation of bone marrow-derived cells began immediately after the first data in mouse was published 85,86 without any additional animal experiments having been done.

It is striking that the results of this trial were accepted for publication the day after their submission and were published less than 6 months after the results in mouse appeared. The results of this haste should serve as a warning concerning the danger inherent to beginning experimental protocols in humans before obtaining the preclinical information necessary to be able to plan a stringent clinical trial. But if this sequence of events had not already been sufficiently unfortunate, the report from the Strauer group 85 was interpreted by many cardiologists as the starting signal for a flurry of clinical trials where various protocols were used to transplant different types and mixtures of cells into human myocardium without any form of experimental validation in animals.

These trials captured public attention and, due to the optimism of the researchers, created unrealistic expectations in potential candidates and the general public. This lack of caution on the road to clinical implementation brings to mind the wisdom of Clemenceau, the French Prime Minister during WWI, who said "war is too important to leave in the hands of generals. Currently, the results from more than a dozen phase I clinical trials aimed at post-MI myocardial regeneration or treating heart failure via autologous bone-marrow cell transplantation have already been published, and dozens more are in progress world-wide.

As may have been expected, given the foregoing, the available results are inconsi stent , confusing, controversial, and unconvincing, even when viewed in a positive light. Despite the great differences between the protocols used, the only common finding among the different groups is that bone-marrow cell transplantation in post-infarction and chronic heart failure is feasible and safe, at least in the medium-term, in the hands of interventionist cardiologists and experienced surgeons.

A worrying fact is that, although most groups have detected improved ejection fraction in treated patients compared to the placebo group when there is one , the differences in ejection fraction evolution in the different placebo groups is greater than the improvement detected in the treated groups. In this sense, it is worthwhile noting that the groups that detect greater improvement in ventricular function in treated patients are generally those which detect less positive evolution in the control groups, and vice versa.

These results raise doubts, both concerning the validity of the reported improvements and the methods used to assess the results of the cellular transplantation. Thus, it is interesting to note that in the longest follow-up trial, the modest increase in ejection fraction detected at 6 months post-transplantation disappeared at 18 months since the placebo group improved more than the treated one.

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Despite the results of the clinical trials generally being presented with a positive bias, and the charged and poorly informed comments from some people on the periphery of this discipline, it is increasingly clear that at the very least the transplantation methods used in humans up to the present do not produce the 'miraculous' results originally found in mice. Furthermore, several trials have not detected any effect attributable to transplanted cells, 98,, although these trials suffer from flaws similar to those found in studies with positive results.

Thus, it is surprising that, faced with this sobering and confusing situation, many clinical researchers working in this field try to ignore the fact that clinical myocardial regeneration is already in crisis even before moving beyond phase I trials. Many researchers who, 4 years ago, boldly initiated premature clinical trials with no experimental data of their own, are now putting forward alternative interpretations to explain the marginal results they have obtained and, at the same time, to justify including patients in the same type of protocols, 95,, sometimes endorsed by prestigious international societies.

Similarly, clinical trials in patients on the waiting list for transplantation, which are poorly designed because they are unable to determine the fate of the transplanted cells, are presented as models of clinical research. The current situation is serious and threatens the future of this field. After having transplanted bone-marrow cells into more than patients there is still not a single solid piece of evidence demonstrating whether the protocols used are capable of leading to regeneration in the human heart.

Furthermore, there are no data from animal studies that can help guide us through the confusion or clarify it, since, until now, all the experimental data in favor of regeneration have only been obtained in mouse 71,72, and even these have been challenged by some researchers.

The lack of solid experimental data on such a high-profile and clinically important topic is a mistake for which both basic researchers and clinicians are responsible. With few exceptions, 92,95 clinical researchers have not undertaken preclinical trials of the protocols and types of cells they have been transplanting into humans.

In turn, basic researchers have squandered a lot of energy and resources on two totally irrelevant discussions both for basic research on regeneration and for its clinical application: One of the outcomes of these internal conflicts is that this discipline has not generated any new information in the last 4 years regarding identifying cells with myocardial regenerative capacity or on the biological bases of the presumed beneficial effects observed in mouse and, possibly, in humans. Meanwhile, the number of clinical trials continue to proliferate as if the preclinical data that justify applying these procedures in humans were a completely resolved matter.

The cells used to produce myocardial regeneration in mouse were selected by c-kit expression, the membrane receptor for stem cell factor SCF , a protein expressed in hematopoietic stem cells and in a small fraction of other bone-marrow cells and other tissues. However, in clinical trials, when the entire mononuclear fraction of the bone marrow is not used, the transplanted cells are selected on the basis of CD expression, an antigen of unknown function expressed in hematopoietic and endothelial stem cells, among others.

However, not a single publication has demonstrated myocardial regeneration by using either the mononuclear fraction or CDpos cells in animals or humans.

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Even though several publications have suggested that, at least in mouse, hematopoietic stem cells do not have cardiac regenerative capacity, and that this capacity is probably limited to a cell type with the characteristics of mesenchymal stem cells from bone-marrow stroma, 76,80, clinical trials with bone marrow continue to be planned with the aim of transplanting the maximum possible number of hematopoietic stem cells into the myocardium.

Leaving aside the fact that we still do not know the precise identity of the bone-marrow cells with cardiac regenerative capacity, not a single reputable publication has demonstrated the possibility of anatomically and functionally regenerating a myocardium with the mass and thickness of the human heart, a fact which cannot be extrapolated from the data obtained in mouse, as already discussed.

Assuming that it is possible to repair human myocardium, there is no data on the type and number of cells necessary for this, which route and administration method are the most efficient, and so on. Given the state of this field, it is unsurprising that, despite the huge investment in material and human resources in myocardial regeneration clinical trials, it still remains impossible to show that a single human life has been saved or even extended. As a result, the argument put forward by some clinical researchers and defended by a consensus adopted by the European Society of Cardiology, by which the severity of the clinical condition treated justifies the heterodox methods used until now, is highly unconvincing.

Even putting aside the architectural challenge of mass, thickness, the complexity of the vascular system, and the type and organization of human myocardium fibers compared to those of mouse, the clinical trials involve serious flaws other than the identity of the regenerative cells. Accepting as a demonstrated fact that cells with regenerative capacity are bone-marrow cells with the characteristics of the stem cells which are included in the transplanted cells, and making the most conservative extrapolations of the data obtained in mouse and the most optimistic regarding the quantity of stem cells in bone marrow, the patients who have received the greatest number of cells 91 could have regenerated between 1 and 5 g of myocardium at most in fact, far smaller quantities are involved.

The problem is much more serious in the case of the skeletal myoblast transplantation where, at most, only milligrams of tissue 61 can be produced. Furthermore, it is undeniable that none of the methods available for measuring ventricular function, whether invasive or not, have the sensitivity needed to measure the functional contribution of 5 g of myocardium.

Thus, no clinical protocol transplants enough cells for them or their descendants to have a detectable and direct effect on cardiac function, even if they survived and nested effectively, multiplied from 1 to and completely differentiated in cardiac tissue. This means that, even if the modest and transient positive functional results published up to now were real, they could not be the outcome of myocardial regeneration directly produced by the transplanted cells.

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The positive effects of cellular transplantation on ventricular function done until now, if real, must necessarily be due to a paracrine effect of the transplanted cells on the myocytes and stem cells in the surviving myocardium. Very recently experimental data have been obtained supporting this hypothesis.

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Due to the currently chaotic situation in the field of myocardial regeneration via cellular transplantation, it is not surprising that the controversy concerning the effectiveness of this therapeutic modality is increasingly bitter and on the way to getting worse. As expected, skepticism concerning the potential and even the feasibility of producing cardiac regeneration with physiological relevance has gradually increased to the point of reaching a level that threatens to destroy this discipline's future at root.

Sadly, both clinical and basic researchers in this field have contributed to the development of this situation and we have to accept our share of responsibility. Other specialties facing problems as difficult as those involving the myocardium, or even harder ones, have shown that is possible to follow a more sensible and productive course. For example, we only need to compare the state of confusion concerning cardiac regeneration via cellular transplantation with the field of neuronal regeneration in the CNS. Despite its earlier beginning and having generated more extensive and in-depth information on the origin, biology, and regenerative potential of fetal and adult neuronal stem cells obtained from many experiments with different animal models, including primates, the first phase I clinical trial with neuronal stem cells has just been approved by the Food and Drug Administration for the treatment of Batten disease a neural ceroid lipofuscinosis.

Given that both clinical and basic researchers are equally responsible for the current chaos and confusion, it is vital to take decisions aimed at redirecting and focusing research on the use of stem cells for myocardial regeneration and its clinical application in the most productive way possible without putting patients at unnecessary risk. Fortunately, one of the most attractive and positive characteristics of scientific process is that, given sufficient time, the mistakes made due to both commission and omission are always rectified. The challenge facing the medico-scientific community is to identify the corrections needed to avoid missing opportunities and, at the same time, to avoid affecting the patients adversely.

Age distribution of the sample.. Problems related to CVR included hypercholesterolemia in 45 students 7. History of DM in second-degree relatives was reported by Table 2 shows the anthropometric measurements by sex and age. Table 3 shows the proportion of adolescents with abnormal anthropometric data.. Mean BMI of the sample was The proportion of adolescents with BMI higher than P85 was Using Cole criteria, There were no adolescents with malnutrition..

Percent fat estimated from WHR was No significant difference was seen between males and females.. WC exceeded P75 in Central obesity, as defined by WC greater than P90, was found in 7. Mean WHR was 0. Twenty-one percent of students had WHR greater than 0. Table 5 shows the number of students with more than one CVRF overweight, abdominal obesity, diabetes, HBP, hypercholesterolemia, or cardiovascular disease. There were 84 adolescents Adolescents with one or more cardiovascular risk factors.. SBP above the 90th percentile was found in Table 2 shows the mean BP values of the sample stratified by age..

Table 6 details the correlations found between the different CVRFs. Correlations between the different anthropometric variables.. Study limitations in relation to studies previously conducted in Spain, included the age intervals considered, which differ from those in some other studies, making comparison of results difficult. An additional limitation is self-reporting of health problems by the surveyed students, which is not always reliable, particularly at earlier ages. For the same reason, another limitation would be that blood glucose and lipid profile tests were not performed, and the study therefore relied on statements by adolescents for these factors..

No agreement exists in epidemiological studies on the cut-off points of BMI that define obesity in children. Mean BMI was In our study, however, BMI was significantly greater in males Prevalence was significantly greater in females Our study does not agree with that of Serra Majem et al.

In our study, BMI shows a mild-moderate increase with age, as occurs in the reference population, 11 but this does not occur in the Serra-Majem et al. Our results as regards overweight and obesity are lower than those reported in a study conducted in Granada 21 that found prevalence rates of overweight and obesity of The prevalence of obesity found, 7.

A comparison with international studies using the same percentile criteria but the Cole et al. Tables, 12 would provide higher obesity rates in our study, but we consider more adequate the values obtained according to reference standards for our population. Assessment of obesity based on BMI is a widely used method, but is an indirect estimation of percent body fat.

WC is an anthropometric variable predicting CVR, 25,26 because it determines fat distribution. Abdominal obesity, reported in Mean WHR was below the limit of 0.

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No WHR standards adapted to our population are available, but a high correlation was found to BMI, in agreement other authors 15 who showed a good correlation of this parameter with other indirect methods to measure obesity.. Caution should be taken with these data, because adolescents do not always have an adequate knowledge of the diseases of their parents, and surveys were conducted in the absence of the parents..

In this study, These numbers should cause concern, as this is a sample of pre-adults aged 12—17 years. Despite their short age, more than one out of every 10 adolescents had two CVRFs. Based on these results, it is concluded that immediate and continued educational interventions aimed at improving habits and lifestyles are required to prevent progression to cardiovascular disease and type 2 diabetes mellitus in adult age.. The authors state that no experiments with humans or animals have been conducted in this research.

The authors state that all procedures used met the regulations of the relevant ethics research committee and the World Medical Assembly and the Declaration of Helsinki.. No personal data have been stored. As a minor sample was recruited, written consent was obtained from the parents or legal guardians of the participants.

Data required for the study were managed in aggregate form, with no individual identification of subjects.. The study was not funded by any person or company other than the research group.. RMG contributed to study conception and design, data interpretation, writing of draft article and critical review of contents, and final approval of the submitted version.. PGR contributed to data collection, analysis and interpretation, writing of draft article, and final approval of the submitted version..

MFC contributed to data collection, analysis and interpretation, writing of draft article, and final approval of the submitted version.. ARR contributed to data collection, analysis and interpretation, writing of draft article, and final approval of the submitted version..

NVC contributed to data analysis and interpretation, writing of draft article, and final approval of the submitted version.. NFAR contributed to study conception and design, data analysis and interpretation, writing of draft article, and final approval of the submitted version.. JAFP contributed to study conception and design, data analysis and interpretation, writing of draft article, and final approval of the submitted version..

IRE contributed to study conception and design, data interpretation, writing of draft article and critical review of contents, and final approval of the submitted version..

The authors state that they have no conflicts of interest.. Please cite this article as: Previous article Next article. December Pages Finally, the legal rules summarized here should act as a guide for daily consultation because our patients need to know when they can drive a vehicle again, either privately or to earn a living, safe in the knowledge that not only do they meet the legal requirements, but that they do so without threatening anyone's safety.

Calls from Spain 88 87 40 9 to 18 hours. Images subject to Copyright. Previous Article Vol November Next article. Heart Disease and Vehicle Driving: Novelties in European and Spanish Law. Iberoamerican Cardiovascular Journals Editors' Network. Syncope history and presence of limiting symptoms are considered, as well as each treatment. Driving permitted 2 wk after implantation for primary prevention and at 3 mo without discharges or recurrence for secondary prevention.

Driving permitted 6 weeks after surgical implantation and 1 mo after percutaneous implantation. Driving permitted 3 mo after surgical implantation and 1 mo after percutaneous implantation. Both groups must fulfill the requirements for functional class, LVEF, arrhythmias, and absence of syncope. Driving permitted if patients are asymptomatic and without severe ischemia or exercise-induced arrhythmias. For all forms of artery disease, the coexistence of ischemic heart disease must be evaluated. Driving not permitted with symptomatic carotid stenosis. Driving not permitted in either group until resolution of deep venous thrombosis.