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Original Contribution |

Progression of Left Ventricular Diastolic Dysfunction and Risk of Heart Failure FREE

Garvan C. Kane, MD, PhD; Barry L. Karon, MD; Douglas W. Mahoney, MS; Margaret M. Redfield, MD; Veronique L. Roger, MD, MPH; John C. Burnett, MD; Steven J. Jacobsen, MD, PhD; Richard J. Rodeheffer, MD
[+] Author Affiliations

Author Affiliations: Division of Cardiovascular Diseases, Departments of Internal Medicine (Drs Kane, Karon, Redfield, Roger, Burnett, and Rodeheffer) and Health Science Research (Mr Mahoney and Dr Roger), Mayo Clinic and Medical School, Rochester, Minnesota; and Department of Preventive Medicine, University of Southern California Keck School of Medicine and Southern California Permanente Medical Group, Los Angeles (Dr Jacobson).


JAMA. 2011;306(8):856-863. doi:10.1001/jama.2011.1201.
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Published online

Context Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations.

Objective To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure.

Design, Setting, and Participants Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N = 2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 [1997-2000]). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 (2001-2004). The cohort of participants returning for examination 2 (n = 1402 of 1960 surviving [72%]) then underwent follow-up for ascertainment of new-onset heart failure (2004-2010).

Main Outcome Measures Change in diastolic function grade and incident heart failure.

Results During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval [CI], 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 [95% CI, 1.77-4.72]). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P < .001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 [95% CI, 1.01-3.48]).

Conclusions In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up.

Figures in this Article

Heart failure is a progressive condition that increases in incidence with advancing age.110 There is an emerging emphasis on understanding the progression from heart failure risk factors to asymptomatic ventricular dysfunction and eventually to symptomatic heart failure and death.6,7 Therefore, it is important to have population-based information on changes in cardiac function over time.

Heart failure may develop with reduced or preserved left ventricular ejection fraction (LVEF), each form accounting for approximately half of cases.4,7,1015 Echocardiographic classification of diastolic function in cross-sectional community studies has shown diastolic dysfunction to be highly prevalent and associated with heart failure.1114 However, little is known about time-dependent changes in diastolic function or their relationship to clinical heart failure.

We randomly selected a cohort of 2042 persons 45 years or older, the Olmsted County Heart Function Study (OCHFS).11 A cross-sectional evaluation of diastolic function in examination 1 (1997-2000) has been reported.11 We report now a reevaluation of this cohort, examination 2 (2001-2004). After examination 2, the cohort was followed passively and incident heart failure events ascertained (2004-2010). The objectives were to measure changes in diastolic function over time, to identify factors predictive of change in diastolic function, and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure.

The institutional review boards of Mayo Clinic and Olmsted Medical Center approved this study. Participants provided written informed consent for evaluation and medical record follow-up.

Participants

In 2000 the population of Olmsted County, Minnesota, was 112 255; 90% were white, 81% urban, and 11% 65 years or older. Characteristics of this community and its use in population-based research (the Rochester Epidemiology Project) have been described.16

In 1997 a random sample of county residents 45 years or older was identified by applying a sampling fraction of 7% within each sex- and age-specific (5 years) stratum. Of the 4203 persons invited, 2042 participated in examination 1. A comparison of invited participants and nonparticipants was performed.17 Examination 1 (1997-2000) included physical examination, echocardiography, and medical record abstraction. Four years later, all participants were invited to return, and 1402 participated in examination 2 (2001-2004). All data collected at examination 1 were recollected at examination 2. Incident heart failure between examinations 1 and 2 was diagnosed by the Framingham criteria.2,11 Diabetes was based on physician diagnosis and treatment. Myocardial infarction and hypertension were diagnosed according to criteria from the World Health Organization and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, respectively.11,18

After examination 2, long-term surveillance for incident heart failure was accomplished by methodology previously validated in Olmsted County.9 From examination 2 to November 2010, incident heart failure was identified using code 428 from the International Classification of Diseases, Ninth Revision, Clinical Modification, which identifies 90% of Framingham criteria–validated cases.9 Codes were assigned by trained coders according to physician diagnoses in outpatient and inpatient records (not by hospital billing records).

Healthy Subgroup

At examination 1, a subset of participants was identified without heart failure, hypertension, coronary artery disease, diabetes, or use of cardiovascular medications.

Echocardiograms

Ejection fraction was measured by quantitative 2-dimensional echocardiography, as previously reported.11 Systolic dysfunction was defined as LVEF less than 50%. Decreased LVEF was defined as a decrease of more than 7.5% (ie, 1-SD decrease).

Diastolic function was assessed by pulse-wave Doppler examination of mitral flow (before and during Valsalva maneuver), pulmonary venous flow, and Doppler imaging of the medial mitral annulus.11,19,20 Diastolic dysfunction was graded on a 4-point ordinal scale: (1) normal; (2) mild diastolic dysfunction (abnormal relaxation without increased left ventricular end-diastolic filling pressure [decreased ratio of early to late ventricular filling velocity {E:A ratio} <0.75]); (3) moderate or “pseudonormal” diastolic dysfunction (abnormal relaxation with increased left ventricular end-diastolic filling pressure [E:A ratio of 0.75-1.5 and deceleration time >140 ms, plus 2 other Doppler indices of elevated end-diastolic filling pressure]); (4) or severe diastolic dysfunction (advanced reduction in compliance [ie, markedly increased stiffness], with restrictive filling [E:A ratio >1.5 and deceleration time <140 ms, plus Doppler indices of elevated left ventricular end-diastolic filling pressure]).

For participants with atrial fibrillation, diastolic function was classified as indeterminate unless restrictive physiology (E:A ratio >1.5, deceleration time <140 ms) was present. Valvular heart disease was assigned for moderate to severe echocardiographic valvular stenosis or regurgitation.

Echocardiogram Reading Agreement

Echocardiograms at examinations 1 and 2 were performed by the same 3 echocardiographers according to standardized protocols and reviewed by an echocardiologist (B.L.K., M.M.R.).11 Echocardiographers and echocardiologists were masked to clinical and examination 1 echocardiogram findings. Interreader agreement was assessed for the echocardiologists, who independently reviewed sets of echocardiograms chosen to represent a range of ventricular function, and was comparable.

Nonreturning Participants

To assess for examination 2 participation bias, characteristics of examination 1 participants who returned for examination 2 were compared with those who did not.

Statistical Analysis

Comparisons between categorical variables at examinations 1 and 2 were made using the McNemar test; continuous variables were compared using the Wilcoxon signed-rank test. Ordinal logistic regression was used to adjust the association of clinical variables with the progression of diastolic dysfunction for age and sex. Cox proportional hazards regression models were used to identify factors associated with incident heart failure after examination 2.

Models were developed using stepwise techniques with consideration of clinically relevant variables having P < .10 by univariate analysis: age, sex, hypertension, diabetes, coronary disease, incident myocardial infarction, LVEF, diastolic dysfunction, left atrial volume index, and ratio of mitral peak velocity of early filling to medial mitral annular tissue velocity (E:e′). For persons with incomplete data, additional categorical variables (test performed, test not performed) were included.

Time-varying effects of covariates were assessed using 2 models: the first censored all participants at the median event time (3.5 years), and the second involved only those at risk beyond 3.5 years. Long-term follow-up is based on the Kaplan-Meier product-limit method and compared between groups using the log-rank test.

Analyses were performed using SAS versions 8.0 and 9.2 and JMP version 8.0 (SAS Institute Inc, Cary, North Carolina). Analyses were 2-sided; P < .05 was used to indicate statistical significance.

Cohort Characteristics

Of the 4203 eligible Olmsted County residents invited to participate in examination 1, 2042 (49%) participated. Analysis of potential participation bias in examination 1 has been reported in 500 randomly selected participants and 500 nonparticipants; there was no significant difference in the prevalence of cardiovascular disease.17 Cross-sectional analyses of examination 1 participants have been reported.7,11,1925 Eighty-two examination 1 participants died before examination 2, and 1402 of the 1960 surviving examination 1 participants (72%) returned for examination 2. These 1402 participants are the focus of the present analysis. (Figure 1)

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Figure 1. Study Flow
Graphic Jump Location

The mean age of the 1402 study participants at examination 1 was 61 (SD, 9.5) years, with 34.1% 65 years or older. Examination 2 was performed 4.0 (SD, 0.3) years after examination 1, by which time 46.9% of participants were 65 years or older. At examination 2 there was an increase in the prevalence of comorbid conditions: hypertension increased from 25.8% (361/1402) to 42.4% (594/1402) (P < .001), diabetes from 6.3% (88/1402) to 10.3% (145/1402) (P < .001), and heart failure from 1.1% (16/1402) to 2.2% (31/1402) (P = .03). Despite the increased number of participants fulfilling diagnostic criteria for hypertension, mean systolic blood pressure decreased from 130.7 (SD, 19.8) mm Hg at examination 1 to 126.0 (SD, 19.1) mm Hg at examination 2 (P < .001). Concomitantly, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers increased from 8.7% (123/1402) to 17.9% (251/1402) (P < .001) and use of β-blockers from 13.6% (190/1402) to 21.6% (303/1402) (P < .001).

Changes in Diastolic Function

Diastolic function grade could be assigned in 1058 of 1402 participants (75.5%) at both examinations 1 and 2. At examination 2, diastolic dysfunction was present but not gradable in 112 persons, and diastolic function could not be measured in 139 persons because of arrhythmia or incomplete echocardiographic data (Table 1).

Table Graphic Jump LocationTable 1. Clinical and Echocardiographic Characteristics of Participants (N = 1402)

From examination 1 to examination 2, the prevalence of diastolic dysfunction of any degree increased from 23.8% (95% confidence interval [CI], 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Moderate or severe diastolic dysfunction increased from 6.4% (95% CI, 4.9%-7.9%) to 16.0% (95% CI, 13.7%-18.2%) (P < .001).

Within-individual changes are depicted in Table 2. Over 4 years, 23.4% (95% CI, 20.9%-26.0%) of participants experienced worsening of diastolic function, 67.8% (95% CI, 64.8%-70.6%) remained unchanged, and 8.8% (95% CI, 7.1%-10.5%) experienced improved diastolic function. Elevated ventricular filling pressure (E:e′ ratio ≥10) increased from 30.6% (95% CI, 27.9%-33.6%) to 57.2% (95% CI, 54.6%-139.3%) (P < .001).

Table Graphic Jump LocationTable 2. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in All Participantsa
Factors Predictive of Worsening Diastolic Function

Age was predictive of the development of diastolic dysfunction, especially ages 65 years or older (odds ratio [OR], 2.85 [95% CI, 1.77-4.72]), as was E:e′ ratio at examination 1 (OR, 1.14 [95% CI, 1.06-1.23]) (Table 3).

Table Graphic Jump LocationTable 3. Factors Predictive of the Development of Diastolic Dysfunction From Examination 1 to Examination 2a
Diastolic Function in Healthy Participants

Five hundred thirty-one participants were without hypertension, diabetes, coronary artery disease, heart failure, or use of cardiovascular medications. Incidence of diastolic dysfunction of any degree increased from 11.3% (60/531 [95% CI, 8.6%-14.0%]) at examination 1 to 29.8% (158/531 [95% CI, 25.9%-33.7%]) at examination 2 (P < .001) (eTable). In 423 of the 531 healthy participants (79.7%), diastolic function grade could be classified at both examinations. Among 423 healthy participants, 84 (19.9% [95% CI, 16.0%-23.7%]) showed worsening diastolic function, 318 (75.2% [95% CI, 70.8%-79.1%]) remained the same, and 21 (5.0% [95% CI, 2.9%-7.0%]) improved (Table 4). Consistent with these findings, prevalence of elevated ventricular filling pressure (E:e′ ratio ≥10) increased from 17.9% (95/531 [95% CI, 14.6%-21.2%]) to 45.0% (239/531 [95% CI, 40.8%-49.3%]) (P < .001) (eTable).

Table Graphic Jump LocationTable 4. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in 423 (of 531) Healthy Participants Whose Diastolic Function Grade Could Be Classified at Both Examinations
Change in Systolic Function

Ejection fraction could be measured using 2-dimensional echocardiography in 947 of 1402 participants (67.5%) at both examinations. Within-individual decrease in LVEF, defined as a decrease of more than 7.5% (ie, >1 SD), occurred in 76 of 947 participants in whom LVEF could be measured (8.0%). However, LVEF less than 50% was unchanged in 24 of 1402 participants (2.3%) at examination 1 and 23 of 1402 (2.4%) at examination 2 (Table 1).

Incident Heart Failure Between Examination 1 and Examination 2

Among participants without heart failure at examination 1, Framingham criteria heart failure developed by examination 2 in 12 of 1386 participants (0.9%). Among these, 83% (5/6 with gradable diastolic function) had diastolic dysfunction at examination 1, compared with 24% (310/1289) who did not develop heart failure between examinations (P < .001). Consistent with this observation, left atrial volume index was greater in participants with heart failure (36 [SD, 12.9] cc/m2) vs those without heart failure (24 [SD, 6.8] cc/m2) (OR, 1.73 [95% CI, 1.12-2.70]).

None of the 12 participants with incident heart failure had LVEFs less than 50% at examination 1, and only 1 had an LVEF less than 50% at examination 2. Medical record abstraction revealed that 4 of the 12 participants experienced a transient decrease in LVEF to less than 50% when clinically symptomatic, only to recover normal LVEF by examination 2. Causes of these transient systolic heart failure events were uncontrolled hypertension (n = 2), rapid atrial fibrillation (n = 1), and apical ballooning syndrome (n = 1). The 1 participant with incident heart failure whose LVEF was less than 50% at examination 2 had sustained a myocardial infarction.

Heart Failure Surveillance After Examination 2

Surveillance after examination 2 identified both new inpatient and outpatient heart failure diagnoses. During 6.3 (SD, 2.3) years of additional follow-up, 81 participants developed heart failure. Age 65 years or older was the most potent predictor of heart failure (hazard ratio [HR], 8.38 [95% CI, 4.4-16.0]) (Table 5). Multivariable analysis demonstrated the independent predictive power of diastolic dysfunction (HR, 1.81 [95% CI, 1.01-3.48]), hypertension (HR, 2.21 [95% CI, 1.32-3.84]), diabetes (HR, 1.77 [95% CI, 1.0-3.01]), and coronary artery disease (HR, 2.07 [95% CI, 1.27-3.32]).

Table Graphic Jump LocationTable 5. Baseline Factors Predictive of the Development of Incident Heart Failure After Examination 2

Persistent or worsening diastolic dysfunction was associated with heart failure (Figure 2). Cumulative heart failure incidence was 2.6% (95% CI, 1.4%-3.8%) in participants whose diastolic function remained normal or normalized between examinations; 7.8% (95% CI, 5.8%-13.0%) in those with persistent, or progression to, mild diastolic dysfunction; and 12.2% (95% CI, 8.5%-18.4%) in those with persistent, or progression to, moderate or severe diastolic dysfunction (P < .001).

Place holder to copy figure label and caption
Figure 2. Cumulative Incidence of Heart Failure After Examination 2
Graphic Jump Location

Groups represent 3 grades of severity and change in diastolic dysfunction from examination 1 and examination 2. Persons with heart failure at examination 2 and those in whom diastolic function could not be classified at both examinations 1 and 2 are excluded, leaving 1047 persons at risk after examination 2.

Time-varying effects of covariates were examined using Cox models before and after the median event time of 3.5 years. In the initial 3.5 years after examination 2, age, hypertension, diabetes, coronary artery disease, diastolic dysfunction, left atrial volume index, and E:e′ ratio were associated with increased heart failure risk. In persons still at risk past 3.5 years, the effects of diabetes and E:e′ ratio disappeared.

Potential for Participation Bias at Examination 2

Among 2042 examination 1 participants, 82 died before examination 2; of the 1960 surviving participants, 1402 (71.5%) returned for examination 2. Survivors who did not return were older (66.3 [SD, 12] vs 61.1 [SD, 10] years, P < .001) and had a higher prevalence of comorbid conditions at examination 1 (hypertension, 33.4% vs 24.5% [P < .001]; diabetes mellitus, 9.8% vs 6.3% [P = .004]; prior myocardial infarction, 7.8% vs 2.1% [P < .001]; heart failure, 4.5% vs 1.1% [P < .001]). Diastolic dysfunction was more prevalent among nonreturning than returning participants (41.1% vs 25.1%, P < .001), as was LVEF of 50% or less (8.9% vs 2.4%, P < .001). Mortality follow-up demonstrated better survival for returning than for nonreturning participants (98% vs 96%, respectively, at 1 year; 96% vs 91% at 3 years; and 90% vs 86% at 5 years). Nonreturning participants experienced greater mortality risk (HR, 4.0 [95% CI, 2.9-5.4]; P < .001).

Our initial report from the OCHFS cohort provided cross-sectional estimates of left ventricular dysfunction prevalence in the community and characterized the relationship between ventricular dysfunction and clinical status.11 This report adds a longitudinal “change within individual” dimension to left ventricular function measurements and clinical status.

There was a marked progression of diastolic dysfunction: 23% of participants showed worse diastolic function, 68% were unchanged, and 9% improved. A similar pattern of worsening diastolic function also was observed in a subset of healthy participants. Incident heart failure during 6.3 (SD, 2.3) years of follow-up was associated with age, hypertension, diabetes, coronary artery disease, and diastolic dysfunction. Persistent or worsening diastolic dysfunction between examinations 1 and 2 was an independent risk factor for subsequent heart failure.

Temporal Change in Left Ventricular Diastolic Function

Community population studies report that approximately half of patients with heart failure have preserved LVEF.11,15 Heart failure, with or without reduced LVEF, is marked by recurrent hospitalizations and 5-year mortality of 30% to 35%.9,10 Echocardiographic measurements of diastolic function in population-based cohorts show that approximately 7% of persons older than 45 years have moderate to severe diastolic dysfunction, most of whom report few, if any, symptoms.11,13

The current longitudinal data confirm and extend the cross-sectional association reported between age and diastolic dysfunction: over a 4-year interval, middle-aged and elderly persons were 3 times more likely to manifest poorer diastolic function than better diastolic function.1114 That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges.

The biological pathways leading to heart failure with preserved LVEF are manifold, and understanding its pathophysiology remains a work in progress. Contributing factors include changes in myocardial relaxation and elastic recoil, changes in ventricular load and diastolic stiffness, external constraint, and abnormal systolic function.2636 Age-related loss of peripheral vascular elasticity, and its effect on left ventricular load and stiffness, may play an important role in this process.20,3742 Measurements of the interaction between left ventricular function and vascular load suggest that ventriculovascular coupling may play a role in the development of the diastolic dysfunction component of heart failure with preserved LVEF.30,31,3335,37 Indeed, previous cross-sectional analyses from this OCHFS cohort have shown significant correlations between age and vascular, ventricular end-systolic, and ventricular end-diastolic stiffness.20

Incident Heart Failure

Surveillance studies of the entire Olmsted County population from 1987-2001 (100 000-125 000 persons) have documented a constant incidence of heart failure with reduced LVEF but an increase in heart failure with preserved LVEF.15 The current analysis identifies diastolic dysfunction as an independent predictor of these heart failure events.

However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during long-term follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF. Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons.20,3537 The assessment of the few heart failure events between examinations 1 and 2 suggests some of these superimposed cardiovascular disease processes. An important clinical implication may be that prevention of risk factors for superimposed events, especially hypertension, might be fundamental to reducing heart failure with preserved LVEF.

Study Strengths and Weaknesses

Strengths of this study include its population-based randomly selected cohort, the ability to make protocolized serial observations for research purposes, the opportunity to examine interval clinical events in the cohort, and the ability to collect data on nonreturning participants. Study participants underwent a uniform evaluation at examinations 1 and 2 using the same measurement methods. An additional strength is the ability to ascertain both inpatient and outpatient heart failure diagnoses during long-term follow-up using a validated International Classification of Diseases, Ninth Revision, Clinical Modification code methodology.

Several weaknesses warrant discussion. Comparison of participants who returned for examination 2 with those who did not return indicates that nonreturning participants had more baseline hypertension, diabetes, myocardial infarction, heart failure, and diastolic dysfunction as well as increased subsequent mortality. Therefore, the worsening diastolic dysfunction we report in returning participants may underestimate that finding in the whole cohort. Survival bias and participation bias may contribute to underestimation of the overall effect of diastolic dysfunction on heart failure in the cohort. The use of medical records for ascertainment of clinical outcomes has been used successfully in this population. However, some degree of misclassification could underestimate the strength of the observed associations. Last, our cohort was more than 95% white, so generalizability to other ethnic or racial populations may not be valid.

Longitudinal evaluation of participants in the population-based OCHFS cohort reveals that left ventricular diastolic dysfunction is highly prevalent, tends to worsen over time, and is associated with advancing age. Worsening diastolic function can be detected even in apparently healthy persons. Although confirmation in other studies would be helpful, our data suggest that persistence or progression of diastolic dysfunction is a risk factor for heart failure in elderly persons.

Corresponding Author: Richard J. Rodeheffer, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (rodeheffer.richard@mayo.edu).

Author Contributions: Drs Kane, Mahoney, and Rodeheffer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kane, Mahoney, Redfield, Roger, Jacobsen, Rodeheffer.

Acquisition of data: Karon, Mahoney, Roger, Jacobsen, Rodeheffer.

Analysis and interpretation of data: Kane, Karon, Mahoney, Roger, Burnett, Jacobsen, Rodeheffer.

Drafting of the manuscript: Kane, Mahoney, Roger, Rodeheffer.

Critical revision of the manuscript for important intellectual content: Karon, Mahoney, Redfield, Burnett, Jacobsen, Rodeheffer.

Statistical analysis: Kane, Mahoney, Rodeheffer.

Obtained funding: Jacobsen, Rodeheffer.

Administrative, technical, or material support: Burnett, Jacobsen, Rodeheffer.

Study supervision: Rodeheffer.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by National Heart, Lung, and Blood Institute grant R01-55502, grant 1UL1RR024150 from the National Institutes of Health (NIH) National Center for Research Resources, and the Mayo Foundation. The research was supported by NIH HL-R01-55502 (Dr Rodeheffer), NIH AR-36582 (Dr Jacobsen), and NIH HL-63281 (Redfield). The project was supported by NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Awards Grant UL RR024150 and by the Rochester Epidemiology Project, grant R01-AG034676 from the National Institute on Aging, and the Mayo Foundation.

Role of the Sponsor: The study sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Additional Contributions: We thank Tammy Burns (Mayo Clinic) and Kasey Muetzel (Mayo Clinic) for invaluable assistance in manuscript preparation. Neither of these individuals received any compensation for their contributions apart from their employment. This article is dedicated to the memory of Kenneth L. Baughman, MD, physician and mentor.

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PubMed   |  Link to Article
 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [published correction appears in Arch Intern Med. 1998;158(6):573].  Arch Intern Med. 1997;157(21):2413-2446
PubMed   |  Link to Article
Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study.  J Am Coll Cardiol. 2005;45(1):87-92
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study.  Circulation. 2005;112(15):2254-2262
PubMed   |  Link to Article
Okura Y, Ohno Y, Ramadan MM,  et al.  Characterization of outpatients with isolated diastolic dysfunction and evaluation of the burden in a Japanese community: Sado Heart Failure Study.  Circ J. 2007;71(7):1013-1021
PubMed   |  Link to Article
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study.  Circulation. 2004;109(25):3176-3181
PubMed   |  Link to Article
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender.  J Am Coll Cardiol. 2002;40(5):976-982
PubMed   |  Link to Article
McKie PM, Rodeheffer RJ, Cataliotti A,  et al.  Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure.  Hypertension. 2006;47:874-880
PubMed   |  Link to Article
Munagala VK, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Association of newer diastolic function parameters with age in healthy subjects: a population-based study.  J Am Soc Echocardiogr. 2003;16(10):1049-1056
PubMed   |  Link to Article
Ommen SR, Nishimura RA, Appleton CP,  et al.  Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study.  Circulation. 2000;102(15):1788-1794
PubMed   |  Link to Article
Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone.  J Am Coll Cardiol. 1997;30(1):8-18
PubMed   |  Link to Article
Hurrell DG, Nishimura RA, Ilstrup DM, Appleton CP. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study.  J Am Coll Cardiol. 1997;30(2):459-467
PubMed   |  Link to Article
Redfield MM. Understanding “diastolic” heart failure.  N Engl J Med. 2004;350(19):1930-1931
PubMed   |  Link to Article
Borlaug BA, Lam CSP, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction.  J Am Coll Cardiol. 2009;54(5):410-418
PubMed   |  Link to Article
Chantler PD, Lakatta EG, Najjar SS. Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise.  J Appl Physiol. 2008;105(4):1342-1351
PubMed   |  Link to Article
Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle.  N Engl J Med. 2004;350(19):1953-1959
PubMed   |  Link to Article
Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure.  Heart Fail Clin. 2008;4(1):23-36
PubMed   |  Link to Article
Kass DA, Bronzwaer JGF, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure?  Circ Res. 2004;94(12):1533-1542
PubMed   |  Link to Article
Kass DA. Ventricular arterial stiffening: integrating the pathophysiology.  Hypertension. 2005;46(1):185-193
PubMed   |  Link to Article
Zile MR, Gaasch WH, Carroll JD,  et al.  Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?  Circulation. 2001;104(7):779-782
PubMed   |  Link to Article
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, II: the aging heart in health: links to heart disease.  Circulation. 2003;107(2):346-354
PubMed   |  Link to Article
Abhayaratna WP, Barnes ME, O’Rourke MF,  et al.  Relation of arterial stiffness to left ventricular diastolic function and cardiovascular risk prediction in patients > or =65 years of age.  Am J Cardiol. 2006;98(10):1387-1392
PubMed   |  Link to Article
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, I: aging arteries: a “set up” for vascular disease.  Circulation. 2003;107(1):139-146
PubMed   |  Link to Article
Gerstenblith G, Frederiksen J, Yin FCP, Fortuin NJ, Lakatta EG, Weisfeldt ML. Echocardiographic assessment of a normal adult aging population.  Circulation. 1977;56(2):273-278
PubMed   |  Link to Article
Grewal J, McCully RB, Kane GC, Lam C, Pellikka PA. Left ventricular function and exercise capacity.  JAMA. 2009;301(3):286-294
PubMed   |  Link to Article
Cheng S, Fernandes VRS, Bluemke DA, McClelland RL, Kronmal RA, Lima JAC. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis.  Circ Cardiovasc Imaging. 2009;2(3):191-198
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Flow
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Cumulative Incidence of Heart Failure After Examination 2
Graphic Jump Location

Groups represent 3 grades of severity and change in diastolic dysfunction from examination 1 and examination 2. Persons with heart failure at examination 2 and those in whom diastolic function could not be classified at both examinations 1 and 2 are excluded, leaving 1047 persons at risk after examination 2.

Tables

Table Graphic Jump LocationTable 1. Clinical and Echocardiographic Characteristics of Participants (N = 1402)
Table Graphic Jump LocationTable 2. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in All Participantsa
Table Graphic Jump LocationTable 3. Factors Predictive of the Development of Diastolic Dysfunction From Examination 1 to Examination 2a
Table Graphic Jump LocationTable 4. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in 423 (of 531) Healthy Participants Whose Diastolic Function Grade Could Be Classified at Both Examinations
Table Graphic Jump LocationTable 5. Baseline Factors Predictive of the Development of Incident Heart Failure After Examination 2

References

Rodeheffer RJ, Jacobsen SJ, Gersh BJ,  et al.  The incidence and prevalence of congestive heart failure in Rochester, Minnesota.  Mayo Clin Proc. 1993;68(12):1143-1150
PubMed   |  Link to Article
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study.  N Engl J Med. 1971;285(26):1441-1446
PubMed   |  Link to Article
Levy D, Kenchaiah S, Larson MG,  et al.  Long-term trends in the incidence of and survival with heart failure.  N Engl J Med. 2002;347(18):1397-1402
PubMed   |  Link to Article
Senni M, Tribouilloy CM, Rodeheffer RJ,  et al.  Congestive heart failure in the community: trends in incidence and survival in a 10-year period.  Arch Intern Med. 1999;159(1):29-34
PubMed   |  Link to Article
Mosterd A, Hoes AW, de Bruyne MC,  et al.  Prevalence of heart failure and left ventricular dysfunction in the general population: the Rotterdam Study.  Eur Heart J. 1999;20(6):447-455
PubMed   |  Link to Article
Hunt SA, Abraham WT, Chin MH,  et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society.  ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.  Circulation. 2005;112(12):e154-e235
PubMed   |  Link to Article
Ammar KA, Jacobsen SJ, Mahoney DW,  et al.  Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.  Circulation. 2007;115(12):1563-1570
PubMed   |  Link to Article
Redfield MM. Heart failure—an epidemic of uncertain proportions.  N Engl J Med. 2002;347(18):1442-1444
PubMed   |  Link to Article
Roger VL, Weston SA, Redfield MM,  et al.  Trends in heart failure incidence and survival in a community-based population.  JAMA. 2004;292(3):344-350
PubMed   |  Link to Article
Bhatia RS, Tu JV, Lee DS,  et al.  Outcome of heart failure with preserved ejection fraction in a population-based study.  N Engl J Med. 2006;355(3):260-269
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.  JAMA. 2003;289(2):194-202
PubMed   |  Link to Article
Davies M, Hobbs F, Davis R,  et al.  Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study.  Lancet. 2001;358(9280):439-444
PubMed   |  Link to Article
Abhayaratna WP, Marwick TH, Smith WT, Becker NG. Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey.  Heart. 2006;92(9):1259-1264
PubMed   |  Link to Article
Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort.  J Am Coll Cardiol. 1999;33(7):1948-1955
PubMed   |  Link to Article
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction.  N Engl J Med. 2006;355(3):251-259
PubMed   |  Link to Article
Melton LJ III. History of the Rochester Epidemiology Project.  Mayo Clin Proc. 1996;71(3):266-274
PubMed   |  Link to Article
Jacobsen SJ, Mahoney DW, Redfield MM, Bailey KR, Burnett JC Jr, Rodeheffer RJ. Participation bias in a population-based echocardiography study.  Ann Epidemiol. 2004;14(8):579-584
PubMed   |  Link to Article
 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [published correction appears in Arch Intern Med. 1998;158(6):573].  Arch Intern Med. 1997;157(21):2413-2446
PubMed   |  Link to Article
Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study.  J Am Coll Cardiol. 2005;45(1):87-92
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study.  Circulation. 2005;112(15):2254-2262
PubMed   |  Link to Article
Okura Y, Ohno Y, Ramadan MM,  et al.  Characterization of outpatients with isolated diastolic dysfunction and evaluation of the burden in a Japanese community: Sado Heart Failure Study.  Circ J. 2007;71(7):1013-1021
PubMed   |  Link to Article
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study.  Circulation. 2004;109(25):3176-3181
PubMed   |  Link to Article
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender.  J Am Coll Cardiol. 2002;40(5):976-982
PubMed   |  Link to Article
McKie PM, Rodeheffer RJ, Cataliotti A,  et al.  Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure.  Hypertension. 2006;47:874-880
PubMed   |  Link to Article
Munagala VK, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Association of newer diastolic function parameters with age in healthy subjects: a population-based study.  J Am Soc Echocardiogr. 2003;16(10):1049-1056
PubMed   |  Link to Article
Ommen SR, Nishimura RA, Appleton CP,  et al.  Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study.  Circulation. 2000;102(15):1788-1794
PubMed   |  Link to Article
Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone.  J Am Coll Cardiol. 1997;30(1):8-18
PubMed   |  Link to Article
Hurrell DG, Nishimura RA, Ilstrup DM, Appleton CP. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study.  J Am Coll Cardiol. 1997;30(2):459-467
PubMed   |  Link to Article
Redfield MM. Understanding “diastolic” heart failure.  N Engl J Med. 2004;350(19):1930-1931
PubMed   |  Link to Article
Borlaug BA, Lam CSP, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction.  J Am Coll Cardiol. 2009;54(5):410-418
PubMed   |  Link to Article
Chantler PD, Lakatta EG, Najjar SS. Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise.  J Appl Physiol. 2008;105(4):1342-1351
PubMed   |  Link to Article
Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle.  N Engl J Med. 2004;350(19):1953-1959
PubMed   |  Link to Article
Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure.  Heart Fail Clin. 2008;4(1):23-36
PubMed   |  Link to Article
Kass DA, Bronzwaer JGF, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure?  Circ Res. 2004;94(12):1533-1542
PubMed   |  Link to Article
Kass DA. Ventricular arterial stiffening: integrating the pathophysiology.  Hypertension. 2005;46(1):185-193
PubMed   |  Link to Article
Zile MR, Gaasch WH, Carroll JD,  et al.  Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?  Circulation. 2001;104(7):779-782
PubMed   |  Link to Article
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, II: the aging heart in health: links to heart disease.  Circulation. 2003;107(2):346-354
PubMed   |  Link to Article
Abhayaratna WP, Barnes ME, O’Rourke MF,  et al.  Relation of arterial stiffness to left ventricular diastolic function and cardiovascular risk prediction in patients > or =65 years of age.  Am J Cardiol. 2006;98(10):1387-1392
PubMed   |  Link to Article
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, I: aging arteries: a “set up” for vascular disease.  Circulation. 2003;107(1):139-146
PubMed   |  Link to Article
Gerstenblith G, Frederiksen J, Yin FCP, Fortuin NJ, Lakatta EG, Weisfeldt ML. Echocardiographic assessment of a normal adult aging population.  Circulation. 1977;56(2):273-278
PubMed   |  Link to Article
Grewal J, McCully RB, Kane GC, Lam C, Pellikka PA. Left ventricular function and exercise capacity.  JAMA. 2009;301(3):286-294
PubMed   |  Link to Article
Cheng S, Fernandes VRS, Bluemke DA, McClelland RL, Kronmal RA, Lima JAC. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis.  Circ Cardiovasc Imaging. 2009;2(3):191-198
PubMed   |  Link to Article
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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