4. Family History of Early Atherosclerotic Cardiovascular Disease
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.
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
relativeheart 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 yearsis 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.
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.,,,,,,
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. 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.,
Endothelium-dependent dilation of the brachial artery (FMD) is impaired in young
subjects with a family history of premature coronary heart disease.
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. 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. 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
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. 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. 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. 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 (LDLC), insulin,
and glucose after age 17 years.
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 LDLC as well as glucose.
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. 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 LDLC,
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.
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.
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
- 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 41. Evidence-Based Recommendations for Use of Family History in Cardiovascular
Grades reflect the findings of the evidence review.
Recommendation levels reflect the consensus opinion of the Expert
Supportive actions represent expert consensus suggestions from
the Expert Panel provided to support implementation of the recommendations; they
are not graded.
Take detailed family history (FHx) of CVDa
at initial encounter and/or at 3y, 9-11y & 18 y members
If (+) FHx identified, evaluate patient for other CV risk factors, including dyslipidemia,
hypertension, diabetes, obesity, history of smoking, and sedentary lifestyle
If (+) FHx and/or CV risk factors identified, evaluate family, especially parents,
for CV risk factors
Update FHx at each non-urgent health encounter
Use FHx to stratify risk for CVD risk as risk profile evolves
Educate parents about the importance of FHx in estimating future health risks for
all family members
Review FHx of heart disease with young adult patient
Educate patient about family/ personal risk for early heart disease including need
for evaluation for all CV risk factors
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
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