pubmed thesis topics in cardiology

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Article Contents

Introduction, conclusions, acknowledgements.

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Hot topics and trends in cardiovascular research

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• Figures & tables
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Diane Gal, Bart Thijs, Wolfgang Glänzel, Karin R Sipido, Hot topics and trends in cardiovascular research, European Heart Journal , Volume 40, Issue 28, 21 July 2019, Pages 2363–2374, https://doi.org/10.1093/eurheartj/ehz282

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Comprehensive data on research undertaken in cardiovascular medicine can inform the scientific community and can support policy building. We used the publication output from 2004 to 2013 and the 2014 references to these documents, to identify research topics and trends in the field of cardiovascular disease.

Text fragments were extracted from the titles and abstracts of 478 000 publications using natural language processing. Through machine-learning algorithms, these text fragments combined to identify specific topics across all publications. A second method, which included cross-references, assigned each publication document to a specific cluster. Experts named the topics and document clusters based on various outputs from these semi-automatic methods. We identified and labelled 175 cardiovascular topics and 20 large document clusters, with concordance between the approaches. Overarching, strongly growing topics in clinical and population sciences are evidence-based guidance for treatment, research on outcomes, prognosis, and risk factors. ‘Hot’ topics include novel treatments in valve disease and in coronary artery disease, and imaging. Basic research decreases its share over time but sees substantial growth of research on stem cells and tissue engineering, as well as in translational research. Inflammation, biomarkers, metabolic syndrome, obesity, and lipids are hot topics across population, clinical and basic research, supporting integration across the cardiovascular field.

Growth in clinical and population research emphasizes improving patient outcomes through novel treatments, risk stratification, and prevention. Translation and innovation redefine basic research in cardiovascular disease. Medical need, funding and publishing policies, and scientific opportunities are potential drivers for these evolutions.

Current policies for public funding of health research increasingly focus on innovation, with a final goal to improve health outcomes. 1 To support policies, roadmaps are established, for example for diabetes 2 and respiratory 3 diseases. In the USA, the joint Academies developed a document to guide national policy in health 4 with a dedicated document for cardiovascular medicine 5 that includes general directions for research. In Europe, building a roadmap for cardiovascular research is one of the tasks of the ERA-CVD network. 6 Expert opinion guides the exercise but a macro and global-level overview of past cardiovascular research can enrich the debate and strengthen the basis for recommendations. The breadth of cardiovascular research is astounding, 7 with research undertaken across a variety of institutions and with each piece of research having its own scope/focus or topic. It is thus challenging to review and summarize all the research that has been undertaken.

Identifying all the relevant research is the first hurdle to overcome, then classifying or identifying topics of research is the next significant hurdle. Journal classification systems offer little assistance, as they are not granular enough to identify more specific topics within broader fields. Thesauri or medical dictionaries, such as PubMed or the International Classification of Diseases (ICD), do not offer an overview of time-dependent changes in topics or changing concepts.

Identifying key topics using semi-automatic approaches based on text analysis is an alternative solution that takes advantage of recent developments in high-level informatics. As this is not reliant on a predefined classification, it may result in different outcomes. Various methods use natural language processing (NLP) to extract topics or clusters from text. For example, the bibliometric community has compared the results when varying methods are applied to a set of astronomy publications, focusing on the importance having topic expert input throughout the process. 8 The recent CardioScape project analysed abstracts of 2476 research projects awarded 2010–12 as published by funding bodies. The authors assigned research project to topics, based on the abstract text, using a semi-automatic process that tested and trained the data to more quickly allocate abstracts to a topic than depending solely on expert review. They produced a detailed taxonomy or classification of cardiovascular research based on the list of topics of the European Society of Cardiology, creating a hierarchical list of over 600 topics. 9

Here, we aim to identify topics in published cardiovascular research and their evolution between 2004 and 2013, assessing whether they have appeared, disappeared, or changed over time. In a comprehensive approach, we use a combination of existing methods for text mining, network analysis, and clustering, and further develop these tools to handle a large dataset of >400 000 publications.

In our study, we use two different and complementary approaches. A first one detects topics across the collection of publications, counting number of documents, and relations between topics. A second one maps document networks into clusters with an identifiable subject of research. These approaches are described here in brief, with more detail provided in the Supplementary material online .

Data sources

The dataset includes the reference, abstract, address, and citation data for 478 006 cardiovascular publications from 2004 to 2013, including 2014 references to these documents, using an expert informed search strategy and references to core cardiovascular journals, as previously published. 7 The documents span across >5000 journals, and include cardiovascular publications in leading general journals in medical and life sciences ( Supplementary material online , Table S1 ). We obtained the data from Clarivate Analytics Web of Science Core Collection (WoS) through a custom data license held by ECOOM, KU Leuven.

Text pre-processing

We took all titles and abstracts of the above publications, and extracted the noun phrases (text fragments of various lengths) using the NLP framework developed at Stanford. 10   Supplementary material online , Figure S1 illustrates the subsequent data flow for the analysis.

Topic modelling

For this approach, we applied latent Dirichlet allocation (LDA) 11 to the above-mentioned text fragments from the titles and abstracts of all publications. This LDA approach groups the text fragments to identify topics and allocates documents to topics. In this approach, a document contributes to several topics. Of note, general terms or terms that are used frequently across the majority of documents are filtered out as part of the methodology, resulting in groups of highly specific text fragments and, consequently, topics, as illustrated in Supplementary material online , Figure S2 .

At least three cardiovascular experts (listed in the Acknowledgements section) named each topic based on a set of the top 40 text fragments representing a topic. Further rounds of cross-review validated and consolidated the naming process. A final review of all topics ensured naming consistency across the topics and allowed for additional expert-based classification as clinical, basic, or population research.

We then calculated the number of documents that contributed to a topic, using probability analysis in LDA. Furthermore, we calculated the co-occurrence of topics in the publications, and visualized the outcome of this network analysis using VOSViewer ( www.vosviewer.com ). 12

Document clustering

For this second approach, the dataset was reduced to two periods, and we analysed the cardiovascular publications from 2006 to 2008 and those from 2011 to 2013, separately. For each time period, we then calculated the similarities between documents based on the noun phrase text fragments from the titles and abstracts of all publications and based on the references in these publications, using adapted cosine calculations and a hybrid document clustering algorithm, as previously described. 13 We then applied the Louvain 14 community detection algorithm to identify clusters of similar documents. For this method, each document is only located in one cluster. Subsequently, we applied the DrL/OpenOrd algorithm 15 to map and visualize the documents and clusters. We used R 16 in a high-powered cloud-based parallelized computing environment for all operations.

We identified and described the core documents, 13 the most common text fragments, as well as, the most highly cited documents and the most productive authors in each cluster, to name the clusters. For each document cluster, we identified the most highly representative topics from the LDA topic model.

Evolution of cardiovascular topics—trends and ‘hot’ topics

We identified 175 topics, listed alphabetically in Supplementary material online , Table S2 . This list groups specific topics within areas such as atherosclerosis, coronary artery disease, arrhythmias, heart failure, and their evolution over time.

For a visual and comprehensive overview, we prepared a map of the topics and their interrelation, based on co-occurrence within publications using a network analysis ( Figure 1 A ). This map identifies different categories of research: population (at the top, blue), clinical (left, green/yellow), and basic research (right, red). Large topics in each category define overarching interests such as Evidence-guided-treatment and Outcomes and prognosis in clinical research, and Epidemiology of CVD and risk factors in population research, topics that have seen large growth in numbers of publications since 2004 ( Figure 1 B ). Cell signalling and gene transcription is a central topic for basic research, with modest growth ( Figure 1 B ).

Main areas and organization of research focus. ( A ) Visual presentation of the topics in 2013 and how they relate to each other, based on how often the topics are included in the same publication. Each circle represents one topic and each group of topics is highlighted in a separate colour; the most similar documents and clusters are located closer to each other based on VOSviewer mapping. ( B ) Evolution of overarching topics.

More focused ‘hot’ topics that experienced a large growth in number of publications are presented in Figure  2 .

Topics with large growth. For population research, the eight topics that increased more than two-fold in volume are shown; for clinical research, 27 topics increased more than two-fold and 10 of these are presented; for basic research only two topics had more than a two-fold increase, and the top 8 growers are presented. Overarching topics are shown in Figure 1 B .

In population research, risk factors with research on metabolic syndrome, lipids, diabetes, physical activity, and mental health are prominent. In clinical research, patient management after myocardial infarction (MI) and outside the hospital are leading topics, but the true ‘hot’ topic was aortic valve disease that saw a surge of interest, related to transaortic valve repair, starting 2008. Though still small in numbers, heart failure research and stem cells saw substantial growth. This last clinical topic complements the major hot topics in basic research, on stem cells and cardiac repair and tissue engineering. In basic research, increasing translational output in metabolic syndrome and diabetes use mostly mouse models. Focused topics are organelle studies on mitochondria and endoplasmic reticulum.

Table  1 complements the fast growing topics of Figure  2 with additional leading 2013 topics. Most of these also have grown since 2004, but two topics, even if large, seem to have lost momentum, i.e. longitudinal studies on blood pressure, and basic research in cardiac electrophysiology.

Large topics in 2013

PCOS, polycystic ovary syndrome.

Only four topics in clinical, and none in population research, saw a decrease, whereas seven topics in basic research saw a decline in output ( Figure 3 A ). Across all topics, the growth in publication output, measured as the number of documents in 2013 divided by the number of documents in 2004, was significantly larger in clinical and population research topics than in basic research topics ( Figure 3 B ).

Unequal growth of research output across categories. ( A ) Topics that saw a decrease of >5%, i.e. 4/102 clinical and 7/50 basic research topics. ( B ) Average growth in each category. Each dot presents a topic; the values are the fractional growth, i.e. the number of documents in 2013 divided by the number of documents in 2004. Kruskal–Wallis followed by Dunn’s test for multiple comparisons; *** P < 0.0001 basic vs. clinical and vs. population.

When considering the overall output and growth of publications across the categories of population, clinical and basic research, the data suggest that the share of basic research publications is declining.

Document clusters define large research areas and trends

The size of topics represents the activity within each of these—documents contribute to more than one topic. In a complementary approach, we examined how documents group together based on the similarity of their text and of their references, whereby each document can belong to one cluster only, effectively dividing the total publication output into different areas. The hybrid clustering algorithm was applied to two datasets, i.e. the publications from 2006 to 2008 and 2011 to 2013.

In each period, 10 large clusters emerged, accounting for >90% of all documents.

To identify trends, we compare the two periods and examine the evolution over time ( Figure  4 ). In the graph legends, emerging areas are marked by green triangle, decreasing ones with a red triangle. Risk scoring in the population and related patient management are the leading areas, growing over time (top position). In 2011–13, a large cluster emerges that relates to gene and stem-cell therapy, including research on inducible pluripotent stem cells. Documents within this cluster include research on ischaemic heart disease and arrhythmias. Haemodynamics and biomechanics are another emerging area that includes documents on atherosclerosis and vascular diseases such as aneurysms, but also heart failure and assist devices. Aortic valve disease is a newly defined area in 2011–13. Imaging also becomes very prominent as an area in its own right. Whereas in 2006–08, hypertension was a defined area, this is no longer identifiable in 2011–13.

Distribution of document clusters in 2006–08 and in 2011–13. ( A ) In 2006–08, the 10 largest clusters represent 93% of the total publication output in this period. ( B ) In 2011–13, the 10 largest clusters represent 92% of the total publication output in this period. The colour codes for similar clusters are maintained across the periods. However, some clusters are present in only one period. The clusters are arranged by size, reading clockwise from the top, and the legends arranged accordingly. Red triangles mark clusters that disappeared and green triangles emerging clusters.

For the last period, we also examined the structure and interrelation of clusters, using a graphical rendering, giving insight in the size, composition, and presence of subclusters ( Figure  5 ).

Document clusters’ map 2011–13. A visual presentation of documents in clusters and subclusters: the most similar documents and clusters are located closer to each other, based on the DrL two-dimensional mapping layout technique.

In this force-directed DrL graph layout, the documents and clusters are mapped to minimize the distance between the most similar documents and maximize the distance between non-linked documents. This produces a two-dimensional co-ordinate layout where the documents closest to each other share the most similarities since they share common text fragments and references. Conversely, documents and clusters on the edges of the graph have the least similarity to other documents or clusters.

Cluster 2 on gene and stem cells is dense and separate, yet touches and interacts with Cluster 5 [acute coronary syndrome (ACS) and MI]. Cluster 9 on imaging is spread out in subclusters at different locations, including one near Cluster 5 (ACS and MI), and one near Cluster 4 (heart failure). Cluster 8 (arrhythmias) is also split with one part closer to heart failure, another to anticoagulation and atrial fibrillation.

Further naming the subclusters is presently beyond reach, as it would require a lot of expert input and resources. However, linking the clusters and the topics adds granularity to the larger research areas and provides internal methodological validation of the cluster naming.

Table  2 presents the most highly associated topics in the ten largest document clusters in each period. Overall, agreement with the LDA topics is high and provides more detail on the research contained in the clusters. E.g., the cluster ‘Haemodynamics’ is now showing different areas of focus, i.e. in congenital disease, aortic, and valvular diseases; the topic ‘Arrhythmias’ is more populated with device research in the second time period compared to the first.

Cluster names and topics present within clusters

AF, atrial fibrillation; ANS, autonomic nervous system; BP, blood pressure; CABG, coronary artery bypass grafting; CRT, cardiac resynchronization therapy; CT, computed tomography; CV, cardiovascular; DES, drug-eluting stent; ECG, electrocardiogram; HF, heart failure; LV, left ventricular; NOAC, new oral anticoagulant; PTCI, percutaneous transluminal coronary intervention; RV, right ventricle; STEMI, ST elevated myocardial infarction.

The method for identification of topics in cardiovascular publication output allowed the visualization and evaluation of trends in cardiovascular research. Over a 10-year period significant shifts occur.

Identification of cardiovascular research topics through natural language processing

In cardiovascular research, topics are generally predefined in a taxonomy that can be hierarchical and/or matrix structured. The CardioScape project approach (see Introduction section) was well suited to its purpose of the analysis of 2476 project abstracts in a single time period and using an existing taxonomy has the advantage of recognizable areas of research. The bottom-up approach used here lent itself well to analysis of much larger numbers of documents and generated a topic list that represents the interests from the community during the period under study.

A recent study by the WHO working to identify cardiovascular disease research output from random sets of publications from PubMed required a significant amount of expert-based review of only a small proportion of the published articles. 17 The current approach was more comprehensive in coverage of the field, but despite reliance on advanced automated analysis, experts still had an important role in interpreting and linking concepts to validate the results.

In the current naming of topics and clusters, experts frequently used terms that connect to a classic hierarchical list in the field, including major diseases, and recognizing clinical, population, and basic discovery research. Nevertheless, the approach uncovered specific emerging areas of research such as transcatheter aortic valve implantation (TAVI), topics consistent with broad trends, such as risk stratification and evidence-based guidance, and innovation (gene and stem cell research). Some of these terms would not appear in a classic taxonomy and thus the NLP approach offers novel insights.

The present study was not attempting to classify all research but to capture and identify the most common and evolving topics over time in the cardiovascular field by using a comprehensive set of cardiovascular publications across some 5000 journals.

Emphasis on improving clinical care and risk assessment

The most represented and fast growing topics across the documents are evidence-based guidance for treatment and research on outcomes and prognosis. These result underscore the attention given to guidelines and evidence based medicine (EBM). 18–23 Part of this research is likely to represent the large number of clinical trials taking place in the cardiovascular field, 24 which over time have had a significant effect on the reduction of mortality from CVD due to establishing the effectiveness and safety of a number of drugs and medical interventions in cardiovascular disease. 25 The presence of policy related topics, such as the topics on quality of care and health economics likewise supports the focus on implementation research and a shift of focus from reducing acute mortality to care in chronic disease.

Growth of research on risk factors emphasizes the importance of preventative medicine, evident in both the topics analysis and the document cluster analysis. However, some specific blood pressure studies declined over time, perhaps reflecting the change in focus on the single risk factor of ‘blood pressure’ to a multivariable spectrum and newly identified risk factors. We have also previously shown that hypertension has moved more closely to clinical cardiovascular research over time. 26

Smaller topics illustrate crosstalk with non-cardiovascular diseases, because of shared risk factors or common methods used in research or occurrence of cardiovascular complications. The latter is particularly evident in two topics that focus on cardiovascular complications in pregnancy and in cancer.

Innovation and translation in clinical and basic science

Major diseases such as ischaemic heart disease and arrhythmias, remain present over time but shifts can be seen. There is for example, a larger focus on atrial fibrillation, in particular embolic risk, on novel treatments, such as stem cells in heart failure, and transcatheter aortic valve interventions as a dominant element within the topic of valvular heart disease. 19 Imaging is present in several topics but emerges as a cluster in its own right in the document analysis. Many of these changes are driven by technological innovation and translation.

Basic research as a whole saw its share decline, but with interesting shifts in content. Although the topic analysis and mapping identifies basic research topics as a category, there are complementarities across categories. Stem cell research, tissue engineering, and biomechanical factors saw rapid growth and are also present in clinical topics. This also applies to inflammation and diabetes. Animal models for disease are rapidly growing topics consistent with growth of translational research.

An analysis of the countries of authorship of the publications in the emerging clusters of discovery research shows that the USA leads in the number and share of publications (30%+), followed mostly by Germany, or the UK or Italy. However, for the large document cluster on genes and stem cells in 2011–13, the second most productive country is China, contributing 17.5% of the publications in this cluster (Supplementary material online, Figure S3 ).

Interestingly, inflammation, biomarkers, metabolic syndrome, obesity, and lipids are hot topics with growing research output in population, clinical and basic research, indicating integration and crosstalk across the spectrum of cardiovascular research.

Drivers of change

Technology and opportunity-driven scientific interest, but also strategic choices and funding policies are likely to influence trends in research. CardioScape studied public and charity funding in the years 2010–12 and describes major investments in clinical research. Yet the share of publication output globally for clinical research appears to be substantially larger than the share of funding for clinical research reported in CardioScape. This could be explained by clinical research funded by other sources, such as industry or local funding, which are not included in the CardioScape analysis. Also, the present data represent global output. Major research investments in China, and the emphasis on clinical research in the USA, can contribute to some of the global trends.

The slower growth in basic science could reflect a slower growth in investment. This can be absolute or relative towards the increasing costs of advanced research methodology. Another reason could be editorial pressure for more comprehensive papers that may reduce quantity to the benefit of rich content in individual papers.

Finally, growing translational research may blur the boundaries between basic and clinical research and lead to an apparent slower growth in discovery research.

Policy perspectives

Policy development is a forward looking exercise. In health research, medical needs identified by health data and expert opinion, are an important consideration. 27 Past research output helps to identify areas that may need more investment. Research funders also use input from society. 28 When assessing current priorities in cardiovascular research for the Dutch 28 and British 29 Heart Foundations we can see that research into heart failure and arrhythmias are common across their top priorities. Focus on healthy lifestyles is a top priority in the Dutch Heart Foundation as well as in the US vision and strategic agenda. 4   ,   5 At the macro-level, the data presented here indicate that some of the main issues presented in these research agendas are actively pursued but others less so.

Study limitations

Limitations of studying research topics have been addressed in the bibliometric field. 8 The reliance of expert input is a limitation and potential source of bias that we tried to minimize by using mixed panels.

The current approach was not sufficiently granular to extract recent emerging topics that contain a limited number of documents. In addition, publication output is somewhat delayed vs. actual research and experts may be aware of ongoing research with still limited output. In this case, the method and dataset can be used to interrogate about specific developments (see Supplementary material online , Table S3 for data on micro-RNA and personalized medicine).

As the data set ends in 2013, very recent developments are not covered. This relates to the methodological complexity. Web of Science data including 2014 references were available mid-2015, the cardiovascular publications dataset was complete in 2016 and algorithms for analysis including re-iterative expert review required another 18 months. A similar time lag is seen in other studies that rely on data mining and processing. 9 Congress abstracts could be considered as a source to identify emerging topics but have several limitations. They are of a different nature than papers and the scope of a congress shapes content of selected abstracts. We provide a complementary survey of 3000 abstracts from the 2018 congress of the European Society of Cardiology, illustrating the strong presence of clinical research at this event, within the topics of Clusters 1 and 3–7 of Table  2 ( Supplementary material online , Figure S4 ). Two emerging topics were cardio-oncology and digital health, each representing however <25 abstracts.

In the present analysis, quality and impact of studies in a particular domain were not evaluated, though highly cited papers were part of the cluster identification. In their analysis of poorly cited papers covering 165 000 papers in 1997–2008, Ranasinghe et al . 30 noted the highest percentage of poorly cited papers in the clinical and population research category. Nevertheless, as they and others 31 have noted, citations are not the only parameter to assess impact, in particular in clinical medicine.

Identification of leading research topics and trends illustrates the emphasis on improving clinical medicine, and the growing interest in risk stratification and preventive medicine. Translation and innovation redefine cardiovascular research. Linking the present data with the insights of the professional community and of funders and society, may contribute to the building of a future research roadmap.

The authors thank to the following experts for their review of the text fragments and input into the names of the topics: Dr Matthew Amoni, Dr Peter Haemers, Prof Sian Harding, Dr Frederik Helsen, Prof Gerd Heusch, Prof Tatiana Kuznetsova, Prof Tobias Op‘t Hof, Prof Frank Rademakers, Dr Sander Trenson, Dr Bert Vandenberk, and Dr Maarten Vanhaverbeke.

D.G. had a PhD Fellowship through KU Leuven.

Conflict of interest: K.R.S. is Past Editor-in-Chief of Cardiovascular Research (2013–17). W.G. is Editor-in-Chief of Scientometrics .

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• basic science research

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Clinical Research Directions In Pediatric Cardiology

Purpose of review.

Clinical research in pediatric cardiology is under-appreciated and under-funded, yet it has enormous implications for cardiovascular health and healthcare over the entire life-course. Renewed interest in federally funded clinical research makes it timely to propose a comprehensive research agenda that, with its associated rationale, will attract public funds for research into child cardiovascular health and disease.

Recent findings

We propose here a comprehensive pediatric cardiology research agenda consisting of 22 topics and associated research questions. We describe the following five topics in more detail: 1) the need for life-course studies of pediatric cardiac disease and epigenetic factors for later onset of cardiovascular effects; 2) the need to study cardiometabolic disease risk in children; 3) recent pediatric cardiology clinical trials and observational studies; 4) the need to explore the role of physical activity in preventing and treating pediatric cardiology patients; and 5) the need to develop and implement evidence-based interventions to manage pediatric cardiovascular problems.

If the field of pediatric cardiology can adopt a comprehensive research agenda that identifies the most-needed studies, then research could be better coordinated, long-term and collaborative studies would be more readily organized and funded, and the overall financial and scientific efficiency of research in pediatric cardiology would be improved. Targeted research efforts are more likely to realize potential breakthroughs in areas such as genetic and epigenetic screening, biomarkers, cardioprotective strategies, life-course studies, long-term monitoring technologies, environmental influences on disease, evidence-based practice guidelines, and more rapid and safer development of drugs.

Introduction

Children comprise 26% of the US population but are the target of only 9% of research funds. Given this limited share of research funds, it is both desirable and necessary to establish research priorities. In fact, a clear research agenda can help guide not only pediatric cardiology research but public health policy as well; poor cardiac health at birth and during childhood has repercussions throughout life. For example, health status during the perinatal, postnatal, and childhood periods has a major impact on adult health status: poor cardiac health as a child equates to poor health as an adult.

Elsewhere, we have described a proposed pediatric cardiology research agenda [ 1 - 3• ]. Here, we identify 22 topics and associated research questions that form a comprehensive research agenda ( Table 1 ). We discuss five areas of pediatric cardiology research in detail, describing several advances illustrating the impact that such research can have on health throughout life. These five areas are: 1) life-course studies of cardiovascular disease, including the epigenetic fetal origins of disease as well as late effects and long-term cardiac consequences; 2) risk factors for pediatric cardiometabolic disease; 3) needed clinical trials and observational studies in pediatric cardiology; 4) the value of physical activity in treating cardiac disease in children; and 5) how to study pediatric cardiac problems and to implement evidence-based findings.

1. Life-course Studies of Pediatric Cardiovascular Disease

New information has recently been published on the late cardiovascular effects of anthracycline chemotherapy in long-term survivors of childhood cancer [ 4•• , 5•• ]. Anthracycline toxicity remains one of the best-studied environmental exposures during early childhood that is associated with pervasive, persistent, and, in many cases, progressive late cardiotoxicity. Despite improvements in dilated cardiomyopathy soon after anthracycline chemotherapy, especially in girls treated at younger ages and receiving higher doses of anthracycline, long-term follow-up of childhood cancer reveals a restrictive cardiomyopathy, the incidence of which increases with time. Cardiovascular-related morbidity and mortality rates are significantly increased in these patients at 20 and even 30 years after exposure. Radiation therapy is also associated with progressive late cardiovascular toxicity [ 6• ].

These studies [ 4•• , 5•• , 6• ] illustrate the need for life-course analyses of the relationships between early environmental exposures and late cardiovascular effects ( Table 1 , Topics 1 through 3, 5 through 10, and 12) in terms of the mechanisms and time course of injury, monitoring issues, screening techniques, epigenetic factors, environmental and genetic susceptibilities, biomarker development, individual and population disparities, and clinical trial designs.

The importance of long-term follow-up of the effects of medications and chronic illnesses for late cardiovascular health and diseases was recently illustrated in a study of HIV-infected children at high risk for cardiovascular diseases in which medications such as antiretroviral therapy and other disease factors markedly increased their risk of these diseases ( Table 1 , Topics 3, 5, 6, 9, and 11) [ 7•• ].

Other clinical situations have shown that otherwise healthy children may be put at risk by maternal exposures in utero . For example, children born to HIV-infected mothers have a persistent and progressive risk for cardiovascular disease, as well as mortality rates that appear to be related to maternal health and exposures, emphasizing the importance of fetal and developmental origins of subsequent disease [ 8• , 9• , 10• , 11• ]. Furthermore, maternal dietary intake may influence the child's subsequent cardiovascular health or risk. Second-trimester maternal calcium intake appears to affect systolic blood pressure during early childhood, for example [ 12• ]. Thus, the fetal and developmental origins of adult cardiovascular disease and the importance of longer follow-up studies are parts of the proposed pediatric cardiology clinical research plan ( Table 1 , Topics 3 through 6,11,12).

Other topics in pediatric cardiology research are also of emerging interest. These topics include developing biomarkers and understanding the mechanisms of reversible and irreversible myocardial injury during early childhood that may be related to chronic adrenergic stimulation, as might occur in a child on inotropic therapy in a cardiac critical care unit ( Table 1 , Topics 1 through 3, 6, and 9) [ 13• ]. Additionally, research into models of comprehensive long-term care of pediatric cardiology patients with chronic illnesses is now available ( Table 1 , Topics 3, 10, 11, 12, and 21) [ 14•• ]. Finally, studies comparing real-world clinical management of pediatric cardiology patients with clinical practice guidelines indicate that new implementation strategies are needed because clinical practice in this field does not conform to known standards ( Table 1 , Topics 12, 14) [ 15•• ].

2. Risk Factors for Cardiometabolic Disease in Children

The importance of waist circumference and body mass index as predictors of the long-term risk of premature cardiovascular disease has also been recognized ( Table 1 , Topics 3 and 9 through 12 [ 16•• ]. More than 17% of children in the United States aged 2 to 19 years are obese, and another 34% are overweight and at risk for becoming obese [ 17•• ]. In the proposed research plan, childhood obesity and its complications are thus a top priority.

Recent studies have reported an association between childhood obesity and the development of a cluster of cardiometabolic disease risk factors characterized by variable combinations of insulin resistance, dyslipidemia, and hypertension, which some authors have termed “metabolic syndrome” [ 17 , 18•• ]. In turn, this clustering is associated with the onset of type 2 diabetes and long-term atherosclerotic cardiovascular complications in both childhood and adulthood [ 19 , 20 ].

Nearly one million adolescents aged 12 to 19 years in the US, or about 4% of the population in this age range, have signs and symptoms of metabolic syndrome [ 18•• ]. Among overweight adolescents, the prevalence is nearly 30%. Among 8- to 11-year-olds, national prevalence estimates of metabolic syndrome risk factors ranged from 2% to 9%, using two age-, sex-, and ethnicity-adjusted definitions [ 21•• ].

Identifying individual children and adolescents who either are at risk for or who have metabolic syndrome has remained more elusive and controversial. Much of the controversy surrounding metabolic syndrome in children is in its definition [ 18•• , 22 ]. Definitions of pathological processes are typically based on endpoints. The difficulty in defining these predictors of cardiovascular risk in childhood is that most children have not experienced the endpoint of interest (atherosclerotic cardiovascular disease). Thus, there is technically no single, established operational definition of metabolic syndrome in children [ 17•• ]. The challenge is to set an appropriate cut-point for each risk factor that takes into account age and sex, as well as continuous growth, the onset of puberty, and perhaps ethnic background and setting these cut-points should be a research priority as such. One approach has been to use age- and sex-adjusted percentiles as the cut-points for these risk factors, which raises the issues of which percentiles maximize both the sensitivity and specificity of the prediction and on what cohort these cut-points are determined: an historical cohort from before the current obesity epidemic, perhaps as far back as the first or second National Health and Nutrition Examination Surveys, or a more current cohort that may potentially be skewed toward higher risk.

The American Heart Association has stated that further research is necessary to define pediatric metabolic syndrome. Specific areas of inquiry include the need to: 1) assess large-scale observational and outcome studies to determine stability and predictive power of future chronic disease (e.g. diabetes and cardiovascular disease); 2) clarify the molecular basis of metabolic syndrome; 3) establish the importance of environmental exposures or toxins in the development of metabolic syndrome; 4) determine the appropriate use of medical management in treating insulin resistance, pre-hypertension, early vascular changes, elevated triglyceride levels, and low high density lipoprotein cholesterol levels; 5) identify the pathways linking insulin resistance and obesity with other metabolic syndrome components beginning early in life; 6) better understand leptin biology and the mechanisms of weight regulation; 7) assess any genetic predisposition and prenatal and neonatal factors that promote the development of insulin resistance and metabolic syndrome; and 8) determine whether the mechanisms and pathways of metabolic syndrome vary among racial or ethic groups [ 17•• ].

Only systematic, long-term follow-up of well characterized pediatric cohorts into adulthood will provide the information needed to define appropriate age-, sex-, and race or ethnicity-specific cardiovascular risks in childhood. Such studies should allow earlier and more aggressive lifestyle interventions as well as more appropriate pharmacologic treatment of these children.

3. Recent Clinical Trials and Observational Studies in Pediatric Cardiology

Results from the Pediatric Cardiomyopathy Registry (a study funded by the National Heart Lung and Blood Institute since 1995) indicate that children with Duchenne or Becker muscular dystrophy in addition to cardiomyopathy are at greater risk of premature mortality than are children with other causes of cardiomyopathy [ 23•• ]. As a result, regular cardiac evaluations can now be recommended for children with muscular dystrophy early in their presentation to optimize the application of potentially beneficial cardiac therapies.

In 2004, Lipshultz et al. reported the results of a randomized clinical trial in which dexrazoxane, a free radical scavenger, prevented or reduced the cardiac injury associated with doxorubicin treatment for childhood acute lymphoblastic leukemia [ 24 ]. Although a 2007 report suggested that dexrazoxane increased the incidence of secondary malignancies in children with Hodgkin's disease [ 25 ], a follow-up analysis of the 2004 study of high-risk children with acute lymphoblastic leukemia found that dexrazoxane was not associated with an increased risk of secondary malignant neoplasms [ 26•• ]. The authors of the 2004 study concluded that given the potential importance of dexrazoxane as a cardioprotectant, it should continue to be used and studied in doxorubicin-containing pediatric cancer treatment regimens.

Interest in the use of cardiac biomarkers to evaluate cardiac status in children is increasing ( Table 1 , Topic 9). Cardiac troponin T (cTnT) is a serum biomarker associated with myocardial injury from a variety of causes. In a study of 32 healthy newborns, cTnT levels were elevated in both cord (24 or 76%) and peripheral blood (30 or 94%) and were high enough to be associated with myocardial infarction in 2 (0.6%) of these infants [ 27•• ]. Other biomarkers associated with cardiac disease or dysfunction were also found in smaller proportions of this sample. The authors concluded that subclinical myocardial injury occurs in apparently healthy newborns, but whether this injury is pathologic or a response to the stress of the immediate perinatal period or to other prenatal factors remains to be determined.

Another biomarker used to assess cardiac status is N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), which is secreted by myocytes in the cardiac ventricle. This biomarker is elevated in patients with both asymptomatic and symptomatic ventricular dysfunction, including congestive heart failure. Mangat et al. found that elevated and rising brain natriuretic peptide (BNP) levels, the active hormone, were associated with both abnormal echocardiographic measurements of left ventricular dysfunction as well as with clinical assessments of cardiac-related disability using either the New York Heart Association or the Ross (for non-ambulatory infants) classifications [ 28• ]. In children with congestive heart failure, a serum BNP level greater than 290 pg/mL was associated with death, transplantation, or listing for transplantation [ 28• ].

Maher et al. found that BNP was useful in identifying heart disease in children admitted to emergency departments. The mean BNP level was 3290 pg/mL in children with acute presentations of congenital or acquired heart disease and 17 pg/mL in children with respiratory or other infections [ 29•• ]. Another recent report found that neuroendocrine (NT-proBNP levels) and inflammatory activation (levels of C-reactive protein, tumor necrosis factor-alpha or soluble tumor necrosis factor receptor II) were associated with more severe symptoms and dilated cardiomyopathy in children with heart failure [ 30•• ].

4. The Role of Physical Activity in Preventing and Treating Cardiac Disease in Children

The benefits of a healthy life style in health and sickness are well documented [ 21•• ]. Substantial evidence currently indicates that among children with chronic disease that can lead to, or is a result of, cardiac dysfunction, structured exercise programs can improve some clinical endpoints and are safe in the right environment.

In light of the rapidly increasing rates of childhood obesity, interest is now even greater in ascertaining its cardiovascular effects in children with and without chronic illness ( Table 1 , Topic 11) [ 31•• ]. Children with chronic disease, especially those with cardiac dysfunction, are at risk for sedentary lifestyles and poor nutrition that can lead to overweight and exacerbate or promote cardiac dysfunction [ 32 ]. Massin et al. outlines the atherosclerotic cardiovascular risk of children with congenital heart disease [ 32 ]. Up to 25% of children with congenital or acquired heart disease are overweight [ 33 ]. Emerging evidence suggests that children with congenital heart disease, cardiomyopathy (congenital or acquired), cardiac transplantation, or metabolic cardiac risk (secondary to obesity) can benefit from increased physical activity and improved nutrition ( Table 1 , Topic 12) [ 34 ].

Children with congenital heart disease can show baseline de-conditioning, regardless of previous surgical repair. Children with hypoplastic left heart syndrome had a progressive age-related decline in exercise performance regardless of surgical strategy with children aged 13 to 17 years achieving only 60% of predicted maximum oxygen uptake [ 35•• ]. However, children with ventricular septal defects, repaired or not, had normal physical activity levels and fully participated in exercise [ 36• ]. Other studies have shown that repair of the Fontan fenestration improves aerobic and exercise capacity [ 37 ], but some patients showed improvements only in ventilation [ 38 ]. Paridon et al. [ 39•• ] showed that although maximal aerobic capacity was reduced, higher oxygen saturation was associated with better exercise performance; boys and adolescents were particularly affected.

Similarly, it appears that children with congenital or acquired cardiomyopathy and those who have undergone cardiac transplantation benefit from a structured and supervised exercise rehabilitation program [ 34 , 40•• ]. Two children with idiopathic dilated cardiomyopathy completed a 3-month, hospital-based circuit-training program where their strength, body composition, quality of life and overall activity level improved over baseline [ 40•• ]. Another recent study showed that heart transplant recipients benefited from a home-based exercise rehabilitation program: endurance, peak oxygen consumption, and strength all improved [ 41 ]. Both studies showed the programs were safe and feasible in these populations. The potential for de-conditioning, along with increased metabolic risk and the likelihood that exercise programs can be beneficial, should also be considered in children with cardiac dysfunction as a result of cancer treatments [ 42 ], renal disease [ 43 ], and HIV infection [ 44 ], to name a few. Miller et al. outlines the response to a structured exercise program in children with HIV, a disease that presents metabolic and cardiomyopathic risk [ 44 ].

As discussed in other sections of this article, the prevalence of childhood obesity and its metabolic consequences are now out of control [ 45 ]. The risk of atherosclerotic disease in childhood is a real concern. Physical activity and nutrition are key components of any obesity intervention program, and recent studies have shown that those children with metabolic syndrome had a lower Healthy Eating Index and lower physical activity levels [ 45 ]. Metabolic syndrome, in turn, is associated with reduced cardiorespiratory fitness, low physical activity, and living in an urban environment [ 46 ]. A high-intensity, progressive, resistance training program improved central and whole body adiposity in overweight children, suggesting a conferred risk reduction for cardiometabolic sequelae [ 47•• ]. A Cochrane Review of 26 school-based physical activity programs showed that these programs increased the duration of physical activity and maximum oxygen uptake and reduced television viewing and cholesterol levels [ 48• ]. Participation in school sports programs substantially increased the number of endothelial progenitor cells, which in turn correlates with improved vascular function and that may protect against cardiovascular disease [ 49 ].

5. How to Study Pediatric Cardiac Problems and to Implement Evidence-based Findings

Several recent papers have described models for conducting and improving pediatric cardiac clinical research, such as establishing a clinical research division and conducting registry-based research, both of which have provided infrastructures that have lead to investigator successes [ 50•• , 51•• ]. Having a formal clinical research infrastructure improves both the planning and conducting of research by refining hypotheses; better controlling error, confounding, and bias; improving the accuracy of data collection and processing; and providing quality checks for analyzing and interpreting data.

The need for more and improved research is driven by the fact that prescribing medications to children in the absence of formal pediatric clinical trails can result in substantial risks to their health; an unfortunate but common occurrence in pediatric cardiology. Pediatric medications must be tested in an ethical and safe environment that is supported by scientific excellence ( Table 1 , Topics 3,12,15 through 17). In particular, we need to determine whether comparative trials, in which groups of patients are compared to determine the effectiveness of interventions, threaten the application of personalized medicine in pediatric cardiology, in which patient characteristics and individual genomic information are used to craft individual management strategies ( Table 1 , Topics 3 through 22) [ 52• , 53• , 54• ]. The specialized statistical methods needed to analyze long-term follow-up studies with missing data illustrate the requirements for this kind of research [ 55• ]. The components needed to develop a comprehensive research agenda, some research priorities, and some proposed directions in research for pediatric cardiology are detailed in Table 1 .

Conclusions

We conclude the following:

• Clinical research in pediatric cardiology must accelerate rapidly in the near future if we are to reduce cardiovascular morbidity and mortality for the entire population.
• Epigenetic cardiovascular factors clearly affect development.
• We need a greater understanding of the timeframe over which cardiovascular risk remains modifiable.
• We need to identify validated biomarkers as surrogate endpoints for clinically important cardiovascular disease.
• Multi-disciplinary, multiple-site life-course study groups are essential for accurately determining the risk of exposures and to identify vulnerable sub-populations. Such study groups would also inform future clinical studies and trials.
• Local infrastructure [ 50•• ] and expertise in pediatric cardiology clinical research is highly variable and must be strengthened to increase the discovery of both incremental and break-through advances in care.

Acknowledgments

Supported by the NIH (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, CA068484, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, HD80002), the Children's Cardiomyopathy Foundation, the Women's Cancer Association, the Thrasher Foundation, and the STOP Children's Cancer Foundation.

Abbreviations

Disclosures: No conflicts of interest or sponsorships are noted.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp.xx-xx).

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A literature review of cardiovascular disease management programs in managed care populations

Affiliation.

• 1 Health Net, Inc., 21281 Burbank Blvd., B5 Woodland Hills, CA 91367, USA. [email protected]
• PMID: 15298531
• PMCID: PMC10438131
• DOI: 10.18553/jmcp.2004.10.4.326

Objectives: (1) To review the literature on cardiovascular disease management programs in managed care populations, (2) compare the rigor of the studies and their findings by disease state, and (3) posit directions for future research.

Summary: A total of 20 studies conducted in managed care populations were reviewed: 5 in patients with congestive heart failure (CHF), 9 in hypertensive patients, and 6 in hyperlipidemia and/or coronary artery disease (hyperlipidemia- CAD) patients. Management of CHF involved multifaceted programs that included the participation of multiple health care professionals, patient and physician education, promotion of intensive drug therapy and lifestyle modifications, and close patient monitoring. The most common CHF management strategies were case management and physician education, with an emphasis on close patient monitoring. Hypertension and hyperlipidemia-CAD intervention programs focused on chronic outpatient management and regular follow-up, with an emphasis on self-management skills. These programs were managed through regular and periodic interventions, including pharmacist-managed clinics and automated provider notices. Many of the studies employed "before-after" comparisons in the absence of a truly experimental design and posed significant limitations due to variations in the outcomes measured, lack of transparent disease severity stratification, and variation across types of managed care organizations.

Conclusion: A number of cardiovascular disease management strategies in the literature reported promising results. Many of the multidisciplinary CHF disease management programs were more complex than were programs for hypertension and hyperlipidemia-CAD, due, at least in part, to the nature and severity of the disease. A lack of agreement on appropriate economic and clinical outcomes for evaluating the effectiveness of cardiovascular disease management strategies is readily apparent.

Copyright 2004 Academy of Managed Care Pharmacy

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