Phenomics and Robust Multiomics Data for Cardiovascular Disease Subtyping.

The complex landscape of cardiovascular diseases encompasses a wide range of related pathologies arising from diverse molecular mechanisms and exhibiting heterogeneous phenotypes. This variety of manifestations poses significant challenges in the development of treatment strategies. The increasing availability of precise phenotypic and multiomics data of cardiovascular disease patient populations has spurred the development of a variety of computational disease subtyping techniques to identify distinct subgroups with unique underlying pathogeneses. In this review, we outline the essential components of computational approaches to select, integrate, and cluster omics and clinical data in the context of cardiovascular disease research. We delve into the challenges faced during different stages of the analysis, including feature selection and extraction, data integration, and clustering algorithms. Next, we highlight representative applications of subtyping pipelines in heart failure and coronary artery disease. Finally, we discuss the current challenges and future directions in the development of robust subtyping approaches that can be implemented in clinical workflows, ultimately contributing to the ongoing evolution of precision medicine in health care.

Integrating Clinical Data and Imputed Transcriptome from GWAS to Uncover Complex Disease Subtypes: Applications in Psychiatry and Cardiology.

Classifying subjects into clinically and biologically homogeneous subgroups will facilitate the understanding of disease pathophysiology and development of targeted prevention and intervention strategies. Traditionally, disease subtyping is based on clinical characteristics alone, but subtypes identified by such an approach may not conform exactly to the underlying biological mechanisms. Very few studies have integrated genomic profiles (e.g., those from GWASs) with clinical symptoms for disease subtyping. Here we proposed an analytic framework capable of finding complex diseases subgroups by leveraging both GWAS-predicted gene expression levels and clinical data by a multi-view bicluster analysis. This approach connects SNPs to genes via their effects on expression, so the analysis is more biologically relevant and interpretable than a pure SNP-based analysis. Transcriptome of different tissues can also be readily modeled. We also proposed various evaluation metrics for assessing clustering performance. Our framework was able to subtype schizophrenia subjects into diverse subgroups with different prognosis and treatment response. We also applied the framework to the Northern Finland Birth Cohort (NFBC) 1966 dataset and identified high and low cardiometabolic risk subgroups in a gender-stratified analysis. The prediction strength by cross-validation was generally greater than 80%, suggesting good stability of the clustering model. Our results suggest a more data-driven and biologically informed approach to defining metabolic syndrome and subtyping psychiatric disorders. Moreover, we found that the genes "blindly" selected by the algorithm are significantly enriched for known susceptibility genes discovered in GWASs of schizophrenia or cardiovascular diseases. The proposed framework opens up an approach to subject stratification.

Examining "race" in physiology.

Racial disparities in cardiovascular and cerebrovascular health outcomes are well described, and recent research has shed light on the mechanistic underpinnings of those disparities. However, "race" is a social construct that is poorly defined and continually evolving and is historically based on faulty premises. The continued categorization by race in physiological research suggests that there are inherent differences between races, rather than addressing the specific underlying factors that result in health disparities between groups. The purpose of this Perspectives article is to provide a brief history of the genesis of categorization by race, why such categorization should be reconsidered in physiology research, and offer recommendations to more directly investigate the underlying factors that result in group disparities in cardiovascular and cerebrovascular health.

Characterization of Brazilian hospital admissions due to cardiovascular diseases: a longitudinal study.

BACKGROUND: Cardiovascular diseases (CVD) are the main cause of death and comorbidities worldwide. It is estimated that three quarters of all deaths related to CVD occur in low and middle income countries such as Brazil. Furthermore, it is estimated that emerging countries will present the highest worldwide prevalence of such diseases by 2050. In view of the above, this study aims to characterize Brazilian hospital admission distribution classified by the ICD-10 in adults between 2008 and 2017 in Brazil. METHODS: This is a longitudinal descriptive study in which all data regarding hospital admissions registered in the Brazilian Hospital Information System of "Sistema Único de Saúde" (SIH/SUS) due to cardiovascular diseases (ICD-10) were included. All admissions from private or public services linked to the SUS from 2008 and 2017 were evaluated. The following variables were collected: number of hospital admissions, place of hospitalization classified by the ICD-10 and mortality rate at the federal level and according to regions. Absolute values and frequency of hospital admissions were grouped according to sex, age and living region as well as the number of deaths. The extracted data was stored in a Microsoft Excel 2013 program spreadsheet. Statistical analysis was performed by GraphPad Prism version 5.0 software. RESULTS: There was a total of 11,345,821 hospital admissions due to CVD registered between 2008 and 2017. Individuals from 50 to 79 years old were the most affected. Heart failure (21.3%), other ischemic heart diseases (13.3%) and stroke (11.4%) were responsible for almost half of the hospital admissions associated to CVD. The number of registered deaths caused by any CVD was 867,838 and the national mortality rate was 7.82. CONCLUSION: CVD were responsible for around 10% of all hospital admissions in Brazil between 2008 and 2017. Moreover, it was possible to observe a decrease in hospital admissions as well as mortality rate over time after implementing governmental strategies to prevent cardiovascular diseases.

Cardiology on the cutting edge: updates from the European Society of Cardiology (ESC) Congress 2020.

The 2020 annual Congress of the European Society of Cardiology (ESC) was the first ever to be held virtually. Under the spotlight of 'the cutting edge of cardiology', exciting and ground-breaking cardiovascular (CV) science was presented both in basic and clinical research. This commentary summarizes essential updates from ESC 2020-The Digital Experience. Despite the challenges that coronavirus disease 2019 (COVID-19) has posed on the conduct of clinical trials, the ESC Congress launched the results of major studies bringing innovation to the field of general cardiology, cardiac surgery, heart failure, interventional cardiology, and atrial fibrillation. In addition to three new ESC guidelines updates, the first ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease were presented. As former ESC president, Professor Casadei undoubtedly pointed out the ESC Congress 2020 was a great success. During the ESC 2020 Congress, BMC Cardiovascular Disorders updated to seven journal sections including Arrhythmias and Electrophysiology, CV Surgery, Coronary Artery Disease, Epidemiology and Digital health, Hypertension and Vascular biology, Primary prevention and CV Risk, and Structural Diseases, Heart Failure, and Congenital Disorders. To conclude, an important take-home message for all CV health care professionals engaged in the COVID-19 pandemic is that we must foresee and be prepared to tackle the dramatic, long-term CV complications of COVID-19 patients.

Development and Use of Prediction Models for Classification of Cardiovascular Risk of Remote Indigenous Australians.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death for Indigenous Australians. There is widespread belief that current tools have deficiencies for assessing CVD risk in this high-risk population. We sought to develop a 5-year CVD risk score using a wide range of known risk factors to further improve CVD risk prediction in this population. METHODS: We used clinical and demographic information on Indigenous people aged between 30 and 74 years without a history of CVD events who participated in the Well Person's Health Check (WPHC), a community-based survey. Baseline assessments were conducted between 1998 and 2000, and data were linked to administrative hospitalisation and death records for identification of CVD events. We used Cox proportional hazard models to estimate the 5-year CVD risk, and the Harrell's c-statistic and the modified Hosmer-Lemeshow (mH-L) χ2 statistic to assess the model discrimination and calibration, respectively. RESULTS: The study sample consisted of 1,583 individuals (48.1% male; mean age 45.0 year). The risk score consisted of sex, age, systolic blood pressure, diabetes mellitus, waist circumference, triglycerides, and albumin creatinine ratio. The bias-corrected c-statistic was 0.72 and the bias-corrected mH-L χ2 statistic was 12.01 (p-value, 0.212), indicating good discrimination and calibration, respectively. Using our risk score, the CVD risk of the Indigenous Australians could be stratified to a greater degree compared to a recalibrated Framingham risk score. CONCLUSIONS: A seven-factor risk score could satisfactorily stratify 5-year risk of CVD in an Indigenous Australian cohort. These findings inform future research targeting CVD risk in Indigenous Australians.

SARS-CoV-2 Infection and Cardiovascular Disease: COVID-19 Heart.

Coronavirus disease (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The symptoms of the disease range from asymptomatic to mild respiratory symptoms and even potentially life-threatening cardiovascular and pulmonary complications. Cardiac complications include acute myocardial injury, arrhythmias, cardiogenic shock and even sudden death. Furthermore, drug interactions with COVID-19 therapies may place the patient at risk for arrhythmias, cardiomyopathy and sudden death. In this review, we summarise the cardiac manifestations of COVID-19 infection and propose a simplified algorithm for patient management during the COVID-19 pandemic.

Incidence of Acute Cardiovascular Event After Acute Exacerbation of COPD.

BACKGROUND: There is a lack of comprehensive view of the association between acute exacerbation of COPD (AECOPD) and the risk of acute cardiovascular events. OBJECTIVE: To determine the association of AECOPD with 30-day and 1-year incidences of acute cardiovascular event. DESIGN: Self-controlled case series analysis using population-based datasets from three US states from 2005 through 2011. PARTICIPANTS: Patients aged ≥ 40 years with AECOPD. MAIN MEASURES: The primary outcome was a composite of an ED visit or hospitalization for acute cardiovascular events, including acute myocardial infarction, heart failure, atrial fibrillation, pulmonary embolism, and stroke. We compared the incidence of each patient's acute cardiovascular event during the first 30-day period before the index AECOPD (30-day reference period) in comparison with that during the 30-day period after the index AECOPD. Likewise, with the 1-year period before the index AECOPD as reference, we also estimated incidence rate ratios (IRRs) for each patient's outcomes during 1-year period after the index AECOPD. KEY RESULTS: Overall, there were 362,867 patients with an ED visit or hospitalization for AECOPD. Compared with the 30-day reference period, the incidence of acute cardiovascular event in the 30-day period after the AECOPD was significantly higher (IRR, 1.34; 95%CI, 1.30-1.39; P < 0.001). Likewise, compared with the 1-year reference period, the incidence during the 1-year period after the AECOPD was also higher (IRR, 1.20; 95%CI, 1.18-1.22; P < 0.001). For each of acute cardiovascular conditions, the associations remained significant (all P < 0.05). CONCLUSIONS: AECOPD was associated with increased 30-day and 1-year incidences of acute cardiovascular event.

Cardiovascular risk biomarkers and metabolically unhealthy status in prepubertal children: Comparison of definitions.

BACKGROUND AND AIMS: The early onset of cardio-metabolic abnormalities, known as metabolically unhealthy (MU) status, is highly associated with obesity and cardiovascular disease (CVD), as well as with increased morbidity and mortality later in life. Given the lack of a consensus MU classification for prepubertal children, we aimed to compare available MU definitions in terms of their association with CVD risk biomarkers. METHODS AND RESULTS: A total of 930 prepubertal children (622 with overweight/obesity, 462 males) aged 5-10.9 years were recruited, anthropometric measures were taken and biomarkers were analyzed. Children were classified using eight MU definitions based on different cut-offs for blood pressure, triacylglycerides, high-density lipoprotein cholesterol, glucose and homeostasis model assessment for insulin resistance (HOMA-IR). MU prevalence in children with overweight/obesity ranged between 30% and 60% across definitions. Plasma concentrations of resistin, leptin, myeloperoxidase (MPO) and total plasminogen activator inhibitor 1 (tPAI-1) were higher, and those of adiponectin were lower, in MU compared to MH children with overweight/obesity. Linear regression analyses confirmed the contribution of MPO and tPAI-1 concentrations to MU status, with most significant results derived from definitions that use age and sex-specific criteria and that account for HOMA-IR. CONCLUSION: Plasma concentrations of MPO and tPAI-1 are increased in prepubertal MU children irrespective of having normal-weight or overweight/obesity. Inclusion of age and sex-specific cut-offs for cardio-metabolic components as well as insulin resistance criteria increases the quality of MU definitions as seen by their stronger association with CVD biomarkers concentrations.

The Effect of Reference Group Classification and Change in Alcohol Consumption on the Association Between Alcohol Consumption and Cardiovascular Disease.

BACKGROUND: Many studies suggest that mild alcohol consumption can help avert cardiovascular disease (CVD). This study investigated the association between alcohol consumption and CVD incidence, and assessed whether this differed by reference group classification. As alcohol consumption amounts may change over time, the results of simple and time-dependent analyses were compared. METHODS: Data were from a community-based cohort study on 40- to 69-year-old Koreans recruited in 2001 to 2002. A total of 8,330 participants were followed up for 10 years and classed as nondrinkers (0 g/d), drinker group 1 (<15 g/d), and drinker group 2 (≥15 g/d). The risk of CVD, including myocardial infarction and coronary artery disease, was compared among groups using simple and time-dependent Cox analysis. Occasional drinkers (<2.5 g/d), nondrinkers, and lifetime abstainers were used as comparison reference groups. RESULTS: Simple Cox analysis indicated that drinker group 1 exhibited a significantly lower risk of myocardial infarction (hazard ratio [HR]: 0.44, 95% confidence interval [CI]: 0.21, 0.92) and coronary artery disease (HR: 0.61, 95% CI: 0.4, 0.94) than nondrinkers. Time-dependent analysis based on alcohol consumption change showed that the beneficial effects of drinker group 1 were significant only for myocardial infarction, not for coronary artery disease. The benefits did not change significantly when either nondrinkers or lifetime abstainers were the reference group. However, when occasional drinkers were included in the reference group, the benefits of drinker group 1 were not significant for myocardial infarction (HR: 0.65, 95% CI: 0.29, 1.45) or coronary artery disease (HR: 0.71, 95% CI: 0.42, 1.19). Occasional drinkers and drinkers had more similar sociodemographic characteristics than did nondrinkers and drinkers. CONCLUSIONS: Further studies on alcohol consumption and its effects on health must use repeated measurement to define drinking status, as simple and time-dependent analyses can show different alcohol consumption risks. These findings do not indicate a beneficial effect of drinking <15 g/d when occasional drinkers and nondrinkers are included in the reference group.

Failure of fertility therapy and subsequent adverse cardiovascular events.

BACKGROUND: Infertility may indicate an underlying predisposition toward premature cardiovascular disease, yet little is known about potential long-term cardiovascular events following fertility therapy. We investigated whether failure of fertility therapy is associated with subsequent adverse cardiovascular events. METHODS: We performed a population-based cohort analysis of women who received gonadotropin-based fertility therapy between Apr. 1, 1993, and Mar. 31, 2011, distinguishing those who subsequently gave birth and those who did not. Using multivariable Poisson regression models, we estimated the relative rate ratio of adverse cardiovascular events associated with fertility therapy failure, accounting for age, year, baseline risk factors, health care history and number of fertility cycles. The primary outcome was subsequent treatment for nonfatal coronary ischemia, stroke, transient ischemic attack, heart failure or thromboembolism. RESULTS: Of 28 442 women who received fertility therapy, 9349 (32.9%) subsequently gave birth and 19 093 (67.1%) did not. The median number of fertility treatments was 3 (interquartile range 1-5). We identified 2686 cardiovascular events over a median 8.4 years of follow-up. The annual rate of cardiovascular events was 19% higher among women who did not give birth after fertility therapy than among those who did (1.08 v. 0.91 per 100 patient-years, p < 0.001), equivalent to a 21% relative increase in the annual rate (95% confidence interval 13%-30%). We observed no association between event rates and number of treatment cycles. INTERPRETATION: Fertility therapy failure was associated with an increased risk of long-term adverse cardiovascular events. These women merit surveillance for subsequent cardiovascular events.

Comparing chronic condition rates using ICD-9 and ICD-10 in VA patients FY2014-2016.

BACKGROUND: Management of patients with chronic conditions relies on accurate measurement. It is unknown how transition to the ICD-10 coding system affected reporting of chronic condition rates over time. We measured chronic condition rates 2 years before and 1 year after the transition to ICD-10 to examine changes in prevalence rates and potential measurement issues in the Veterans Affairs (VA) health care system. METHODS: We developed definitions for 34 chronic conditions using ICD-9 and ICD-10 codes and compared the prevalence rates of these conditions from FY2014 to 2016 in a 20% random sample (1.0 million) of all VA patients. In each year we estimated the total number of patients diagnosed with the conditions. We regressed each condition on an indicator of ICD-10 (versus ICD-9) measurement to obtain the odds ratio associated with ICD-10. RESULTS: Condition prevalence estimates were similar for most conditions before and after ICD-10 transition. We found significant changes in a few exceptions. Alzheimer's disease and spinal cord injury had more than twice the odds of being measured with ICD-10 compared to ICD-9. HIV/AIDS had one-third the odds, and arthritis had half the odds of being measured with ICD-10. Alcohol dependence and tobacco/nicotine dependence had half the odds of being measured in ICD-10. CONCLUSION: Many chronic condition rates were consistent from FY14-16, and there did not appear to be widespread undercoding of conditions after ICD-10 transition. It is unknown whether increased sensitivity or undercoding led to decreases in mental health conditions.

[DIFFERENTIAL APPROACH TO THE EVALUATION OF RIGHT VENTRICULAR SYSTOLIC FUNCTION BY PULSED WAVE DOPPLER ULTRASOUND].

A method for diagnostics of systolic function of the right ventricle of the heart in patients with cardiovascular disease is proposed. Its application expands possibilities for detecting disorders of the discharge RV function using a conventional pulsed wave Doppler ultrasonography.

ECHOCARDIOGRAPHIC CHARACTERISTICS OF DIFFERENT WHO/ISH CARDIOVASCULAR DISEASE RISK GROUPS.

The objective of the study was to analyze association of echocardiographic TOD variables with the CVD risk groups defined by WHO/ISH. A cross-sectional study was conducted between (September 2008 - December 2010) Consecutive sample of 146 participants were enrolled in the study, 97 (66.4 %) women and (49) 33,6 % men, mean age. Study population was categorized in three groups according to WHO/ISH risk categories: Group 1 included population with risk less than 10% according to WHO/ISH, in Group 2 there were united two WHO/ISH risk categories (10-10.9% and 20-29.9%) and Group 3 represented population of 30-39.9% and more than 40% of CVD risk. Routine Echocardiography was conducted. The data was analyzed using SPSS, version 21. The distribution of echocardiography characteristics in WHO/ISH groups was statistically different for LA, PSP and EF (P<0.05). In groups I and II LA were only mildly dilated, while in group III was revealed moderate LA enlargement. The mean PSP was in normal range in groups I and II and mildly to moderate elevated in group III. The mean EF was in normal range for all the groups with tendency of reduction from group I to group III. Unlike this we have not found statistically significant differences in other echocardiographic variables, as IVS, PWT, LVD and LVEDV and they were in normal range for all risk groups. According to the findings of our study and considering that our study population is without any clinical presentation of cardiovascular disease and still have statistically significant tendency toward increase in LA and PSP we argue that those variables can be considered as early predictors of cardiovascular disease. Furthermore, it is recommended to include echocardiographic examination as part of the CVD risk evaluation protocol in selected population.

Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Although studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose-response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality. METHODS: PubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model. RESULTS: Forty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88-1.10) or CHD (RR: 0.92; 95% CI, 0.85-1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69-0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89-0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77-0.86) and 0.90 (95% CI, 0.81-0.99), respectively. CONCLUSIONS: Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.

The existence of standard-biased mortality ratios due to death certificate misclassification - a simulation study based on a true story.

BACKGROUND: Mortality statistics are used to compare health status of populations; optimally, they base on individual death certificates. However, determining cause of death is error-prone. E.g. cardiovascular disease (CVD) death determination is characterized by sensitivity (SE) and specificity (SP) lower than 85%. Furthermore, differential misclassification may be present in case of homogenous target populations. We investigate the bias of standardized mortality ratios (SMR), based on real-world data. METHODS: CVD mortality of 6378 ethnic German repatriates was assessed and the SMR calculated. Non-differential age-dependent misclassification was introduced into data by scenarios of equal SE and SP in a range of 0.7 to 0.85. The bias between originally reported and actual SMR was calculated for each pair of values. Additionally, four differential misclassification scenarios were simulated, reflecting two extreme scenarios of both quality criteria varied in the cohort but fixed to either higher or lower in the reference, and two scenarios of crossed criteria values. RESULTS: In case of non-differential misclassification the bias is always towards the null-hypothesis. The lowest bias was 13.5% (SE, SP = 0.85 constantly), the maximum bias was 40% (SP = 0.7). However, in case of differential misclassification the observed SMR can be on the wrong track. If SP is high but SE low in the cohort, negative bias up to -10% can occur. In case SE is low but SP is high in the reference, the bias remains always positive. In the opposite case plus SP is high in the cohort, the bias can reach -30%. CONCLUSION: SMR values are always biased due to the diagnostic test character of death determination. In majority of epidemiological studies the bias should be towards the null-hypothesis (non-differential misclassification). However, caution is needed in case of differential misclassification, possibly experienced in studies on homogenous subgroups, and in large prospective cohorts with specifically trained personnel.

Diagnostic role of head-up tilt test in patients with cough syncope.

AIMS: The aim of this study was to describe the head-up tilt (HUT) test and carotid sinus massage (CSM) responses, and the occurrence of syncope with coughing during HUT in a large cohort of patients. METHODS AND RESULTS: A total of 5133 HUT were retrospectively analysed to identify patients with cough syncope. Head-up tilt followed by CSM were performed. Patients were made to cough on two separate occasions in an attempt to reproduce typical clinical symptoms on HUT. Patients with cough syncope were compared with 29 age-matched control patients with syncope unrelated to coughing. A total of 29 patients (26 male, age 49 ± 14 years) with cough syncope were identified. Coughing during HUT reproduced typical prodromal symptoms of syncope in 16 (55%) patients and complete loss of consciousness in 2 (7%) patients, with a mean systolic blood pressure reduction of 45 ± 26 mmHg, and a mean increase in heart rate of 13 ± 8 b.p.m. No syncope or symptoms after coughing were observed in the control group. The HUT result was positive in 13 (48%) patients with the majority of positive HUT responses being vasodepressor (70% of positive HUT). Carotid sinus massage was performed in 18 patients being positive with a vasodepressor response causing mild pre-syncopal symptoms in only 1 patient. CONCLUSION: Syncope during coughing is a result of hypotension, rather than bradycardia. Coughing during HUT is a useful test in patients suspected to have cough syncope but in whom the history is not conclusive.

Women and Cardiovascular Disease: What Can Health Care Providers Do to Reduce the Risks?

Cardiovascular disease impacts everybody and places significant burdens on the health care system. Educating women on their risks and how to reduce these risks will not only make women more aware but will help to improve lives and reduce health care costs. This commentary will review heart disease in women and what women can do to improve their cardiovascular health.

Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: A population-based cohort study of 32,308 one-year survivors.

The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population-based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one-year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0-2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person-years. At the end of follow-up 12% of the survivors were ≥ 50 years of age and 4.5% ≥ 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ∼500-600 per 100,000 person-years at age ≥ 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5-5.9), valvular dysfunction (4.6; 3.8-5.5) and cerebrovascular diseases (3.7; 3.4-4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow-up for this rapidly growing population.

Paediatric cardiovascular clinical trials: an analysis of ClinicalTrials.gov and the Food and Drug Administration Pediatric Drug Labeling Database.

Recent regulatory initiatives in the United States of America and Europe have transformed the paediatric clinical trials landscape by significantly increasing capital investment and paediatric trial volume. The purpose of this manuscript was to review the impact of these initiatives on the paediatric cardiovascular trials landscape when compared with other paediatric sub-specialties. We also evaluate factors that may have contributed to the success or failure of recent major paediatric cardiovascular trials so as to inform the optimal design and conduct of future trials in the field.