CLINICAL PERSPECTIVE

This Article Abstract Full Text (PDF) Correction Correction (v115,pe535) All Versions of this Article: 115/15/1982    most recent CIRCULATIONAHA.106.659763v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lam, C. S.P. Articles by Redfield, M. M. Search for Related Content PubMed PubMed Citation Articles by Lam, C. S.P. Articles by Redfield, M. M. Related Collections Cardio-renal physiology/pathophysiology Other heart failure Congestive Other hypertension Clinical Studies

(Circulation. 2007;115:1982-1990.)
© 2007 American Heart Association, Inc.

Heart Failure

Cardiac Structure and Ventricular–Vascular Function in Persons With Heart Failure and Preserved Ejection Fraction From Olmsted County, Minnesota

Carolyn S.P. Lam, MBBS, MRCP; Véronique L. Roger, MD, MPH; Richard J. Rodeheffer, MD; Francesca Bursi, MD, MSc; Barry A. Borlaug, MD; Steve R. Ommen, MD; David A. Kass, MD; Margaret M. Redfield, MD

From the Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn (C.S.P.L., V.L.R., R.J.R., B.A.B., S.R.O., M.M.R.); Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.S.P.L.); Department of Cardiology, University Policlinico Hospital, Modena, Italy (F.B.); and Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md (D.A.K.).

Correspondence to Margaret M. Redfield, MD, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905. E-mail redfield.margaret{at}mayo.edu

Received August 21, 2006; accepted February 16, 2007.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background— Mechanisms purported to contribute to the pathophysiology of heart failure with normal ejection fraction (HFnlEF) include diastolic dysfunction, vascular and left ventricular systolic stiffening, and volume expansion. We characterized left ventricular volume, effective arterial elastance, left ventricular end-systolic elastance, and left ventricular diastolic elastance and relaxation noninvasively in consecutive HFnlEF patients and appropriate controls in the community.

Methods and Results— Olmsted County (Minn) residents without cardiovascular disease (n=617), with hypertension but no heart failure (n=719), or with HFnlEF (n=244) were prospectively enrolled. End-diastolic volume index was determined by echo Doppler. End-systolic elastance was determined using blood pressure, stroke volume, ejection fraction, timing intervals, and estimated normalized ventricular elastance at end diastole. Tissue Doppler e' velocity was used to estimate the time constant of relaxation. End-diastolic volume (EDV) and Doppler-derived end-diastolic pressure (EDP) were used to derive the diastolic curve fitting () and stiffness (ß) constants (EDP=EDV^ß). Comparisons were adjusted for age, sex, and body size. HFnlEF patients had more severe renal dysfunction, yet smaller end-diastolic volume index and cardiac output and increased EDP compared with both hypertensive and healthy controls. Arterial elastance and ventricular end-systolic elastance were similarly increased in hypertensive controls and HFnlEF patients compared with healthy controls. In contrast, HFnlEF patients had more impaired relaxation and increased diastolic stiffness compared with either control group.

Conclusions— From these cross-sectional observations, we speculate that the progression of diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease.

Key Words: diastole • heart failure • hypertension • mechanics

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
Heart failure (HF) with normal ejection fraction (EF) (HFnlEF) is a major public health problem of increasing prevalence.¹ In contrast to the improvements in survival observed in patients with HF and reduced EF, mortality for patients with HFnlEF has remained stable, emphasizing the lack of proven therapies.¹ An important barrier to advances in therapy is relative uncertainty about the fundamental pathophysiological mechanisms. Left ventricular (LV) diastolic dysfunction (impaired relaxation and increased passive diastolic stiffness), increased systolic ventricular–vascular stiffening, and cardiac volume overload have been implicated in previous seminal studies.^2–9 Although well designed, these important studies were small, with both control and HFnlEF cohorts subject to potential limitations in regard to selection and referral bias and, in some instances, with populations preselected for features of cardiac remodeling or dysfunction. The relative incidence of each putative mechanism remains to be defined in large, prospectively enrolled, control and HF populations recruited from the same community and studied in a comprehensive and uniform manner.

Clinical Perspective p 1990

In this study of residents of Olmsted County, Minn, we used previously validated noninvasive methods to assess LV volume,¹⁰ end-systolic LV¹¹ and effective arterial stiffness (elastance),¹² LV relaxation,^13,14 and diastolic elastance¹⁵ to compare cardiac structure and ventricular–vascular function in consecutive patients with HFnlEF with those observed in randomly selected persons without cardiovascular disease or with hypertension but no HF. We hypothesized that more advanced diastolic dysfunction and systolic ventricular–vascular stiffening distinguish HFnlEF from disease-free and hypertensive control subjects without HF in this community.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
Study Setting
The unique aspects of Olmsted County favoring population-based research have been previously described.¹⁶ The study was approved by the Mayo Institutional Review Board.

Identification of Patients and Study Procedures
Subject groups were as follows: nonobese controls without cardiovascular disease (CON), subjects with hypertension but without HF (HTN), and patients with HFnlEF. To recruit the first 2 groups, a random sample of the population 45 years of age was prospectively identified and evaluated as previously described.¹⁶ Data from this study have previously been published, but these subsets and many of the indexes presented here have not. Medical records were reviewed by trained nurse-abstractors using established criteria for hypertension and HF. Clinical diagnoses of coronary artery disease, diabetes mellitus, valvular heart disease, cardiomyopathy, atrial fibrillation, and transient ischemic attack or stroke were recorded. In each participant, cuff blood pressure, height, and weight were measured and body mass index and body surface area (BSA) were calculated. Echocardiographic assessment of EF was performed by M-mode, quantitative, and semiquantitative 2-dimensional methods. Subjects with EF <50% were excluded. Of 2042 participants, 617 had none of the above validated or suspected cardiovascular diagnoses, a systolic pressure <140 mm Hg at the time of echocardiography, and a body mass index <30 kg/m², thus constituting the CON group. Subjects with hypertension but no HF (n=719) constituted the HTN group. The HFnlEF group was prospectively identified in an Olmsted County HF surveillance study by real-time interrogation of electronic medical records using natural language processing techniques.¹⁷ Briefly, all inpatient and outpatient electronic notes were searched (most within 24 hours of presentation) using a wide range of terms indicative of HF, enabling rapid identification of all potential cases of HF with a diagnostic sensitivity of 100%.¹⁷ The final diagnosis of HF was validated by trained nurse-abstractors using the Framingham criteria. Of 811 HF patients identified between September 10, 2003, and August 24, 2005, 570 (70%) consented to participate, and 516 (91%) underwent echocardiography within a median (25th, 75th percentile) of 1 day (range, 1 to 5 days) of diagnosis. Of these, 276 patients had EF 50%. Hemodynamically significant valve disease was detected on Doppler echocardiography in 32 patients (11.6%), who were excluded. The remaining 244 patients made up the HFnlEF group. Reflecting the ethnic composition of the community, subjects were almost exclusively white.

Plasma brain natriuretic peptide was determined by immunoradiometric assay (nonextracted) using an antibody to human brain natriuretic peptide (Shionogi Co Ltd, Tokyo, Japan). Glomerular filtration rate was estimated using the simplified modification of diet in renal disease study equation. All echocardiograms were performed by registered diagnostic cardiac sonographers using standardized instruments and techniques¹⁶ and were reviewed by a cardiologist (C.S.P.L., M.M.R.).

Assessment of Cardiac Volume
LV volume was determined in each subject by 3 methods. The Teichholz method¹⁸ used short-axis LV dimension measured from 2-dimensional or M-mode images. This was available in 532 CON (86%), 551 HTN (77%), and 222 HFnlEF (91%) subjects. In 73 subjects, LV short-axis dimension was measured from both 2-dimensional and M-mode images and correlated well (r=0.73, P<0.001) with no systematic error (mean±SD difference, 0.79±4.2 mm, Bland-Altman analysis) and no relationship between mean difference and the average of the 2 methods (r=0.02, P=0.85). LV volume calculated by the area-length formula¹⁰ used both long- and short-axis LV dimensions. This was available in 496 CON (80%), 492 HTN (68%), and 188 HFnlEF (77%) subjects. LV volume also was calculated independently of geometric assumptions by dividing stroke volume (SV; using left ventricular outflow tract dimension and pulsed-wave Doppler velocity profile) by EF. This was available in 611 CON (99%), 697 HTN (97%), and 223 HFnlEF (91%) subjects. Left atrial volume was calculated by the ellipse formula.¹⁹ LV mass and relative wall thickness were calculated by standard methods.¹⁰ Measurements were indexed to BSA when appropriate. LV hypertrophy (LVH) was defined as LV mass index >95 g/m² (women) or >115 g/m² (men), and LV geometry was classified as normal, concentric remodeling, concentric LVH, or eccentric LVH.¹⁰

Determination of Vascular Function
Effective arterial elastance (Ea) was estimated as end-systolic pressure divided by SV.¹² End-systolic pressure was estimated as systolic pressure times 0.9, as previously validated.^11,12 Total arterial compliance was estimated by the SV-to-pulse-pressure ratio²⁰ and systemic vascular resistance index by mean arterial pressure divided by cardiac index times 80.

Determination of LV End-Systolic Elastance
The modified single-beat method was used to estimate end-systolic elastance (Ees) from arm-cuff pressures, SV, and pre-ejection and total systolic periods determined on continuous-wave Doppler of aortic flow, EF, and an estimated normalized ventricular elastance at arterial end diastole, as previously validated^11,21 and used in recent studies.^4,22,23

Determination of Early LV Relaxation Velocity and Filling Pressures
The medial mitral annular early diastolic velocity (e') was determined by spectral tissue Doppler imaging using standard methods. The e' velocity is relatively preload independent and inversely related to the time constant of isovolumic relaxation (), which was derived from this formula: [=(14.70–100e')/0.15].^13,14 Early transmitral flow velocity (E) was measured by pulsed-wave Doppler. End-diastolic pressure (EDP) was estimated as follows: (EDP=11.96+0.596 · E/e'), as previously determined from Doppler and invasive EDP measurements at our institution.¹³

Determination of LV Diastolic Stiffness
The recently developed and validated single-beat approach proposed by Klotz et al¹⁵ was used to characterize the EDP–end-diastolic volume (EDV) relationship (EDPVR, where EDP=EDV^ß; is a curve-fitting constant and ß is a diastolic stiffness constant). On the basis of the premise that volume-normalized EDPVRs share a common shape, this method allows estimation of and ß and hence the entire EDPVR from a single pressure–volume point. Measured EDP and EDV were used to derive and ß in each subject. A modified method was used when EDP was >28 mm Hg to address the recognized mathematical limitations of the original equations (see the Appendix). To account for covariance in and ß,²⁴ both of which are indicative of the shape and position of the EDPVR, derived and ß in each subject were used to predict the EDV at a common EDP of 20 mm Hg (EDV₂₀). Comparison of EDV₂₀ indexed to BSA (EDVI₂₀) was then used as a comparison of overall diastolic stiffness between groups.

Statistical Analysis
Categorical variables were compared by use of Pearson’s ² test. Continuous variables were log transformed as necessary and compared between groups through the use of 1-way ANOVA with Bonferroni’s correction for multiple unadjusted comparisons. Regression analysis was used to adjust for age, sex, and BSA or the presence of other diseases in group comparisons, where the dependent variable was the normally distributed continuous (linear least-squares regression) or categorical (logistic regression) outcome variable of interest; factors entered into the model were age, sex, BSA, and group (dummy variable). Any interaction between these variables also was evaluated and accounted for as appropriate. All analyses were 2 sided, and significance was judged at P<0.05.

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Subject Characteristics
HFnlEF patients were older, were more obese, had higher prevalence of coronary artery disease and diabetes mellitus, and had lower glomerular filtration rate than HTN or CON (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Subject Characteristics

LV Structure
After adjustment for age and sex, EDVI in HFnlEF was similar (area-length) or smaller (Teichholz and Doppler) compared with CON and smaller (by all 3 methods) compared with HTN (Table 2). After adjustment for age and sex, SV index in HFnlEF was smaller compared with CON or HTN, whereas cardiac index in HFnlEF was similar to that in CON but reduced compared with HTN. After adjustment for age and sex, LV mass index, relative wall thickness, and ratio of LV mass to volume were increased in HFnlEF and HTN compared with CON, but these parameters were similar in HFnlEF and HTN. The percent LVH was greater in HTN and HFnlEF than CON but similar in HFnlEF and HTN. LV geometry patterns varied considerably in both control populations and HFnlEF. Although HFnlEF patients had more concentric LVH and less normal geometry compared with CON, these patterns were not significantly different compared with HTN after adjustment for age.

View this table: [in this window] [in a new window]   TABLE 2. Measures of Cardiovascular Structure and Function

Vascular Function
With adjustment for age, sex, and BSA when appropriate, Ea, systemic vascular resistance index, and pulse pressure were increased whereas arterial compliance was decreased in HFnlEF and HTN compared with CON, but all these parameters were similar in HFnlEF and HTN (Table 2). Unadjusted comparisons gave similar results.

LV Systolic Stiffness
After adjustment for age, sex, and BSA, Ees was increased in HFnlEF and HTN compared with CON but was similar in HFnlEF and HTN (Table 2). Similar results were observed in unadjusted comparisons and after normalizing Ees for LV mass (Ees times LV mass) and EDV (Ees times EDV) (and adjusting for age and sex), suggesting that the differences in Ees could not be attributed solely to differences in chamber size. Systolic vascular-ventricular coupling ratio (Ea/Ees) was preserved across groups. Predicted end-systolic pressure–volume relationship equations derived from group-averaged data are given in Figure 1.

View larger version (16K): [in this window] [in a new window]   Figure 1. Schematic of group-averaged end-systolic pressure–volume relationship (ESPVR), where ESP=Ees(ESV–V0) (V0 is volume intercept). Solid lines represent the mean ESPVR; dotted lines, 95% CI for each group. For comparison of Ees (slope) between groups, *P<0.05 vs CON.

Estimated LV Filling Pressures
EDP was higher in HFnlEF compared with both CON and HTN (Figure 2), with corroborating evidence of elevated filling pressures provided by plasma brain natriuretic peptide and left atrial volume index measurements.

View larger version (17K): [in this window] [in a new window]   Figure 2. Bar graphs of EDVI, indexed left atrial volume (LAVI), EDP, plasma brain natriuretic peptide (BNP), and derived by subject group. Data are mean±SD. *P<0.05 vs CON; P<0.05 vs HTN.

LV Diastolic Function
In both unadjusted and adjusted (adjusting for age, sex, and BSA) comparisons, HFnlEF patients had more impaired relaxation (lower e', longer ) and higher ß compared with CON and HTN (Table 2). After adjusting for age and sex and controlling for covariance in and ß, overall diastolic LV stiffness was higher (lower EDVI₂₀) in HFnlEF than in CON or HTN (Table 2). Predicted EDPVR curves derived from group-averaged data are illustrated in Figure 3.

View larger version (20K): [in this window] [in a new window]   Figure 3. Schematic of group-averaged EDPVR, where EDP=EDVß (=curve-fitting constant, ß=diastolic stiffness constant). Solid lines represent the mean EDPVR; dotted lines, 95% CI for each group. For comparison of EDVI20 between groups, *P<0.05 vs CON; P<0.05 vs HTN.

Further Analyses
In view of the large age range of subjects (Table 1) and recognizing that unaccounted confounders may be present at the extremes of ages, a subanalysis of subjects 60 to 95 years of age was performed and gave similar results (Table 3). Further recognizing the potential confounding effects of diabetes and renal function, we adjusted for these, in addition to age, sex, and body size (Table 4). Overall results were similar.

View this table: [in this window] [in a new window]   TABLE 3. Subgroup Analysis in Subjects 60 to 95 Years of Age

View this table: [in this window] [in a new window]   TABLE 4. Analysis Adjusted for Renal Function, Diabetes Mellitus, Age, Sex, and Body Size

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
This is the largest population-based study to date comparing vascular and ventricular structure and function in an HFnlEF cohort with those observed in healthy and hypertensive control populations without HF. The present study serves to confirm, clarify, and extend smaller, seminal studies describing a variety of structural and functional perturbations in more select cohorts with HFnlEF. Several findings are noteworthy. The HFnlEF cohort had worse renal function yet smaller LV volume and cardiac output compared with hypertensive controls. Although LV mass was, on average, increased in HFnlEF compared with healthy controls, HFnlEF patients did not have more severe LVH than hypertensive controls. Compared with healthy controls, the HFnlEF cohort had increases in both the resistive and pulsatile components of vascular load with proportional increases in LV systolic stiffness. However, these abnormalities were similar to those observed in hypertensive controls without HF. In contrast, diastolic dysfunction (both impairment in relaxation and increases in diastolic stiffness) was more severe in HFnlEF patients compared with healthy or hypertensive controls.

The present findings are consistent with previous studies that used invasive assessment of LV function in HFnlEF. Liu et al²⁵ used conductance catheters with preload reduction (multiple-beat method) in 10 patients with LVH and normal EF (7 with HFnlEF) and found impaired relaxation with increased diastolic stiffness in this group compared with 8 younger, healthy control subjects. All subjects were referred for cardiac catheterization at a tertiary center. In a landmark invasive study using a single-beat method, Zile et al² also found more impaired relaxation and higher diastolic stiffness in HFnlEF (n=47). These HFnlEF patients were predominantly male with echocardiographic evidence of LVH who were recruited at a Veterans Administration Hospital as part of a clinical trial and were compared with 10 healthy age-matched control subjects. In both studies, the control group had no cardiovascular disease, raising concern as to whether the observed differences were specifically attributable to HFnlEF or to hypertensive heart disease. Borbely et al²⁶ measured chamber and myocyte stiffness in 12 HFnlEF patients and 8 control subjects and found increased estimated LV diastolic stiffness in HFnlEF by invasive measurements. However, nearly half of the HFnlEF patients and 75% of the control subjects had previously undergone cardiac transplantation, thus confounding the effects of occult rejection or immunosuppression may have influenced the findings.

Other studies used noninvasive methods to characterize diastolic function.²⁷ Ahmed et al⁶ identified 26 patients with LVH and HFnlEF undergoing echocardiography at their tertiary center and showed that these patients had more severe diastolic dysfunction than 39 nonhypertensive control, 14 hypertensive control, and 23 control subjects with LVH but no HF.⁶ The inclusion of hypertensive control subjects was a strength of this study, which focused on HFnlEF patients with LVH.

In the present study, consecutive cases of HFnlEF identified in both the inpatient and outpatient settings, not preselected for any geometric characteristics, were compared with large, randomly selected, and prospectively enrolled control populations from the same community, with all subjects studied in a similar manner using analyses adjusted for potential effects of age, sex, and body size. The present results are consistent with the aforementioned studies in that relaxation and passive diastolic stiffness were impaired in HFnlEF compared with disease-free control subjects. Furthermore, the present data confirm that compared with HTN subjects, HFnlEF patients have more severe diastolic dysfunction. Although the predominant cardiovascular abnormalities and contributing comorbidities in HFnlEF patients may vary according to a number of demographic parameters, it is noteworthy that the presence of diastolic dysfunction is a consistent finding in HFnlEF patients identified in this community and in the diverse settings included in previous studies.^{2,5–9,25,26}

In contrast, Kawaguchi et al,⁴ using either invasive (conductance catheters and multiple-beat model) or noninvasive (single-beat model) measurements, found that relaxation was not significantly different in HFnlEF patients (n=10) compared with young control subjects (n=9) and age- and blood pressure–matched control subjects (n=25), except during stress (isometric handgrip). Additionally, although higher EDPs were observed in HFnlEF, this was due to a parallel upward shift of the diastolic pressure–volume curve rather than to a steeper curve (ie, ß stiffness coefficients were similar), suggesting that exaggerated external forces, rather than increased passive diastolic stiffness, was present in HFnlEF. However, the large variability in ß observed in the HFnlEF group (range, 0.01 to 0.05 mm Hg/mL) may have prevented demonstration of differences in ß in the small numbers of subjects enrolled. Importantly, this study showed that HFnlEF patients had increased Ea and Ees, suggesting that vascular and LV systolic stiffening may contribute to the pathophysiology of HFnlEF by exaggerating systolic load and diastolic dysfunction during exercise. These patients were studied over a 14-year period at a referral center, and although the patients were predominantly female, the mean age was lower than that observed in most population-based studies. Although we also found that Ea and Ees were increased in HFnlEF compared with healthy control subjects, these indexes were not further increased in HFnlEF compared with hypertensive controls in the this study and others.^5,6,9 Nonetheless, these data do not exclude a role for increased vascular and LV systolic stiffening in the pathophysiology of HFnlEF, particularly during exercise or other stressors in which such changes exaggerate hypertensive responses and induce further load-dependent diastolic dysfunction.

The potential for a subgroup of HFnlEF patients to have LV dilatation and a "high-output" form of HF has been reported.³ Maurer et al³ used 3-dimensional and Doppler echocardiography to characterize LV volumes and pressures noninvasively at a tertiary referral center in the New York metropolitan area. Among 35 patients with hypertension and HFnlEF, a subgroup (n=29) of younger, more obese subjects had increased LV volumes associated with increased EDP but no change in Ees or Ea compared with healthy control subjects. These investigators concluded that many (most in their series) HFnlEF patients may have volume overload, without intrinsic diastolic dysfunction as a mechanism for increased filling pressures. In contrast, our data show that on average, compared with healthy or hypertensive controls, HFnlEF patients have normal or decreased LV volumes, respectively. Because ventricular volumes vary with body size, sex, and possibly age in persons without cardiovascular disease, we were careful to adjust for these parameters in all volume comparisons. We accounted not only for the short-axis but also for the long-axis LV dimension when calculating volumes. A further Doppler-based method was used to estimate volumes independently of geometric assumptions. All 3 methods gave the consistent picture that ventricular enlargement was not present in most HFnlEF patients despite their more impaired renal function. In fact, stroke volume and cardiac index were lower in HFnlEF than in HTN subjects. As emphasized previously, however, the present analysis is restricted to group comparisons; because LV volume is a continuous variable with a fairly normal distribution in the HFnlEF population, some patients with HFnlEF will have increased LV volume even though the distribution curve as a whole was not shifted toward larger volumes. Indeed, our findings underscore the variable LV geometric patterns present in HFnlEF.

More recently, Melenovsky et al⁹ used noninvasive methods to study 37 HFnlEF patients, 40 hypertensive control subjects, and 56 nonhypertensive age-, sex-, and race-matched control subjects recruited from an urban setting in Baltimore, Md. This population was largely black, and HFnlEF patients were younger (by a decade) than observed here, more obese, and more predominantly female. As in our study, LV volume did not vary significantly among groups, estimated filling pressures were highest in HFnlEF, and both Ees and Ea were similarly increased in hypertensive control subjects and HFnlEF patients compared with disease-free controls. However, both the HFnlEF and hypertensive groups had much more dramatic LVH than we observed, and although estimated LV diastolic pressures were higher in HFnlEF, many parameters displayed substantial overlap, with little disparity between these 2 groups. Although LV diastolic stiffness was not estimated, the prior study found left atrial enlargement and impaired atrial function in HFnlEF, leading the authors to speculate that impaired atrial function also may play a key role in the transition to HFnlEF among patients with cardiovascular disease. This hypothesis is consistent with clinical studies documenting that new-onset atrial fibrillation is a common precipitant of episodes of acutely decompensated HF, regardless of EF.^28,29 We also found increased left atrial volume in HFnlEF patients compared with either control group. Melenovsky et al⁹ further found that total epicardial cardiac volume was highest in HFnlEF patients and speculated that external forces may contribute to the elevation in filling pressures.

The variable LV geometry patterns observed in HFnlEF patients in our study is noteworthy and consistent with several^2,4,28,30 prior studies, underscoring that despite traditional teaching, concentric LVH or concentric remodeling is not invariably present in HFnlEF. Indeed, there may be important geographic and race-specific differences, with marked concentric LVH being more common in some populations such as blacks, as seen in studies in which these groups are more prominently represented.⁹ Finally, the similar relative wall thickness and ratio of LV mass to volume observed in HTN and HFnlEF suggest that factors other than chamber geometry additionally mediate increased diastolic stiffness in HFnlEF. Changes in the cardiomyocytes themselves²⁶ and/or the extracellular matrix^31,32 may mediate diastolic stiffening and represent potential therapeutic targets in the treatment and/or prevention of HFnlEF.

Study Limitations
Our data are purely observational and cannot prove causality. The more impaired diastolic dysfunction in HFnlEF could be a marker for, rather than a mediator of, progression to HF. Although invasive measurements were not performed, each of the methods used to characterize pressure–volume relationships was validated against gold-standard invasive techniques.

Future Directions
Although total vascular load and indirect measures of vascular stiffness were obtained here, further study is needed to evaluate more direct and perhaps regional measures of vascular stiffening and other assessments of arterial impedance and its impact such as characteristic impedance, wave reflections, and pulse-wave velocity. Hemodynamic data obtained during exercise and other stresses may be key in differentiating HFnlEF and HTN subjects. The study population was mainly white, and potential differences in other racial groups should be examined. Finally, the functional significance of different geometric patterns in HFnlEF deserves further study.

Conclusions
In this large, population-based study, HFnlEF patients had reduced LV volumes and cardiac output compared with hypertensive controls despite more renal impairment. Although HFnlEF patients displayed vascular and LV systolic stiffening compared with normal controls, HFnlEF was distinguished from hypertensive heart disease by the presence of more severe diastolic dysfunction and increased left atrial size. Thus, these data support efforts to ameliorate diastolic dysfunction in order to prevent or treat HFnlEF. Although we speculate that progression of diastolic dysfunction plays a key role in the development of HF symptoms in persons with hypertensive heart disease and a normal EF, further studies characterizing potential differential responses to exercise and other stressors may reveal additional pathophysiological mechanisms and therapeutic targets.

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
A recognized limitation of the original predictions used in the single-beat EDPVR method¹⁵ was the breakdown of the equations as measured EDP approached 30 mm Hg. This limitation was due to the arbitrary choice of V₃₀ (estimated EDV at 30 mm Hg) as a starting point in the original derivation equations for and ß, which therefore became unstable as measured EDP approached 30 mm Hg (>28 mm Hg). This mathematical instability was overcome simply by use of an estimate of EDV at a pressure of 15 mm Hg (V₁₅) instead of V₃₀ for cases when measured EDP was >28 mm Hg. V₁₅ was derived from the EDV-normalized curve in the same fashion¹⁵ as V₃₀ (D. Burkoff, MD, PhD, personal communication, 2006). Similar to the original derivations, and ß were then calculated by solving the following simultaneous equations: Pm=Vm^ß and 15=V₁₅^ß, where Pm is measured pressure (measured EDP) and Vm is measured volume (measured EDV). Dividing the first equation by the second and solving for ß gives the following: ß=log(Pm/15)/log(Vm/V₁₅). Substituting into the first equation yields this: =Pm/Vm^{[log (Pm/15)/log (Vm/V₁₅)]}. EDPVR curves derived using V₁₅ and V₃₀ were well correlated at multiple parts of the curves.

	Acknowledgments

 
Sources of Funding

This work was funded by Public Health Service (NIH HL63281–4, NIH HL72435–2, and NIH HL55502–7).

Disclosures

None.

	References

Top Abstract Introduction Methods Results Discussion Appendix References

 
1. 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: 251–259.[Abstract/Free Full Text]

2. 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: 1953–1959.[Abstract/Free Full Text]

3. Maurer MS, King DL, El-Khoury Rumbarger L, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card Fail. 2005; 11: 177–187.[CrossRef][Medline] [Order article via Infotrieve]

4. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107: 714–720.[Abstract/Free Full Text]

5. Baicu CF, Zile MR, Aurigemma GP, Gaasch WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation. 2005; 111: 2306–2312.[Abstract/Free Full Text]

6. Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006; 113: 2089–2096.[Abstract/Free Full Text]

7. Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006; 113: 296–304.[Free Full Text]

8. van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006; 113: 1966–1973.[Abstract/Free Full Text]

9. Melenovsky V, Borlaug B, Rosen B, Hay I, Ferrucci L, Morell C, Lakatta E, Najjar S, Kass D. Cardiovascular features of heart failure with pre-served ejection fraction versus non-failing hypertensive left ventricular hypertrophy in the urban Baltimore community. J Am Coll Cardiol. 2007; 49: 198–207.[Abstract/Free Full Text]

10. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W. Recommendations for chamber quantification. Eur J Echocardiogr. 2006; 7: 79–108.[Abstract/Free Full Text]

11. Chen CH, Fetics B, Nevo E, Rochitte CE, Chiou KR, Ding PA, Kawaguchi M, Kass DA. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001; 38: 2028–2034.[Abstract/Free Full Text]

12. Kelly RP, Ting C-T, Yang T-M, Liu C-P, Maughan WL, Chang M-S, Kass DA. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992; 86: 513–521.[Abstract/Free Full Text]

13. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. 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: 1788–1794.[Abstract/Free Full Text]

14. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, Lee MM, Park YB, Choi YS, Seo JD, Lee YW. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997; 30: 474–480.[Abstract]

15. Klotz S, Hay I, Dickstein ML, Yi GH, Wang J, Maurer MS, Kass DA, Burkhoff D. Single-beat estimation of end-diastolic pressure–volume relationship: a novel method with potential for noninvasive application. Am J Physiol Heart Circ Physiol. 2006; 291: H403–H412.[Abstract/Free Full Text]

16. 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: 194–202.[Abstract/Free Full Text]

17. Pakhomov SV, Buntrock J, Chute CG. Prospective recruitment of patients with congestive heart failure using an ad-hoc binary classifier. J Biomed Inform. 2005; 38: 145–153.[CrossRef][Medline] [Order article via Infotrieve]

18. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic–angiographic correlations in the presence of absence of asynergy. Am J Cardiol. 1976; 37: 7–11.[CrossRef][Medline] [Order article via Infotrieve]

19. Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol. 2003; 41: 1036–1043.[Abstract/Free Full Text]

20. Chemla D, Hebert JL, Coirault C, Zamani K, Suard I, Colin P, Lecarpentier Y. Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans. Am J Physiol. 1998; 274: H500–H505.[Medline] [Order article via Infotrieve]

21. Senzaki H, Chen CH, Kass DA. Single-beat estimation of end-systolic pressure–volume relation in humans: a new method with the potential for noninvasive application. Circulation. 1996; 94: 2497–2506.[Abstract/Free Full Text]

22. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular–vascular stiffening: a community-based study. Circulation. 2005; 112: 2254–2262.[Abstract/Free Full Text]

23. Maurer MS, El Khoury Rumbarger L, King DL. Ventricular volume and length in hypertensive diastolic heart failure. J Am Soc Echocardiogr. 2005; 18: 1051–1057.[CrossRef][Medline] [Order article via Infotrieve]

24. Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure–volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol. 2005; 289: H501–H512.[Abstract/Free Full Text]

25. Liu C-P, Ting C-T, Lawrence W, Maughan WL, Chang M-S, Kass DA. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy: systolic versus diastolic determinants. Circulation. 1993; 88: 1893–1906.[Abstract/Free Full Text]

26. Borbely A, van der Velden J, Papp Z, Bronzwaer JG, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005; 111: 774–781.[Abstract/Free Full Text]

27. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol. 2006; 47: 500–506.[Abstract/Free Full Text]

28. Chen HH, Lainchbury JG, Senni M, Bailey KR, Redfield MM. Diastolic heart failure in the community: clinical profile, natural history, therapy, and impact of proposed diagnostic criteria. J Card Fail. 2002; 8: 279–287.[CrossRef][Medline] [Order article via Infotrieve]

29. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation. 2000; 101: 2118–2121.[Free Full Text]

30. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002; 288: 2144–2150.[Abstract/Free Full Text]

31. Lopez B, Gonzalez A, Querejeta R, Larman M, Diez J. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol. 2006; 48: 89–96.[Abstract/Free Full Text]

32. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005; 11: 191–195.[CrossRef][Medline] [Order article via Infotrieve]

---

 

CLINICAL PERSPECTIVE

In this large, population-based study, patients with heart failure and normal ejection fraction (HFnlEF) were compared with both healthy and hypertensive control subjects with normal EF. The HFnlEF patients had worse renal function than the healthy or hypertensive control subjects and displayed variable left ventricular geometry. However, on average, HFnlEF patients had reduced left ventricular volumes and cardiac output compared with hypertensive control subjects. Although HFnlEF patients displayed vascular and ventricular systolic stiffening compared with healthy control subjects, HFnlEF was distinguished from hypertensive heart disease by the presence of more severe diastolic dysfunction and increased left atrial size. These data provide further evidence that diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease and a normal ejection fraction. Thus, strategies to ameliorate diastolic dysfunction may prove efficacious in the prevention or treatment of HFnlEF. Further studies, however, are warranted to characterize the heterogeneity among HFnlEF patients and to investigate differential responses to exercise and other stressors that may contribute to the pathophysiology of this syndrome.

This article has been cited by other articles:

				R. Basu, G. Y. Oudit, X. Wang, L. Zhang, J. R. Ussher, G. D. Lopaschuk, and Z. Kassiri Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2096 - H2108. [Abstract] [Full Text] [PDF]

				W. C. Little and J. K. Oh Echocardiographic Evaluation of Diastolic Function Can Be Used to Guide Clinical Care Circulation, September 1, 2009; 120(9): 802 - 809. [Full Text] [PDF]

				C. Tschope and W. J. Paulus Doppler Echocardiography Yields Dubious Estimates of Left Ventricular Diastolic Pressures Circulation, September 1, 2009; 120(9): 810 - 820. [Full Text] [PDF]

				J. A. Chirinos, E. R. Rietzschel, M. L. De Buyzere, D. De Bacquer, T. C. Gillebert, A. K. Gupta, P. Segers, and on behalf of the Asklepios investigators Arterial Load and Ventricular-Arterial Coupling: Physiologic Relations With Body Size and Effect of Obesity Hypertension, September 1, 2009; 54(3): 558 - 566. [Abstract] [Full Text] [PDF]

				B. A. Borlaug, C. S.P. Lam, V. L. Roger, R. J. Rodeheffer, and M. M. Redfield Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J. Am. Coll. Cardiol., July 28, 2009; 54(5): 410 - 418. [Abstract] [Full Text] [PDF]

				S. S. Najjar Heart failure with preserved ejection fraction failure to preserve, failure of reserve, and failure on the compliance curve. J. Am. Coll. Cardiol., July 28, 2009; 54(5): 419 - 421. [Full Text] [PDF]

				E.-Y. Choi, B. W. Choi, S.-A. Kim, S. J. Rhee, C. Y. Shim, Y. J. Kim, S.-M. Kang, J.-W. Ha, and N. Chung Patterns of late gadolinium enhancement are associated with ventricular stiffness in patients with advanced non-ischaemic dilated cardiomyopathy Eur J Heart Fail, June 1, 2009; 11(6): 573 - 580. [Abstract] [Full Text] [PDF]

				C. S.P. Lam, B. A. Borlaug, G. C. Kane, F. T. Enders, R. J. Rodeheffer, and M. M. Redfield Age-Associated Increases in Pulmonary Artery Systolic Pressure in the General Population Circulation, May 26, 2009; 119(20): 2663 - 2670. [Abstract] [Full Text] [PDF]

				C. S.P. Lam, V. L. Roger, R. J. Rodeheffer, B. A. Borlaug, F. T. Enders, and M. M. Redfield Pulmonary hypertension in heart failure with preserved ejection fraction a community-based study. J. Am. Coll. Cardiol., March 31, 2009; 53(13): 1119 - 1126. [Abstract] [Full Text] [PDF]

				G. D. Lewis The role of the pulmonary vasculature in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol., March 31, 2009; 53(13): 1127 - 1129. [Full Text] [PDF]

				M. T. Maeder and D. M. Kaye Heart failure with normal left ventricular ejection fraction. J. Am. Coll. Cardiol., March 17, 2009; 53(11): 905 - 918. [Abstract] [Full Text] [PDF]

				J. Wang and S. F. Nagueh Current Perspectives on Cardiac Function in Patients With Diastolic Heart Failure Circulation, March 3, 2009; 119(8): 1146 - 1157. [Full Text] [PDF]

				F. Antonini-Canterin, S. Carerj, V. Di Bello, G. Di Salvo, S. La Carrubba, O. Vriz, D. Pavan, A. Balbarini, G. L. Nicolosi, and On behalf of the Research Group of the Italian Soc Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view Eur J Echocardiogr, January 1, 2009; 10(1): 36 - 43. [Abstract] [Full Text] [PDF]

				J. McMurray, M. Petrie, K. Swedberg, M. Komajda, S. Anker, and R. Gardner CHAPTER 23 Heart Failure ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]

				B. R. Davis, J. B. Kostis, L. M. Simpson, H. R. Black, W. C. Cushman, P. T. Einhorn, M. A. Farber, C. E. Ford, D. Levy, B. M. Massie, et al. Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Circulation, November 25, 2008; 118(22): 2259 - 2267. [Abstract] [Full Text] [PDF]

				W. C. Little Hypertension, Heart Failure, and Ejection Fraction Circulation, November 25, 2008; 118(22): 2223 - 2223. [Full Text] [PDF]

				P. D. Chantler, E. G. Lakatta, and S. S. Najjar Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise J Appl Physiol, October 1, 2008; 105(4): 1342 - 1351. [Abstract] [Full Text] [PDF]

				M. R. Zile, T. D. Bennett, M. St. John Sutton, Y. K. Cho, P. B. Adamson, M. F. Aaron, J. M. Aranda Jr, W. T. Abraham, F. W. Smart, L. W. Stevenson, et al. Transition From Chronic Compensated to Acute Decompensated Heart Failure: Pathophysiological Insights Obtained From Continuous Monitoring of Intracardiac Pressures Circulation, September 30, 2008; 118(14): 1433 - 1441. [Abstract] [Full Text] [PDF]

				N C Edwards, C J Ferro, J N Townend, and R P Steeds Aortic distensibility and arterial-ventricular coupling in early chronic kidney disease: a pattern resembling heart failure with preserved ejection fraction Heart, August 1, 2008; 94(8): 1038 - 1043. [Abstract] [Full Text] [PDF]

				L Ingle, J G F Cleland, and A L Clark Perception of symptoms is out of proportion to cardiac pathology in patients with "diastolic heart failure" Heart, June 1, 2008; 94(6): 748 - 753. [Abstract] [Full Text] [PDF]

				R. Borrows, M. Loucaidou, G. Chusney, S. Borrows, J. V. Tromp, T. Cairns, M. Griffith, N. Hakim, A. McLean, A. Palmer, et al. Anaemia and congestive heart failure early post-renal transplantation Nephrol. Dial. Transplant., May 1, 2008; 23(5): 1728 - 1734. [Abstract] [Full Text] [PDF]

				D. Westermann, M. Kasner, P. Steendijk, F. Spillmann, A. Riad, K. Weitmann, W. Hoffmann, W. Poller, M. Pauschinger, H.-P. Schultheiss, et al. Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction Circulation, April 22, 2008; 117(16): 2051 - 2060. [Abstract] [Full Text] [PDF]

				S. J. Lester, A. J. Tajik, R. A. Nishimura, J. K. Oh, B. K. Khandheria, and J. B. Seward Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later. J. Am. Coll. Cardiol., February 19, 2008; 51(7): 679 - 689. [Abstract] [Full Text] [PDF]

				B. P. Shapiro, T. E. Owan, S. Mohammed, M. Kruger, W. A. Linke, J. C. Burnett Jr, and M. M. Redfield Mineralocorticoid Signaling in Transition to Heart Failure With Normal Ejection Fraction Hypertension, February 1, 2008; 51(2): 289 - 295. [Abstract] [Full Text] [PDF]

				L. van Heerebeek, N. Hamdani, M. L. Handoko, I. Falcao-Pires, R. J. Musters, K. Kupreishvili, A. J.J. Ijsselmuiden, C. G. Schalkwijk, J. G.F. Bronzwaer, M. Diamant, et al. Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension Circulation, January 1, 2008; 117(1): 43 - 51. [Abstract] [Full Text] [PDF]

				W.H. W. Tang and G. S. Francis The Year in Heart Failure J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2344 - 2351. [Full Text] [PDF]

				J.-M. Tartiere, L. Tartiere-Kesri, and A. Cohen Solal Letter by Tartiere et al Regarding Article, "Cardiac Structure and Ventricular Vascular Function in Persons With Heart Failure and Preserved Ejection Fraction From Olmsted County, Minnesota" Circulation, December 11, 2007; 116(24): e562 - e562. [Full Text] [PDF]

				C. S.P. Lam, V. L. Roger, R. J. Rodeheffer, B. A. Borlaug, S. R. Ommen, M. M. Redfield, F. Bursi, and D. A. Kass Response to Letter Regarding Article, "Cardiac Structure and Ventricular Vascular Function in Persons With Heart Failure and Preserved Ejection Fraction From Olmsted County, Minnesota" Circulation, December 11, 2007; 116(24): e563 - e563. [Full Text] [PDF]

				W. H. Gaasch and W. C. Little Assessment of Left Ventricular Diastolic Function and Recognition of Diastolic Heart Failure Circulation, August 7, 2007; 116(6): 591 - 593. [Full Text] [PDF]

				H. K. Dandapantula, L. Afonso, H. Katkuri, L. Chandu, J. R. Spears, B. P. Shapiro, M. M. McGoon, and M. M. Redfield Unexplained Pulmonary Hypertension in Elderly Patients: Role of Heart Failure With Normal Ejection Fraction, Bernheim Effect, and Reverse Bernheim Effect Chest, June 1, 2007; 131(6): 1987 - 1988. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Correction Correction (v115,pe535) All Versions of this Article: 115/15/1982    most recent CIRCULATIONAHA.106.659763v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lam, C. S.P. Articles by Redfield, M. M. Search for Related Content PubMed PubMed Citation Articles by Lam, C. S.P. Articles by Redfield, M. M. Related Collections Cardio-renal physiology/pathophysiology Other heart failure Congestive Other hypertension Clinical Studies