4. Family History of Early Atherosclerotic Cardiovascular Disease

INTRODUCTION

This section of the Guidelines provides recommendations to pediatric care providers on obtaining and using family histories for early cardiovascular (CV) disease (CVD) in managing CV health in their patients. The section begins with background information on the role of a positive family history of early atherosclerotic disease in evaluating risk for future heart disease. The evidence review and the development process for the Guidelines are outlined in Section I. Introduction and are described in detail in Appendix A. Methodology. As described, the evidence review augments a standard systematic review, where findings from the studies reviewed constitute the basis for recommendations, with each study described in detail. This evidence review combines a systematic review with an Expert Panel consensus process that incorporates and grades the quality of all relevant data based on preidentified criteria. Because of the large volume of included studies and the diverse nature of the evidence, the Expert Panel also provides a critical overview of the studies reviewed for each risk factor, highlighting those that, in its judgment, provide the most important information. Detailed information from every study has been extracted into the evidence tables, which will be available at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm. The conclusions of the evidence review are summarized and graded, and the section ends with the Expert Panel's age-specific family history recommendations. Where evidence is inadequate, recommendations reflect a consensus of the Expert Panel. References are listed sequentially at the end of the section, with references from the evidence review identified by unique PubMed identifier (PMID) numbers in bold text. Additional references do not include the PMID number.

BACKGROUND

A family history of CVD represents the net effect of shared genetic, biochemical, behavioral, and environmental components. In adults, epidemiologic studies have demonstrated that a family history of premature coronary heart disease in a first-degree relative—heart attack, treated angina, percutaneous coronary catheter interventional procedure,  or coronary artery bypass surgery, stroke or sudden cardiac death in a male parent or sibling before age 55 years or a female parent or sibling before age 65 years—is an important independent risk factor for future CVD. The process of atherosclerosis is complex and involves many genetic loci and multiple environmental and personal risk factors. Nonetheless, from a sentinel study in this area, the presence of a positive parental history doubled baseline risk for CVD.^[1]  Offspring risk was strongly inversely related to the age of the parent at the time of the index event. The association of a positive family history with increased CV risk has been confirmed for men, women, and siblings and for different racial and ethnic groups.^{[2],[3],[4],[5],[6],[7],[8]}

OVERVIEW OF THE EVIDENCE FOR IMPACT OF FAMILY HISTORY OF CARDIOVASCULAR DISEASE ON ATHEROSCLEROSIS IN CHILDREN AND ADOLESCENTS

In young subjects, autopsy findings and vascular function abnormalities have been correlated with a family history of premature coronary disease. In infants with a positive family history of early coronary disease, relative luminal narrowing has been demonstrated in the left and right coronary arteries at post mortem compared with infants without such a history.^[9] A series of vascular studies have demonstrated subclinical abnormalities:  Carotid intima-media thickness (cIMT) assessed by ultrasound has been shown to be increased in children, adolescents, and young adults with a parental history of myocardial infarction.^[10],[11] Endothelium-dependent dilation of the brachial artery (FMD) is impaired in young subjects with a family history of premature coronary heart disease.^[12]  In a combined study, cIMT was significantly increased and FMD was significantly reduced in young healthy teenagers whose parents had experienced a myocardial infarction compared with controls with a negative family history.^[13] Two generations of the Framingham Heart Study were evaluated for the presence of coronary artery and abdominal aortic calcification (AAC). A history of premature parental CVD and/or coronary artery disease (CAD) was significantly associated with the presence of coronary artery calcium in young- to middle-aged third-generation cohort subjects; AAC was associated only with parental coronary heart disease.^[14] Although it has not been shown how arterial wall changes early in life relate to adult clinical disease, the presence of both structural and functional abnormalities of arterial function, combined with the large body of epidemiologic data, supports the concept that a positive family history of early CAD is an important independent risk factor for accelerated atherosclerosis.

OVERVIEW OF THE EVIDENCE FOR ASSOCIATION OF FAMILY HISTORY OF CARDIOVASCULAR DISEASE WITH ABNORMAL CARDIOVASCULAR RISK PROFILES IN CHILDREN AND ADOLESCENTS

In addition to its strength as an independent risk factor, the presence of a positive family history is associated with an unfavorable CV risk profile in the family constellation. In offspring, a parental history of early CVD has been shown to be associated with an adverse CV risk factor profile.^[4]  The Muscatine Study and the Bogalusa Heart Study both demonstrate that a history of coronary heart disease in parents is associated with unfavorable CV risk profiles in their children. In the Muscatine Study, selecting children with total cholesterol (TC) above the 95th percentile, identified a family group with increased coronary mortality.^[15]  When index cases were children who were consistently obese on three successive Muscatine surveys, the relative risk of dying from a CV cause was significantly increased for family members compared with lean and random group relatives.^[16] From a cross-sectional analysis of more than 8,000 children in the Bogalusa study, offspring with a history of parental heart attack were significantly overweight after age 10 years and showed elevated levels of TC, low-density lipoprotein cholesterol (LDL–C), insulin, and glucose after age 17 years.^[17]  In a subsequent cohort study of children from the Bogalusa Study with a verified history of parental CAD, the adverse CV risk profile findings of the first study were confirmed:  A positive family history was associated with obesity beginning in early childhood and with elevations of TC and LDL–C as well as glucose.^[18]  The association of a positive family history with an unfavorable CV risk profile suggests that both familial environmental influences and gene-environment interactions may underlie the increased risk associated with a positive family history.

OVERVIEW OF THE EVIDENCE FOR FAMILY HISTORY OF CARDIOVASCULAR DISEASE AND RISK REDUCTION IN CHILDREN AND ADOLESCENTS

The evidence review identified two randomized controlled trials in which the presence of familial CVD was a selection criterion. In a Norwegian study, young first-degree relatives of subjects with verified premature CAD were randomized to either a combined smoking cessation and low-fat diet modification or to usual care.^[19] Outcome variables were smoking rates, lipid profiles, and a range of oxidative, inflammatory, and procoagulant markers. In the intervention group, there was a significant decrease in cholesterol and saturated fat intake with an associated decrease in LDL–C, oxidized LDL, and E-selectin, a vascular adhesion molecule. There was also a decrease in smoking in the intervention group, with an associated decrease in intercellular adhesion molecule-1. A second lifestyle intervention trial in Australian teenagers who were identified when a parent was hospitalized for treatment of angina or myocardial infarction showed minimal decreases in fat intake and serum cholesterol.^[20]

If family history information is to be used to infer risk for CVD, reported information must be accurate. Unfortunately, even in subjects from established epidemiologic studies, the accuracy of reported family history for heart disease is variable. From the Framingham Heart Study, offspring reports of parental CVD and CV risk factors were compared with confirmed medical evidence of parental CV status.^[21]  Positive reports of high blood pressure, diabetes, and high cholesterol were accurate for mothers and fathers. By contrast, positive predictive values for a history of parental heart attack and stroke were low. Although this is partially due to the low prevalence of early onset heart disease in the Framingham population, it also reflects lack of awareness of parental disease. Since the Framingham cohort could be considered to represent a "best-case scenario" for the accuracy of parental CV history, inaccuracy is likely to be even more prevalent in the general population. One role for pediatric health care providers is to educate parents and families about the importance of complete and accurate family health history information. Life circumstances, such as divorce and geographic separation, can make learning about a family history difficult. Although there is nothing that can be done about missing family history information in adopted individuals, encouraging young parents to learn their own health history whenever possible, even when families are fragmented and family members are separated, should help improve future knowledge about this important risk factor.

Conclusions and Grading of the Evidence Review for the Role of Family History in Cardiovascular Health

• Overwhelmingly consistent evidence from observational studies strongly supports inclusion of a positive family history of early coronary heart disease in identifying children at risk for accelerated atherosclerosis and for the presence of an abnormal risk profile (Grade B).
• For adults, a positive family history is defined as a parent and/or sibling with a history of treated angina, myocardial infarction, percutaneous coronary catheter interventional procedure, coronary artery bypass grafting, stroke or sudden cardiac death before age 55 years in men or age 65 years in women. Because the parents and siblings of children and adolescents are usually young themselves, it was the Expert Panel's consensus that when evaluating family history in a child, history should also be ascertained for the occurrence of CVD in grandparents, aunts, and uncles, although the evidence supporting this is insufficient to date (Grade D).
• Overwhelmingly consistent evidence from observational studies shows that identification of a positive family history for CVD and/or CV risk factors should lead to evaluation of all family members, especially parents, for CV risk factors (Grade B).
• Family history evolves as a child matures, so regular updates are necessary as part of routine pediatric care (Grade D).
• Education about the importance of accurate and complete family health information should be part of routine care for children and adolescents. As genetic sophistication increases, linking family history to specific genetic abnormalities will provide important new knowledge about the atherosclerotic process (Grade D).

Table 4–1. Evidence-Based Recommendations for Use of Family History in Cardiovascular Health Care

Grades reflect the findings of the evidence review.
Recommendation levels reflect the consensus opinion of the Expert Panel.
Supportive actions represent expert consensus suggestions from the Expert Panel provided to support implementation of the recommendations; they are not graded.

^a Parent, grandparent, aunt, uncle, or sibling with heart attack, treated angina, CABG/stent/angioplasty, stroke, or sudden cardiac death at < 55 y in males, < 65 y in females

Back to Top

Back to Table of Contents