Working Group on Future Research Opportunities in the ARIC Study
Meeting Summary
July 1,
2008
TABLE
OF CONTENTS
Purpose of the Working Group
The
Working Group was charged with identifying future research
opportunities in the Atherosclerosis Risk in Communities (ARIC)
Study, based on scientific knowledge of the field and an
understanding of the research resource that ARIC has created.
Background of ARIC
Study
The
study was initiated in 1985 with two components: a community-based
surveillance and a prospective cohort. The community surveillance
has been monitoring trends in the incidence of coronary heart
disease (CHD) (1987-) and heart failure (2005-) in four
communities. The cohort study has been examining the etiology and
natural history of cardiovascular disease (CVD) in approximately
16,000 participants aged 45-64 years at baseline from the same
communities under surveillance. The participants received four
clinical exams over 9 years. Since 1998, the participants have
been followed only through annual telephone interview except for a
small proportion of participants enrolled in an ancillary study.
As of 2007, about 13,000 cohort members were still alive.
Draft Plan for Future
Research in ARIC Study
To
maximize the scientific potential in the ARIC study, the Project
Office is considering the possibility of another clinical exam on
the full cohort of remaining participants. The rationale for the
exam was discussed. The ARIC study is a valuable resource for CVD
and heart failure research because of its large cohort size,
biracial and community-based study population, and prevalent CVD
events and their risk factors.
Potential major aims
for the newly proposed clinical exam, which would focus on heart
failure, include: 1) Characterize phenotype and staging of heart
failure, by race and gender; 2) Identify risk markers, triggers,
and modifiers in the initiation and progression of heart failure
(stages A to D), by race and gender; and 3) Identify factors
related to outcomes of heart failure, by race and gender. Other
possible topic areas include diastolic dysfunction, subclinical
cardiovascular disease, physical functioning, renal function,
atrial fibrillation, and cognitive function.
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NHLBI Heart Failure
Research Profile
Dr.
Bild, Deputy Director of the DPPS, provided an overview of the
NHLBI heart failure research supported by two of the extramural
divisions. The Division of Cardiovascular Disease (DCVD) funded
several large studies, including the Specialized Centers of
Clinically Oriented Research (SCCOR), Clinical Heart Failure
Network, Treatment of Preserved Cardiac Function Heart Failure
with an Aldosterone Antagonist (TOPCAT), Interagency Registry for
Mechanically Assisted Circulatory Support (INTERMACS), and the
Surgical Treatment for Ischemic Heart Failure (STICH) Trial. The
studies funded by the Division of Prevention and Population
Sciences (DPPS) were reviewed, including the HF ACTION, Olmsted
County Study, and nine other large NHLBI cohort studies that are
closest in scope to ARIC.
NHLBI supports a broad
spectrum of research in heart failure. The coordination of
multiple research efforts, however, is a challenge. There is also
great opportunity in supporting complementary research programs.
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ARIC Investigators'
Presentations
The
ARIC study has accumulated extensive data on CVD risk factors and
subclinical measures for the cohort beginning from middle age.
Incident CVD-related events were collected through clinical exams
and annual contact before 1998, but since then have been
identified only through telephone interviews, with systematic
chart-review confirmation of coronary and stroke events and since
2005 of heart failure events. Self-reported data may not be
complete and reliable, especially for conditions such as
hypertension, diabetes, and renal function. The study has stored
biological specimens; one million SNPs and numerous candidate
genes are available for future research endeavors. A total of 79
ancillary studies have been funded, mainly by the National
Institute of Health (NIH). Some major contributions of the ARIC
study include: identification of carotid IMT as a subclinical
marker of atherosclerosis, identification of traditional and novel
risk markers and genetic variants for CHD, and development of
prediction equations for CHD and stroke in apparently healthy
individuals.
The investigation of heart failure events
occurring before and after 2005 was discussed. Incident heart
failure cases are identified by retrospective medical chart
review. Significant efforts are made to differentiate
decompensated heart failure from chronic stable heart failure.
Criteria used in ARIC for heart failure classification were
reviewed, including Framingham Heart Study, Boston, NHANES, and
Gothenburg criteria. As acknowledged by the investigators, it is
extremely difficult to fully characterize and capture heart
failure cases based on hospital data alone due to missing key
information, the shifts in the management of these patients to the
outpatient setting for care, and inconsistent diagnostic criteria
used in medical practice and epidemiology.
The cohort
retention rate remains high (90%). Information on heart failure
has been self-reported by the participants through the annual
telephone interview. The Gothenburg questionnaire was included in
the baseline survey and current interview questionnaire. Another
exam could identify individuals with asymptomatic heart failure
and clinical cases managed in outpatient settings, which would
provide opportunities to study the roles of behavioral, genomic
and medical care factors in a full range of heart failure
phenotypes and their associated outcomes. Another exam would also
provide opportunities to develop and calibrate simple tools to
study heart failure in the broader community-based setting,
including an assessment of its magnitude, risk factors, and
long-term outcomes. The ARIC participants are enthusiastic about
the additional and novel scientific information that would be
obtained from another participant exam.
ARIC has
genotyped the entire cohort for genome-wide association study
(GWAS) markers through multiple funding sources, and the study has
become a key component of multiple national and international GWAS
consortia. Future research plans include GWAS of target heart,
lung, and blood phenotypes, follow-up of GWAS to identify
candidate functional mutations, medical re-sequencing, study of
gene-environment interactions, and whole genome and transcriptome
sequencing. Another clinical exam is needed to update phenotype
information, obtain novel aging phenotypes, update informed
consent from participants, and study functional genomics.
A
grant proposal will be submitted to the NIH in the fall of 2008
for a large ancillary study on risk factors associated with
dementia and cognitive impairment in the ARIC cohort. The study
rationale and preliminary data were presented. The plan is to
bring the full cohort back for a brief clinical exam to identify
persons with impaired cognitive function, and then perform brain
MRI on the cases with impaired function and a control group
without the abnormality. If this study is funded, the efforts can
be leveraged with the contract study to enhance efficiency.
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Panel Discussions
Heat Failure Diagnosis and Screening
The
Working Group acknowledged that the diagnosis and classification
of heart failure has been an ongoing challenge to clinical and
epidemiological researchers working in the field. Heart failure
symptoms are not specific and often are not concordant with the
state of ventricular function. Also, patients move across heart
failure classes due to exacerbation and re-compensation. Heart
failure is of mixed etiologies in most hospitalized patients, even
with preserved systolic function or diastolic heart failure, due
to their associated co-morbidities. Although systolic heart
failure appears to be a model of chronic progressive pump failure,
it is unclear if diastolic heart failure is also a progressive
disorder. Research efforts could focus on one or both of two main
entities: preclinical heart failure (stages A and B) vs. heart
failure with clear clinical de-compensation. Three target groups
of interest for heart failure prevention research include: 1)
those without heart failure but with risk factors (stage A), for
whom there is a need to follow and identify precursors (biomarkers
and genetic markers), and 2) those with structural change (stage
B) who move in and out of symptomatic status and as a result are
difficult to identify.3) those with heart failure with preserved
systolic function
ARIC has captured heart failure
cases through community surveillance and follow-up of the original
cohort, and is a great source for studying the utility of various
diagnostic criteria and screening for symptomatic or asymptomatic
heart failure with left ventricular dysfunction. Because the study
has done considerable and high quality work on heart failure
classification, using all major sets of criteria and all
components of these sets, ARIC can provide information on which
elements of diagnostic criteria are most useful in the
classification of heart failure and components of this clinical
syndrome. With a gold standard (detailed phenotyping by imaging
and biomarkers) for comparison, ARIC may develop new approaches to
define heart failure for epidemiologic studies and genetic
research.
The panel recommended that in addition to
echocardiogram assessing systolic function, there should be a
detailed "diastology" echo including tissue Doppler. In
addition with new advances in echo technology, 2-D speckle
tracking echocardiography could be used to measure left
ventricular myocardial strain and strain rate. An echo core lab
would be needed to standardize the imaging procedure and the echo
measurements. The study could consider the measure of left atrial
volume index because it is easy to calculate from the 2-D echo
image and it reflects the severity and chronicity of heart
disease, as HbA1c is for chronic diabetes control. This could also
be obtained from previous echocardiograms to study its association
with clinical events. In terms of biomarkers, the results from the
Framingham Heart Study and Olmstead County study did not support
the value of brain natriuretic peptide (BNP) in screening, but
these studies may be underpowered. Screening for heart failure and
/or its precursors in the elderly may need some imaging modality,
and the ARIC study has many advantages in characterizing
asymptomatic participants and clarifying this issue.
Having
only one detailed assessment of ventricular structure and function
is a limitation for studying disease progression, but should have
significant value in describing the burden of asymptomatic and
symptomatic patients, defining staging of heart failure in a
community-based population, and establishing a baseline for
follow-up. The study could go back to 1987 baseline data and use
genetic and biomarker analyses to advance our present
understanding of the progression of heart failure.
It
would be useful to obtain more proximate measures for diastolic
dysfunction because we do not have a good understanding of this
condition, and therefore cannot effectively manage diastolic
dysfunction as well as we do systolic dysfunction. Renal function
decline, diabetes, and vascular stiffness have all been associated
with diastolic dysfunction, but efforts should be made to
understand the interactions of these and other conditions in
relation to measures of diastolic dysfunction. There may be a need
to pool data from several large cohort studies to obtain enough
patients with mild dysfunction to better describe the phenotype of
preclinical diastolic dysfunction and develop strategies for
prevention and treatment.
The ARIC study could use
electronic medical records to find out in real time whether
participants are hospitalized with de-compensated heart failure
and phenotype them during that hospitalization -- that is, to do a
more active and prospective surveillance. This would also set the
stage for carrying out studies for the triggers, or precipitating
factors, of acute heart failure that is described in the following
section. In the Framingham Heart Study, study staff visits the
participants with acute stroke in the hospital to collect data.
Although this would be very valuable, it would require
considerable effort and expense.
Etiology and Prevention of Heart Failure
Determining
heart failure etiology is important, but assigning etiology can be
very problematic. There is a need to carefully assess medical
history, including drugs and cardiotoxicity, to integrate with
functional history. Family history is also important, but its
reliability is poor. It would be helpful to obtain a structural
etiology as well, which is a further rationale for a repeated exam
and re-phenotyping the remaining cohort. The study could better
define etiologies of heart failure and if possible, collect
detailed information on catheterization and nuclear medicine for
complete phenotyping of these participants.
Although
it is known that hypertension and CAD account for two-thirds of
heart failure cases, most patients with these conditions do not
develop heart failure; therefore, it is important to know what
characteristics determine different rates of progression of this
clinical syndrome and to understand mechanisms behind the
differences. ARIC has the opportunity to understand triggers of
clinical heart failure and how stage A and B patients respond to
environmental exposures or drugs. Currently there is not enough
evidence for treating asymptomatic patients with left ventricular
dysfunction but without a history of MI. Information obtained from
this research can inform physicians how to more effectively manage
these potentially high risk patients, for example, those with a
borderline low ejection fraction.
The panel emphasized
the importance of identifying triggers and precipitating factors
for decompensated heart failure. The possibility of identifying
triggers and precipitating factors through "warm"
(active pursuit) surveillance, even at a selected set of
hospitals, was discussed. ARIC could collect additional data from
those hospitalized, for example, with heart failure and other
acute potential contributory causes including infection,
arrhythmias, physical activity, dietary indiscretion, stress, and
medical non-compliance. Use of a case-crossover design to explore
these associations could be adopted with the use of both in-person
interviews and review of hospital charts. ARIC may also consider
collecting metabolic triggers such as changes in renal function
and troponin leaks below the threshold for acute MI.
The
panel discussed the need to have a study focusing on taking heart
failure genomics as a starting point. Those genetically at risk
may be selected and then followed prospectively. ARIC would be a
set-up for this potential "next big study." However,
such a study would need to have a well-defined phenotype in order
to conduct the best genetic investigations, and so far this does
not exist for heart failure. Efforts are needed to explore the
data to determine which measurements are of value to best
phenotype heart failure. Another exam in the ARIC study could help
improve the phenotype by looking at outcomes and identifying
biomarkers that predict them. The ARIC study has enough DNA to do
full-genome sequencing in most participants. Another exam would
collect new material to replenish DNA supply, save more serum and
plasma, and store material to study the transcriptome. ARIC is an
excellent resource for heart failure genetic research, and the
study is encouraged to collect data that will allow pooling with
other cohorts to improve power for such research.
It
would be worthwhile to compare ARIC and the Cardiovascular Health
Study (CHS) results in heart failure, since the etiology of heart
failure at the same age may differ by birth cohort. For example,
there may be differences in earlier life exposures and treatments,
such as vaccinations, blood pressure control, and use of statins
between CHS and ARIC cohort participants. A younger population
would have been exposed to anti-hypertensives and statins much
longer at the same age than that in CHS. Therefore, heart failure
etiologies and patterns of cardiac dysfunction in ARIC may differ
from those in CHS. The results from ARIC and CHS could be compared
to assess the impact of factors differing between birth cohorts on
heart failure etiology.
ARIC includes a large
proportion of African Americans, which is one of its major
strengths for heart failure research. Thirteen years have passed
since the last clinical exam, and it is important to determine
changes in predisposing factors in the interim, including blood
pressure, lifestyle, dietary intake, psychosocial, and behavioral
factors. Currently, technological advances allow web-based food
frequency questionnaires to be done by phone to assess dietary
intakes. It is important to re-measure physical activity
(objectively if possible), which is important in regulating
autonomic tone. A good physical activity measure with actigraphy
and maybe a 6-minute walk would be much better than a physical
activity questionnaire. Obtaining fitness measures would also be
of interest for a baseline before onset of sarcopenia and frailty.
The study may consider including measures of arterial stiffness
and the treadmill test to look for hyper-reactive blood pressure
response to exercise.
The ARIC study also has
opportunities to understand more about the prevalence of atrial
fibrillation and its association with heart failure development.
For example, the study can examine predisposing factors and
prognostic implications of heart failure preceding atrial
fibrillation or the converse situation. The panel recommended the
report from the recent NHLBI Working Group on atrial fibrillation
regarding the value of inception cohorts and high-risk groups for
primary prevention.
Outcomes Research in Heart Failure
It
is important to collect and adjust for quality of care and patient
compliance measures in studying factors associated with clinical
outcomes in population based studies. For example, how well are
the participants getting integrated care for the spectrum of
geriatric syndromes? ARIC should take advantage of merges with
Medicare, as has been done in the CHS. The study could also link
data with pharmacy databases for more accurate data on medication
use and timing, or to ramp up data collection during periods of
illness. Although it will be difficult to obtain all of the
desired time-sensitive detail necessary to address this, the study
could obtain information by thinking creatively and ramping up
active surveillance.
Diastolic heart failure, as well as
diastolic ventricular dysfunction without flagrant heart failure,
are often not identifiable from discharge codes, so the study
needs to carefully review medical records for these events. For
example, the study could review records of people hospitalized for
other causes such as pneumonia to determine if diastolic heart
failure is in the clinical pathway as a contributor of cause of
death.
ARIC may find ways to involve the physician
community to obtain data on heart failure management and to see if
clinicians agree with ARIC diagnoses for their patients.
Additionally, the study may follow up participants with
significant results to determine if the results reporting changes
physicians' management on heart failure. For example, what happens
to participants with a systolic blood pressure of 140-160? How are
they being treated? Are they avoiding events? Does participation
in ARIC benefit them?
The panel also suggested that
the study obtain information on care-seeking behavior in the
setting of acute heart failure and examine facilitators and
barriers to seeking medical care in a timely manner. The study
could ask participants simple questions about barriers to
accessing health care and acquiring medications. Questions about
time to treatment for heart failure could be included as well by
looking at time from onset of acute and/or premonitory symptoms to
presentation for care. Similar information would also be important
to collect for the ARIC dementia study. Some of the study
components can be studied in particular demographic or clinical
subgroups if interest.
Depression may be a risk factor
for the development of heart failure, which has not been well
demonstrated because the appropriate longitudinal study has not
been done. The ARIC study is ideally suited for testing this
hypothesis. A measure of depressive symptoms could be added to the
assessment. The ARIC study also may consider assessing the impact
of anxiety on the CVD outcomes.
Other Topic Areas
As
the cohort has transitioned from middle age to old age, ARIC
should now focus on studying triggers of events and determining
correlates in progression of subclinical to clinical events. In
both ARIC and CHS studies, a small group of participants had
clinical exams within 30 days before events, which may provide
opportunities for further investigation.
The panel
indicated that healthy aging could be assessed in the context of
heart failure, obesity, or in general. Sample questions include:
What does healthy aging mean to the cohort? How can we define it?
How would participants define it? What kind of bio-repository
would be needed for the future to investigate this and other
research questions?
The panel pointed out that that
there is a controversy whether diastolic heart failure is a
distinct entity or other factors such as vascular stiffness and
neurohormonal may influence it . It is important to consider
vascular aging as well as assess kidney and brain vascular beds.
Vascular stiffness is strongly correlated with other factors. This
could be a unifying theme for the exam. The panel suggested that
the study use a vascular stiffness approach rather than a dementia
approach to identify dementia cases and do case-control MRIs. The
exam should include determinations of cystatin C,
microalbuminuria, and body composition. It is necessary to have
less of an organ approach and more of a system approach to look at
aging in the vascular beds. There may be a global phenotype of
vascular aging that has not yet been identified. Visceral fat and
metabolic changes with increasing inflammation might be a major
part of the system.
The ARIC study can also better
characterize correlates of body composition to answer several
research questions. Does overweight at this age have health
implications, does it matter what people weighed in middle age,
and should people be pressured to lose weight or is being
overweight protective in this group? This issue has remained
unclear. Since obesity comprises 65-70% of all heart failure
patients in some studies, data are needed to help clarify
guidelines in this area. The Health ABC study showed large body
composition differences by race, and therefore body composition
measures by computed tomography (CT) scan are very important.
Characterizing cardiac sarcopenia and fatty infiltration could
also be pursued.
The panel emphasized the value of
research in improving clinical practice and public health. The
importance of translation of knowledge from epidemiologic studies
to actual clinical practice was discussed. The panel recommended
that the NHLBI make efforts to complement research activities in
ARIC with those in its other programs and speed up the process to
make it more informative for clinical practice and prevention
programs.
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Recommendations and
Priorities
The
Working Group acknowledged that the ARIC study is a valuable
resource for research on the progression of subclinical to
clinical cardiovascular disease and heart failure. The group
endorsed the major topic areas as presented for the next possible
exam in ARIC, including heart failure diagnosis and screening,
triggers and modifiers in heart failure development, and outcomes
associated with heart failure. The Working Group provided the
following recommendations and priorities for future research in
the ARIC study, especially in a possible clinical examination.
For the cohort study, an exam is needed to:
Characterize
phenotype and staging of heart failure by echocardiography and
biomarkers, and develop novel criteria for heart failure
diagnosis and screening in the community-based population. The
exam needs to be straightforward and reproducible across all four
field centers. A core lab is needed for an echocardiography
component. The study may consider cardiac MRI for structure and
function in a subset for better data quality and reproducibility.
Consider
alternative study designs, for example, splitting the
participants into 3 groups: one group receiving echocardiogram to
delineate antecedents of left ventricular systolic and diastolic
dysfunction and their associations with prior and subsequent
heart failure; the second group receiving a stress test to
measure blood pressure, heart rate, physical fitness, and ECG
responses to exercise; and the third for both to examine the
relation between direct cardiac measures and exercise findings.
Identify
risk markers, triggers, and precipitating factors in progression
of heart failure (stages A to D), including ventricular and
vascular stiffness; interplay of renal insufficiency, diabetes,
ambulatory blood pressure, and atrial fibrillation; infection;
genomics, proteomic, and metabolic determinants; quality of care
and patient compliance; physical activity, nutrition,
psychological distress, and cognition.
Determine
the contributions of ventricular and vascular stiffness,
diabetes, and renal insufficiency, and their interactions, to the
initiation and progression of diastolic heart failure.
Study
healthy aging in a systematic approach to develop a global
phenotype of vascular aging and to assess visceral fat and
metabolic changes with increasing inflammation.
Examine
the impact of body composition and body weight changes from
middle to old age on the progression and development of heart
failure.
Follow
up participants with significant clinical results from the exam
to assess the impact of results reporting on physicians'
management of heart failure and outcomes.
Suggested
exam components:
Echocardiography
(LV systolic function/mass, tissue Doppler and speckle tracking)
Pulse
wave velocity and central aortic pressure
Anthropometry
6-minute
walk test or treadmill stress test
Ambulatory
blood pressure monitoring
Electrocardiogram
and Holter monitor
BNP,
NT-pro-BNP, Cystatin-C, microalbuminuria
CT
for body composition
Medical
history and medication use
Life
style, diet, depression, and psychosocial factors
Activities
of daily living and quality of life measures
Cognitive
function assessment
For
Community Surveillance:
More
actively characterize cause of death
Include
heart failure management questions, self care attitudes and
practices
Attempt
to speed up the data collection process
Regularly
release the surveillance results in web-based reports rather than
in papers published on an irregular basis
Consider
active surveillance if considering a trigger-type study
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Working Group Members
Robert
Goldberg (Chair); John C Burnett, Richard Devereaux, Emily Harris,
Ray Hershberger, Allan L.Klein, Harlan Krumholz, Terry Lennie,
Donald Lloyd-Jones, Anne Newman, Vasan Ramachandran
NHLBI Staff
Diane
Bild, Kristie Cooper, Michael Lauer, Cheryl Nelson, Hanyu Ni, Jean
Olson, Alice Mascette, Mona Pandey, Phyliss Sholinsky, Lorraine
Silsbee, Paul Sorlie, Gina Wei
ARIC Investigators
Eric
Boerwinkle, Patricia Chang, Lloyd Chambless, Josef Coresh, Aaron
Folsom, Gerardo Heiss, Tom Mosley, Wayne Rosamond, Richey Sharrett
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