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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. 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.
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. As we have repeatedly pointed out, in the case of myocardial therapy with bone-marrow cells, we do not know the identity of the cells with regenerative potential.
Thus, regardless of how detailed and careful the clinical protocols used are, it is impossible to know the number or condition of the effective transplanted cells. Therefore, it is impossible to assess the results of a given therapy when the identity of the therapeutic agent and the dose administered is unknown, especially if the results obtained are marginal or negative, as in the present case. Without this information, any changes made to the protocols to improve results are no more than shots in the dark.
Thus, given the gaps in our knowledge and the tone of the current controversy, it is both of concern and strange that the regulatory bodies of both hospitals and public health-care services continue to approve new clinical trials whose probability of producing convincing results is minimal. As the protocols used, particularly in randomized trials, are invasive, not without risk to individuals and are of no possible benefit bone-marrow extraction under anesthesia or general sedation, intracoronary injection a few days after infarction, both in the control group and treated patients, and so on , our opinion is that the time has come to thoroughly reassess both the basic data and the process most suited to implementing this information in clinical practice.
To this end, we suggest placing a moratorium on new clinical trials on cellular transplantation in myocardium until the necessary information relevant to humans has been obtained from animal models. This will enable us to design clinical trials which, in addition to being safe for the patients, will generate interpretable results, whether positive or negative.
The information obtained from trials designed in this way will in turn permit the rational modification of the protocols to gradually optimize the results. In order to be productive, the suggested moratorium on clinical trials should be used to answer a core number of questions needed to design rational clinical protocols. Among these questions are the following:. Is the capacity of bone-marrow cells to differentiate into myocardial cells a property limited to rodents or is it shared with other species, including humans?.
What is the identity of the bone-marrow cells capable of generating myocardial cells?. What is the short- and long-term fate of the cells transplanted into the myocardium of large animals?. Is it possible to obtain a sufficient number of autologous cells with therapeutic potential to directly produce quantifiable physiological results in hearts similar in size to those in human?. Is the mechanism of action of the transplanted cells a direct contribution to the contractile mass or a paracrine effect on the surviving myocardium?.
What is the most effective route for administration?. What is the optimal time and approach for administration: What is the duration of the detectable beneficial effect on ventricular function in large animals?. What is the best predictor of a positive clinical effect?.
Once we can answer these questions we will be in better position to reassess the potential of this new putative therapeutic modality. However, we should bear in mind that, even if the answers come out in favor of clinical development, this type of therapy still has to overcome three serious obstacles to its widespread application: Slowly, but steadily, the research and clinical cardiovascular community is beginning to accept that adult myocardium has a significant and intrinsic regenerative capacity based on the presence of myocardial stem cells capable of regenerating myocytes and microvasculature.
However, these concepts have still not been incorporated into the protocols designed to regenerate the myocytes lost to ischemic heart disease. All the clinical protocols without exception are based on the concept of the myocardium as tissue made up of differentiated postmitotic cells, lacking stem cells and, thus, having no intrinsic regenerative capacity.
Consequently, regeneration is attempted by transplanting exogenous cells with contractile capacity skeletal myocytes into the myocardium or cells with the potential to convert into myocardial cells bone marrow. This gap between basic knowledge and clinical protocols is mainly due to the short time this field has been under development, and it should be closed within a relatively short period. Given the information available on the biology of cardiac stem cells, and by extrapolating information regarding other organs, it is difficult not to be optimistic about the future of research on myocardial regeneration and its potential to revolutionize cardiovascular medicine.
Once the problems discussed here concerning cellular transplantation are solved, this kind of therapy might act as a bridge to a different therapeutic model. In the near future we should completely develop the methods, restricted to the experimental laboratory up to now, for achieving regeneration in the human heart by using its intrinsic regenerative capacity without having to use cellular transplantation in general and cells extrinsic to the heart in particular.
Furthermore, once these questions are answered, the first clinical trials should be done in terminal heart failure patients on the waiting list for heart transplantation, to thus minimize the risks and, at the same time, ensure that we can document the effects of this therapy directly and in detail. This is a suitable moment to recall that in clinical research, as in life, the more haste, the less speed.
We cannot nor should not forget the negative impact on transplantation caused by Barnard and the most recent problems in genetic therapy. In both cases, progress was delayed for years in the respective medical disciplines because clinical applications started before the necessary experimental information was obtained. If we absorb these historical lessons and act with responsibility and caution, this new discipline of myocardial regeneration, based on deep knowledge of heart stem cell biology, offers us the opportunity to prevent the onset of heart failure or radically alter its prognosis once it appears in a large number of patients with ischemic heart disease.
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Cardiovascular Regenerative Medicine at the Crossroads. Abstract It is now over 4 years since early reports of murine models raised high expectations that bone marrow cell transplantation to the postischemic myocardium could produce physiologically significant myocardial regeneration. In quick succession, a flurry of publications documented the capacity of a variety of other types of adult cell to produce similar results. These publications were all controversial from the start because none addressed the mechanisms involved in the differentiation of transplanted cells.
In addition, each report raised at least as many questions as it answered. Despite these obvious weaknesses, the first phase-I clinical trials were started immediately without any further animal experimentation. Today the results of more than a dozen trials are already in the public domain but we still do not have a single piece of solid data documenting whether any of the approaches used is capable of regenerating contractile cells in the human myocardium. This is one of the main reasons why the controversy over the effectiveness of this therapeutic approach is becoming increasingly heated.
Moreover, skepticism about the efficacy, and even the feasibility, of inducing clinically relevant myocardial regeneration has increased to the point where it threatens the future of this nascent field. The present situation in myocardial generation contrasts sharply with that in neural regeneration. Abdominal obesity, reported in Mean WHR was below the limit of 0. 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.
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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 This item has received. Show more Show less. Background and aim The current guidelines for treatment of high blood pressure do not include any section dedicated to hypertension in children and adolescents or to cardiovascular disease CVD prevention strategies in that age group.
Our study was aimed at identifying cardiovascular risk factors CVRFs in an adolescent sample. Results The study sample consisted of female and male adolescents mean age: El objetivo del estudio es conocer los factores de riesgo cardiovascular RCV en una muestra de adolescentes. Resultados Se seleccionaron mujeres y hombres. Introduction Vascular disease is one of the leading causes of death in industrialized and developing countries. Patients and methods Study design A multicenter epidemiological, cross-sectional study.
Scope Conducted from October to February of the — school year at four schools in Cangas do Morrazo Pontevedra. Sample size calculation Young people account for 5. These were collected from adolescents using a survey. Calibrated portable scales and stadiometers were used. Results were anonymously recorded in an ad hoc form including all questionnaires administered. Procedure The managers of all seven schools providing secondary education in Cangas do Morrazo were contacted in September Refusal of students to participate was respected.
Anthropometric and BP measurements were taken at a different room in students who had already completed the survey. In the weeks subsequent to the study, adequate hygienic and dietary habits were addressed in informative talks at the schools. Data analysis G-Stat 2. Results Sample characteristics The sample consisted of students girls and boys , 5. Table 1 shows distribution by age. Age distribution of the sample. Adolescents with one or more cardiovascular risk factors. Correlations between the different anthropometric variables. Rev Esp Cardiol, 66 , pp.
An Esp Pediatr, 43 , pp. Resultados del estudio enKid — Med Clin Barc , , pp. The French longitudinal study of growth and nutrition: J Hum Nutr Diet, 15 , pp. Sedentarismo, adiposidad y factores de riesgo cardiovascular en adolescentes. Rev Esp Cardiol, 63 , pp.
Rev Esp Cardiol, 60 , pp. Curvas y tablas de crecimiento. Establishing a standard definition for child overweight and obesity worldwide: BMJ, , pp. Nutr Clin Diet Hosp, 31 , pp. The most frequent underlying cardiac condition was ischemic heart disease, followed by dilated cardiomyopathy.
Indications for primary prevention accounted for The total number of implantations increased compared with the previous 2 years. The percentage of implantations for primary prevention indications decreased compared with the previous year.. Implantable cardioverter-defibrillators ICD have demonstrated usefulness in the primary and secondary prevention of sudden cardiac death. The results of several studies have allowed the main indications for ICD implantation to be defined and included in the successive clinical practice guidelines for the management of patients with ventricular arrhythmias or at risk of sudden cardiac death.
Most centers implanting ICD in Spain have collaborated with this registry. Data for the registry were collected on a form available on the SEC web site. The information was entered in the Spanish Implantable Cardioverter-defibrillator Registry database by a technician specifically contracted for this purpose, assisted by a computer specialist from the SEC and a member of the Electrophysiology and Arrhythmias Section, who also carried out data cleaning. The data were analysed by the authors of this article, who are responsible for this publication.
The census data used to calculate the rates per million population for Spain as a whole and for each autonomous community and province were obtained from estimates provided by the Spanish National Institute of Statistics as of 1 January To estimate the representativeness of the registry, the percentage of reported implantations and replacement procedures in relation to the total number of implantations and replacement procedures performed in Spain in was calculated. The percentages for each variable analyzed were calculated on the basis of the total number of reported implantations that included information on the specific variable.
Numerical results are expressed as mean standard deviation or median [interquartile range], depending on the distribution of the variable. Continuous quantitative variables were compared with analysis of variance or the Kruskal-Wallis test. Qualitative variables were compared with the chi-square test.
The relationships between the number of implantations and the number of implantation centers per million population and between the total number of implantations and the number of implantations for primary prevention in each center were evaluated using linear regression models. The response rates for the various fields on the data collection form ranged from A total of centers performing ICD implantation in Spain participated in the registry 8 fewer than in Table 1.
This decrease was due to the grouping of several centers into consortia, which provided pooled data. Of the respondents, 90 were public health care centers in Figure 1 shows the total number of participating centers, the implantation rate per million population, and the total number of implantations by autonomous community according to data collected by the registry.
Implantations by Autonomous Community, Province, and Hospital. Distribution implantation activity in by autonomous community: In total, first and replacement implantations were performed in , more than in Total number of implantations reported to the registry and total number estimated by the European Medical Technology Industry Association The implantation rate recorded in the registry was ,1 per million population, while the rate according to the EUCOMED data was per million population.
Figure 3 shows the changes occurring in the implantation rate per million population over the last 11 years according to the registry and EUCOMED data. Table 1 shows the number of implantations reported to the registry by each participating center. Table 2 lists the number of implantations performed in each province and the rate per million population for the corresponding autonomous community.
Total number of implantations reported to the registry per million population and as estimated by the European Medical Technology Industry Association There were first implantations, representing The rate of first implantations in was The mean age standard deviation [range] of patients receiving an ICD or replacement device was In first implantations, the mean age was Most of the patients were men, representing The most common underlying cardiac condition in first implantations was ischemic heart disease Type of heart disease prompting device implantation first implantations.
The distribution was similar in patients receiving a replacement ICD Figure 5. This information was reported in Left ventricular ejection fraction in registry patients all implantations and first implantations. LVEF, left ventricular ejection fraction. In this variable, the distribution between the total number of implantations and first implantations was also very similar Figure 6.
New York Heart Association functional class in registry patients all implantations and first implantations. The baseline cardiac rhythm, recorded in In first implantations, the largest group consisted of patients with no documented clinical arrhythmia Among the total number of implantation procedures performed, The most common clinical presentation in the overall group and the first-implantation group Distribution of arrhythmias prompting device implantation first implantations and all implantations.
Clinical presentation of arrhythmia in registry patients first implantations and all implantations. SCD, sudden cardiac death. Information on electrophysiological studies was available in patients receiving a first implantation Electrophysiological studies were conducted in only patients