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

Heart failure is a progressive condition that increases in incidence with advancing age.^1- 10 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.^4,7,10- 15 Echocardiographic classification of diastolic function in cross-sectional community studies has shown diastolic dysfunction to be highly prevalent and associated with heart failure.^11- 14 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.

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).

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

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.

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.

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

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.

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.^7,11,19- 25 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)

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).

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).

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).

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).

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).

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).

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.

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]).

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).

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.

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.

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.^11- 14 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.^26- 36 Age-related loss of peripheral vascular elasticity, and its effect on left ventricular load and stiffness, may play an important role in this process.^20,37- 42 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- 31,33- 35,37} 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

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.^20,35- 37 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.

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.