Commentary : beyond vague causal effect estimation of obesity on health outcomes

In the current issue of epidemiology, Danaei and colleagues elegantly estimated both the direct effect and the indirect effect-that is, the effect mediated by blood pressure, cholesterol, glucose, fibrinogen, and high-sensitivity C-reactive protein-of body mass index (BMI) on the risk of coronary heart disease (CHD). they analyzed data from 9 cohort studies including 58,322 patients and 9459 CHD events, with baseline measurements between 1954 and 2001. Using sophisticated and cutting-edge methods for direct and indirect effect estimations, the authors estimated that half of the risk of overweight and obesity would be mediated by blood pressure, cholesterol, and glucose. Few additional percentage points of the risk would be mediated by fibrinogen and hs-CRP. How should we understand these estimates? Can we say that if obese persons reduce their body weight and reach a normal body weight, their excess risk of CHD would be reduced by half through an improvement in these mediators and by half through the reduction in BmI itself? Is that also true if these individuals are prevented from becoming obese in the first place? Can we also conclude that if these mediators are well controlled in obese individuals through other means than a body weight reduction, their excess risk of CHD would be reduced by half? Let us confront these estimates with observations from studies evaluating 2 interventions to reduce body weight, that is, bariatric surgery in patients with severe obesity and intensive lifestyle intervention in overweight patients with diabetes

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.

Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe.

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996-1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into 'isolated' when only a cardiac malformation was present and 'associated' when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20-24 weeks for the majority of associated cardiac defects.

Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI.

This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision-making.

Increased risk of cardiovascular disease (CVD) with age in HIV-positive men : a comparison of the D:A:D CVD risk equation and general population CVD risk equations

OBJECTIVES: The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. METHODS: We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores. RESULTS: A total of 24 323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40-45 years to 6.53, 11.91 and 15.89 in those aged 60-65 years, respectively. The best-fitting models included inverse age for MI and age + age(2) for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population. CONCLUSIONS: We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.

Association study of lipoprotein(a) genetic markers, traditional risk factors, and coronary heart disease in HIV-1-infected patients.

Objectives: General population studies have shown associations between copy number variation (CNV) of the LPA gene Kringle-IV type-2 (KIV-2) coding region, single-nucleotide polymorphism (SNP) rs6415084 in LPA and coronary heart disease (CHD). Because risk factors for HIV-infected patients may differ from the general population, we aimed to assess whether these potential associations also occur in HIV-infected patients. Methods: A unicenter, retrospective, case-control (1:3) study. Eighteen HIV-patients with confirmed diagnosis of acute myocardial infarction (AMI) were adjusted for age, gender, and time since HIV diagnosis to 54 HIV-patients without CHD. After gDNA extraction from frozen blood, both CNV and SNP genotyping were performed using real-time quantitative PCR. All genetic and non-genetic variables for AMI were assessed in a logistic regression analysis. Results: Our results did not confirm any association in terms of lipoprotein(a) LPA structural genetic variants when comparing KIV-2 CNV (p = 0.67) and SNP genotypes (p = 0.44) between AMI cases and controls. However, traditional risk factors such as diabetes mellitus, hypertension, and CD4(+) T cell count showed association (p < 0.05) with CHD. Conclusion: Although significant associations of AMI with diabetes, hypertension and CD4(+) T cell count in HIV-patients were found, this study could not confirm the feasibility neither of KIV-2 CNV nor rs6415084 in LPA as genetic markers of CHD in HIV-infected patients.Highlights:● Individuals with HIV infection are at higher risk of coronary heart disease (CHD) than the non-infected population.● Our results showed no evidence of LPA structural genetic variants associated with CHD in HIV-1-infected patients.● Associations were found between diabetes mellitus, arterial hypertension, CD4(+) T cell count, and CHD.● The clinical usefulness of these biomarkers to predict CHD in HIV-1-infected population remains unproven.● Further studies are needed to assess the contribution of common genetic variations to CHD in HIV-infected individuals.

Molecular insight into heart development and congenital heart disease: An update review from the Arab countries.

Congenital heart defect (CHD) has a major influence on affected individuals as well as on the supportive and associated environment such as the immediate family. Unfortunately, CHD is common worldwide with an incidence of approximately 1% and consequently is a major health concern. The Arab population has a high rate of consanguinity, fertility, birth, and annual population growth, in addition to a high incidence of diabetes mellitus and obesity. All these factors may lead to a higher incidence and prevalence of CHD within the Arab population than in the rest of the world, making CHD of even greater concern. Sadly, most Arab countries lack appropriate public health measures directed toward the control and prevention of congenital malformations and so the importance of CHD within the population remains unknown but is thought to be high. In approximately 85% of CHD patients, the multifactorial theory is considered as the pathologic basis. The genetic risk factors for CHD can be attributed to large chromosomal aberrations, copy number variations (CNV) of particular regions in the chromosome, and gene mutations in specific nuclear transcription pathways and in the genes that are involved in cardiac structure and development. The application of modern molecular biology techniques such as high-throughput nucleotide sequencing and chromosomal array and methylation array all have the potential to reveal more genetic defects linked to CHD. Exploring the genetic defects in CHD pathology will improve our knowledge and understanding about the diverse pathways involved and also about the progression of this disease. Ultimately, this will link to more efficient genetic diagnosis and development of novel preventive therapeutic strategies, as well as gene-targeted clinical management. This review summarizes our current understanding of the molecular basis of normal heart development and the pathophysiology of a wide range of CHD. The risk factors that might account for the high prevalence of CHD within the Arab population and the measures required to be undertaken for conducting research into CHD in Arab countries will also be discussed.

Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI.

This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision-making.

Single centre experience of the application of self navigated 3D whole heart cardiovascular magnetic resonance for the assessment of cardiac anatomy in congenital heart disease.

BACKGROUND: For free-breathing cardiovascular magnetic resonance (CMR), the self-navigation technique recently emerged, which is expected to deliver high-quality data with a high success rate. The purpose of this study was to test the hypothesis that self-navigated 3D-CMR enables the reliable assessment of cardiovascular anatomy in patients with congenital heart disease (CHD) and to define factors that affect image quality. METHODS: CHD patients ≥2 years-old and referred for CMR for initial assessment or for a follow-up study were included to undergo a free-breathing self-navigated 3D CMR at 1.5T. Performance criteria were: correct description of cardiac segmental anatomy, overall image quality, coronary artery visibility, and reproducibility of great vessels diameter measurements. Factors associated with insufficient image quality were identified using multivariate logistic regression. RESULTS: Self-navigated CMR was performed in 105 patients (55% male, 23 ± 12y). Correct segmental description was achieved in 93% and 96% for observer 1 and 2, respectively. Diagnostic quality was obtained in 90% of examinations, and it increased to 94% if contrast-enhanced. Left anterior descending, circumflex, and right coronary arteries were visualized in 93%, 87% and 98%, respectively. Younger age, higher heart rate, lower ejection fraction, and lack of contrast medium were independently associated with reduced image quality. However, a similar rate of diagnostic image quality was obtained in children and adults. CONCLUSION: In patients with CHD, self-navigated free-breathing CMR provides high-resolution 3D visualization of the heart and great vessels with excellent robustness.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95 % CI 1.07-1.86, fluoxetine adjOR 1.43 95 % CI 0.85-2.40, paroxetine adjOR 1.53, 95 % CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95 % CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95 % CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95 % CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95 % CI 1.06-5.68), gastroschisis (adjOR 2.42, 95 % CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95 % CI 1.61-5.61), and clubfoot (adjOR 2.41, 95 % CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study.

BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction.

Association between resistin levels and cardiovascular disease events in older adults: The health, aging and body composition study.

OBJECTIVE: Prospective data on the association between resistin levels and cardiovascular disease (CVD) events are sparse with conflicting results. METHODS: We studied 3044 aged 70-79 years from the Health, Aging, and Body Composition Study. CVD events were defined as coronary heart disease (CHD) or stroke events. «Hard » CHD events were defined as CHD death or myocardial infarction. We estimated hazard ratio (HR) and 95% confidence intervals (CI) according to the quartiles of serum resistin concentrations and adjusted for clinical variables, and then further adjusted for metabolic disease (body mass index, fasting plasma glucose, abdominal visceral and subcutaneous adipose tissue, leptin, adiponectin, insulin) and inflammation (C-reactive protein, interleukin-6, tumor necrosis factors-α). RESULTS: During a median follow-up of 10.1 years, 559 patients had « hard » CHD events, 884 CHD events and 1106 CVD Events. Unadjusted incidence rate for CVD events was 36.6 (95% CI 32.1-41.1) per 1000 persons-year in the lowest quartile and 54.0 per 1000 persons-year in the highest quartile (95% CI 48.2-59.8, P for trend < 0.001). In the multivariate models adjusted for clinical variables, HRs for the highest vs. lowest quartile of resistin was 1.52 (95% CI 1.20-1.93, P < 0.001) for « Hard » CHD events, 1.41 (95% CI 1.16-1.70, P = 0.001) for CHD events and 1.35 (95% CI 1.14-1.59, P = 0.002) for CVD events. Further adjustment for metabolic disease slightly reduced the associations while adjustment for inflammation markedly reduced the associations. CONCLUSIONS: In older adults, higher resistin levels are associated with CVD events independently of clinical risk factors and metabolic disease markers, but markedly attenuated by inflammation.

Ohjauksen ja neuvonnan vaikutukset sepelvaltimoiden ohitusleikkauspotilaiden terveyskäyttäytymiseen, terveyteen ja toimintakykyyn

Effects of counseling and guidance on health behavior, health, and functional abilities of coronary artery bypass (cab) patients Hospital periods of heart patients are brief and full of activity today, and for that reason, the meaning of counseling and guidance becomes emphasized. The present intervention study started based on observations of staff members at the heart organization. According to these observations, there were gaps in counseling and guidance intended for coronary artery bypass (CAB) patients. The purpose of the present intervention study was to describe and evaluate the program on counseling and guidance organized for patients who were referred to CAB operations. More specifically, the study was to assess its short-term (3-month), intermediate (6-month), and long-term (12-month) effects on health behavior, health, and functional abilities of CAB patients of any age on one hand and elderly on the other, as well as on their mortality. The data consisted of those individuals having coronary heart disease (CHD) and living in Uusimaa (n = 365) who went through their first CAB operation at the Helsinki University Hospital between May 7th, 1998 and December 31st, 2001. Based on the need of urgency, they were divided into two groups: 1) surgery with regular referral procedure (non-acute) or 2) surgery in the acute phase of CHD. Randomization into an intervention and a control group was separately carried out within these two groups. A subgroup was formed by including those 65 years or older who were operated on with regular referral procedure. Data on health behavior, health, and functional abilities were gathered with survey questionnaires. Times and causes of death were examined January 1st, 1998 through December 31st, 2004. Intervention included counseling and guidance in small groups. The intervention of the non-acutely operated patients was implemented prior to and following surgery, whereas the intervention of the acutely operated patients was implemented after surgery alone. The control group received regular health care services. Counseling and guidance contributed in positive terms to the frequency of alcohol use among non-acutely operated men and to the frequencies of exercise and functional ability among women. The intervention was also capable of having an effect on the exercise frequencies of elderly and acutely operated men. The present intervention did not have an effect on the body mass index, whereas it had barely a slight effect on the health status of the CAB patients. The findings of the intervention and generalizations resulting from them must be viewed critically because the data analysis utilized a multi-testing situation, many variables, and several subgroups. The study did not involve intention to treat analysis. Additionally, a loss of patients was great especially among the elderly and acutely operated patients.

Parental body condition does not correlate with offspring sex-ratio in Cory's shearwater

We analyzed offspring sex ratio variation in Mediterranean Cory's Shearwater (Calonectris d. diomedea) during two consecutive breeding seasons in two colonies. We test for differential breeding conditions between years and colonies looking at several breeding parameters and parental condition. We then explored the relationship between offspring sex ratio and parental condition and breeding parameters. This species is sexually dimorphic with males larger and heavier than females; consequently we expected differential parental cost in rearing sexes, or a greater sensitivity of male chicks to adverse conditions, which may lead to biased sex ratios. Chicks were sexed molecularly by the amplification of the CHD genes. Offspring sex ratio did not differ from parity, either at hatching or fledging, regardless of the colony or year. However, parental body condition and breeding parameters such as egg size and breeding success were different between years and colonies. Nevertheless, neither nestling mortality nor body condition at fledging varied between years or colonies, suggesting that male and female chicks were probably not differentially affected by variability in breeding conditions.