Lack of Diastolic Reserve in Patients With Heart Failure and Normal Ejection FractionCLINICAL PERSPECTIVE
Background— The genesis of symptoms in patients with heart failure (HF) and normal ejection fraction (HFNEF) is unclear. Most investigations of HFNEF have focused on cardiac function at rest although most of these patients are breathless only on exercise. Stress-induced impairment in systolic or diastolic function could result in these symptoms.
Method and Result— Forty-one patients with HFNEF and 29 controls underwent dobutamine stress echocardiography with color tissue Doppler imaging. Wall motion score index and regional myocardial systolic velocity (Sm) were measured at and peak stress. Systolic (Sa), early diastolic (Ea), and late diastolic (Aa) mitral annular velocities were averaged over the 6 periannular sites. Mitral annular long-axis velocity was lower in the HFNEF than controls at rest. Global, regional, and long-axis systolic function did not worsen with stress in the HFNEF group. The Ea decreased and the E/Ea increased with stress in the HFNEF but not in controls. The 6-minute walk distance was shorter and negatively correlated to the E/EA ratio at rest and stress in the HFNEF group.
Conclusion— Impaired diastolic reserve results in stress-induced increase in the left ventricular end-diastolic pressure in patients with HFNEF giving rise to exercise intolerance.
- heart failure with normal ejection fraction
- diastolic heart failure
- stress echocardiography
- tissue Doppler imaging
- exercise tolerance
Received October 3, 2008; accepted July 29, 2009.
The clinical syndrome of heart failure (HF) may arise in the absence of any substantial abnormality of conventionally measured left ventricular ejection fraction (LVEF). Epidemiological studies suggest that up to half of subjects with HF have a normal LVEF.1–6 The genesis of HF in the absence of reduced global LV systolic function is uncertain and may reflect a great deal of heterogeneity. Misdiagnosis may account for a proportion of cases.7 Transient LV systolic dysfunction may occur because of ischemia or arrhythmia,8 although serial echocardiographic studies have suggested that this is rare.9 Many patients do have selective impairment of long-axis systolic and diastolic dysfunction at rest that do not manifest as a major impairment of global LVEF.10,11
Clinical Perspective on p 35
Most investigations of HF and normal ejection fraction (HFNEF) have focused on cardiac function at rest; however, most patients are breathless only on exertion. The pathophysiological basis of the exercise-induced symptoms and signs in these patients with HFNEF have not been well characterized.
Dobutamine stress echocardiography (DSE) is a standardized method of assessing the heart under stress. Using color tissue Doppler imaging (cTDI) with DSE, global, regional, and longitudinal systolic and diastolic function can be measured.12,13 We used these techniques to test the hypothesis that stress-induced diastolic impairment occurs and might contribute to exercise-induced breathlessness in patients with HFNEF.
From a cohort of 200 consecutive patients with suspected HF referred to a community-based HF program between January 2002 and June 2003, we identified 41 subjects within HFNEF group. The diagnosis of HF was based on clinical evaluation by a cardiologist on the basis of the patients’ previous and current history and physical examination. In concordance with the ESC definition of HF,14 most had previous hospital admissions with acute breathlessness, clinical, and/or radiological evidence of pulmonary congestion, and clinical improvement with diuresis. Patients with pacemakers, severe valvular disease, prosthetic heart valves, inadequate echocardiographic window, and contraindication to DSE were excluded.
Twenty-nine other subjects, referred to the program with suspected HF, without a history of diabetes, hypertension, angina, myocardial infarction (MI), with normal ECG, echocardiogram, and whose breathlessness was thought to be due to other problems (13 with obesity, 8 with obstructive airways disease, 1 with restrictive airways disease, 5 with obesity and obstructive airways disease, and 2 with undetermined cause) acted as controls (control group). All subjects gave written informed consent. The Medical Ethics Committee of the Hull and East Yorkshire NHS Trust approved the protocol.
Demography, medical and drug history, and cardiovascular risk factors were recorded. Hypertension was defined as a previous blood pressure recording on 2 separate occasions of >140 mm Hg systolic or >90 mm Hg diastolic or the ongoing prescription of antihypertensive medication. MI was defined according to World Health Organization criteria. Ischemic heart disease was defined as a history of MI, unstable angina, or angiographic evidence of >50% stenosis of 1 or more coronary arteries with or without a history of revascularization. Patients underwent physical examination, a 12-lead ECG, chest radiograph, and pulmonary function tests. Body mass index >25 kg/m2 was considered overweight and that >30 kg/m2 as obese. Airways disease was diagnosed if FEV1/FVC ratio was <75%. Patients underwent a 6-minute walk test.
Every subject underwent a standard echocardiographic examination and cTDI (GE Vingmed Vivid Five scanner, Horten, Norway). All analyses were done off-line (Echopac 6.3, GE, Vingmed). LV mass was calculated and indexed to the body surface area.15 LV hypertrophy was defined as LV mass index >134 g/m2 in men and >110 g/m2 in women. LV volumes were measured from manually traced endocardial borders and indexed for the body surface area.15 LVEF was measured using modified Simpson rule. E, A velocity, E-wave deceleration time (EDT), and isovolumic relaxation time were measured.
A standard DSE protocol for ischemia was used after discontinuation of β-blockers for 48 hours.16 The test end points were target heart rate (0.85×[220−age]), new or worsening regional wall motion abnormality affecting at least 2 contiguous segments, ventricular arrhythmias, hypotension, significant ST changes, angina, or severe breathlessness. Atropine was administered if end points were not reached with 40 μg · kg−1 · min−1 of dobutamine. Standard images16 (3 cycles edited to exclude ectopic beats) in gray scale with superimposed cTDI data and mitral inflow spectral Doppler were obtained at rest and each stage with breath held in expiration maintaining frame rates of 90 to 100 s−1. Images at rest and peak stress were analyzed off-line. The wall motion score index (WMSI) was calculated at rest and peak stress.15,16 The diastolic mitral inflow variables were measured at rest and at the highest heart rate, where the E and the A waves were separately identified. EDT and isovolumic relaxation time were corrected for heart rate using the Bazett formula.
Annular tissue velocity in systole (Sa), early diastole (Ea), and late diastole (Aa) were measured at rest as previously described.10,11 Sa was measured at peak stress and Ea and Aa at the heart rate at which E and A velocities could be separately measured. Ea/Aa and E/Ea ratios were calculated. Segmental myocardial tissue velocity in systole (Sm) was measured in the 12 nonapical segments at rest and peak stress. A variable was considered abnormal at rest if it was outside the 2SD of published normal values for age and sex.17 The response of Ea, Ea/Aa, and E/Ea ratio to stress was considered the most relevant diastolic parameter for the assessment of these patients. All the images were analyzed by a single investigator (S.C.) blinded to the clinical characteristics of the patients.
To assess the reproducibility of measurements, Sa, Ea, Aa, and Sm were measured in 10 randomly selected patients at rest and peak stress totaling 600 observations.
All analysis were performed using commercially available software (SigmaStat version 3.5, Systat Software, Inc, San Jose, Calif). The continuous variables were described as means and SD, and the categorical data were described as percentages. The means between the study groups were compared by Student unpaired t test assuming unequal variance and Mann-Whitney Rank Sum test as appropriate. The data at rest and peak stress within each group were compared by Student paired t test and Wilcoxon Signed Rank test as appropriate. Proportions were compared using the χ2 test. A 2-tailed P value <0.05 was considered significant. Univariate linear regression analysis was used to correlate the 6-minute walk distance to age, sex, body mass index, maximum heart rate, LV mass, LVEF at rest and E and A velocities, E/A ratio, EDT, isovolumic relaxation time, Sa, Ea, Aa, Ea/Aa ratio, and E/Ea ratio at rest and peak stress. The variables that yielded a P<0.2 were then included in a multiple regression analysis. Pearson correlation was used to determine the associations between individual continuous variables and exercise capacity.
Differences in the measurements of Sa, Ea, Aa, and Sm made by the same investigator (intraobserver variability) were calculated in 10 randomly selected patients at rest and peak stress and reported as mean±SD. Confidence limits (95%) of differences were expressed as absolute values and percentages of the average values of paired velocity measurements.
Modeling the Change Between the Stressed and Resting States
For each variable, a within-pair difference between the stressed and resting state was calculated. Differences between the 2 groups (HFNEF versus controls) were modeled by least-squares regression. The reference group was the controls. Residuals were checked for normality. Each regression model was adjusted for the said resting value, plus age, sex, etiology (diabetes mellitus, MI, and hypertension), resting blood pressure, ejection fraction, LV mass index, and heart rate. CI were generated from 1000 bootstrap resamples.18
Patients with HFNEF (Table 1⇓) had a higher prevalence of hypertension and previous MI and greater use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β-blockers, and spironolactone. The mean body mass index and the prevalence of obesity were similar in each group. The mean FEV1/FVC ratio was higher in the HFNEF group but a similar proportion in each group had a ratio <75%. The blood pressure and LVEF (Table 1⇓) were higher on average in patients with HFNEF.
The intraobserver variability for all velocities was <10% at rest (Sa, 2.4% to 8.1%; Ea, 3.4% to 8.3%; Aa, 3.3% to 8.1%; and Sm, 3.2% to 9.8%) and 13% at stress (Sa, 2.1% to 9.3%; Ea, 2.9% to 12.7%; Aa, 2.7% to 6.3%; and Sm, 4.1% to 12.4%). The reproducibility of the annular measurements was better then that of the myocardial segments.
Response to Stress
No major adverse event occurred during DSE (Table 1⇑). The final dose of dobutamine was higher in the controls. The blood pressures increased with stress in both groups. Intraobserver variability of the measured myocardial velocities remained low at rest (<10%) and peak stress (<15%).
The WMSI was similar in both groups at rest and at stress and did not worsen with stress in either group (Figure 1). Fifty-one percent and 59% patients at rest (P=0.540) and 68% and 69% patients at peak stress (P=0.952) had WMSI of 1 in the HFNEF and control groups, respectively (P=0.12 rest versus stress in HFNEF and P=0.41 rest versus stress in controls). The increases in WMSI did not exceed 20% in any subject. A response to stress could be assigned to 96.5% segments in the HFNEF group and 91.6% in controls (P<0.001). Except for a higher prevalence of scars in the HFNEF group (1.6% versus 0% in the controls, P=0.01), the segmental response to stress was similar in the 2 groups (Table 1⇑).
Six patients in the HFNEF group and none in the control group had low-averaged periannular Sa at rest. It increased from rest to stress in all subjects and by >20% in 90.2% and 89.7% patients in HFNEF and control groups, respectively. Sa was lower in the HFNEF group than the controls at rest and peak stress and increased with stress in both groups (Figure 1). Even after adjusting for a number of baseline covariates, the stress-induced increase in Sa in the HFNEF group was not dissimilar to the controls (Table 2).
Among the segments that could be assessed quantitatively at rest (97.2% in the HFNEF and 98.9% in controls), Sm was low in 18.4% and 9.9% segments in the HFNEF and control groups, respectively (P=0.001). Among the segments that could be assessed quantitatively at rest and stress, the Sm decreased with stress in 27.6% of individual segments in the HFNEF group compared with 28.7% in controls (P=0.73). After adjusting for baseline covariates, the stress-induced increase in Sm in HFNEF group was similar to the controls (Table 2).
The peak LV outflow tract velocity and pressure in the HFNEF group was similar to controls both at rest and at peak stress and increased with stress in both groups. The stress-induced increase in these parameters in HFNEF group was significantly higher compared with controls. This relationship was maintained after adjusting for a number of baseline covariates (Table 2).
Conventionally measured LV diastolic dysfunction was seen in 39% of patients (14 with slow isovolumic relaxation and 2 with restrictive filling pattern) with HFNEF and 52% of the controls (15 with slow isovolumic relaxation), respectively (P=0.29). The changes in the prevalence of the diastolic variables with stress were similar in the 2 groups (Figure 2). E/A decreased with stress by >20% in 26% and 33% patients in HFNEF and controls, respectively (P=0.53). Among the subjects with normal EDT at rest, it increased or failed to decrease in 50% in the HFNEF and 42% in controls (P=0.61) with stress. Among the patients with normal isovolumic relaxation time at rest, it failed to decrease in 58% and 43% in the 2 groups (P=0.37). After adjusting for several baseline covariates, the stress-induced changes in conventional LV diastolic parameters were similar in both groups (Table 2).
With stress, Ea increased in fewer and decreased in greater number of patients than controls (Figure 2).The Ea decreased by ≥20% in 47.5% and 17.3% (P=0.01) and increased similarly in 7.5% and 24.1% (P=0.05) in the HFNEF and controls, respectively. At rest, Ea and Ea/Aa in the HFNEF group was similar to controls. These decreased with stress in the HFNEF group but not in the controls (Figure 3). With stress, E/Ea increased in greater number of patients than controls and decreased in less number of patients than controls (Figure 2). It increased by ≥20% in 72.5% and 31.0% (P=0.001) subjects in the 2 groups, respectively. Among those whose Ea decreased with stress, the E/Ea increased in 97.1% patients in the HFNEF group and 58.3% in the controls (P=0.001). E/Ea in the HFNEF group was higher than the controls at rest and increased only in the HFNEF group with stress (Figure 3). The changes in the Ea, Ea/Aa, and E/Ea with stress in the HFNEF group compared with controls were maintained after adjusting for a number of baseline covariates (Table 2).
The 6-minute walk distance was shorter in HFNEF group compared with controls. On univariate analysis, E/Ea (P<0.001), Ea (P=0.01), E (P<0.001), A (P=0.028) at peak stress; E/Ea (P<0.001), EDT (P=0.045), E (P=0.042), A (P=0.014) at rest; and age (P=0.003) correlated with the 6-minute walk distance. On multivariate analysis, however, only Ea (P=0.014) and E (P=0.042) at peak stress was found be predictive of the 6-minute walk distance. There was a negative correlation between the distance walked and the E/Ea ratio at rest and stress (Figure 4) in the HFNEF group.
This study excludes stress-induced LV systolic dysfunction as a common cause of symptoms in patients with HFNEF. Obesity and obstructive airways disease are also unlikely to account for these symptoms. Impaired diastolic relaxation provoked by stress associated with increased LV end-diastolic pressure is likely to reduce exercise tolerance in these patients.
The symptoms in patients with HFNEF have been attributed to obesity, respiratory disease, and myocardial ischemia.7 This study does not support these hypotheses. High body mass index and abnormal spirometry were equally prevalent in the HFNEF and control groups. Search for myocardial ischemia, transient but extensive enough to impair global LV systolic function has rarely been undertaken in these patients. In most studies, history of coronary artery disease, electrocardiographic evidence of MI or ischemia, and coronary angiography have been used as evidence of ischemia.7,19 Ischemia was systematically evaluated in only 1 (n=20)20 of the 11 studies (n=763) reviewed by Choudhury et al and was found to be absent. Preserved LV systolic function during episodes of pulmonary edema has been reported in hypertensives.9 Studies have suggested exclusive diastolic impairment in patients with HFNEF.21,22 In our patients with HFNEF, global, regional, and long-axis systolic function did not worsen with stress, suggesting that ischemia-induced systolic dysfunction is an unlikely cause of HF. The lack of evidence of LV systolic dysfunction in patients with HFNEF may be due to the remoteness of its estimation relative to the episode of HF.3 Although we did not assess LV function in relation to an episode of HF, it is unlikely that these symptoms were due to LV systolic dysfunction, in the absence of stress-induced systolic abnormalities.
Impaired LV long-axis systolic function at rest has been reported in HFNEF.10,11,23 Consistent with these studies, the resting Sa was lower in the patients compared with controls. Baicu et al21 argued that the impaired resting long-axis systolic function reported in these studies10,11,23 resulted from the inclusion of a substantial number of the patients LVEF <0.50 into the HFNEF group. None of our patients with HFNEF had LVEF <0.50. Contrary to a previous report,24 the Sm of most segments in the 2 groups were similar at rest. The Sa and Sm increased during stress in the HFNEF group as in controls, suggesting improvement rather than a deterioration of the long-axis function with stress.
Effect of Stress on Diastolic Function
The changes in the indices of diastolic function in the controls were consistent with the effects of exercise on these indices in normal middle-aged subjects.25 The effect of stress on LV diastolic indices has rarely been studied in patients with HFNEF. Kitzman et al26 demonstrated an increase in LV filling pressure with exercise in 7 patients with HF and preserved systolic function. Similar changes have been reported in normotensive patients with normal LVEF without inducible myocardial ischemia and exaggerated systolic blood pressure (SBP) response to exercise27 and in about one-third of patients with conventional indications for cardiac catheterization.28 Although these studies did not assess the effect of stress on the diastolic indices specifically in patients with HFNEF, our conclusion that stress impairs LV diastolic relaxation resulting in an increase in the LV end-diastolic pressure in patients with HFNEF is consistent with these findings. The causal relation between exercise intolerance and stress-induced diastolic impairment seen in our study has also been demonstrated in patients with exercise intolerance and normal LV systolic function.28,29
Mechanisms of Stress-Induced Diastolic Dysfunction
The diastolic dysfunction induced by dobutamine stress may have resulted from ischemia, increased SBP, and induced tachycardia. Impaired ventricular relaxation may be a manifestation of early ischemia. Myocardial ischemia impairs ventricular relaxation earlier than systolic contraction.30 In patients with coronary artery disease, ischemia induced by pacing,31 dipyridamole,32 dobutamine,33,34 and exercise35 results in a transmitral flow pattern consistent with delayed relaxation. Even transient, reversible episodes of ischemia can impair LV relaxation and elevate LV filling pressures.36 Regional impairment of myocardial relaxation of ischemic segments has been seen at rest even when systolic contraction is preserved37 and after dobutamine stress38 and coronary occlusion.39
Stress-induced tachycardia may have worsened ischemic diastolic relaxation by increasing myocardial oxygen demand and decreasing coronary perfusion time. Shortening the diastole allows less time for relaxation. This is further amplified in hypertrophied and fibrosed myocardium that is unable to generate a higher rate of diastolic relaxation causing the diastolic pressures to increase.40,41
Stress-induced elevation of SBP may have contributed. Elevated SBP slows LV relaxation due to increased afterload with a resultant increase in the LA pressure.42 In hypertensives, a rapid increase in SBP at rest9 or after exercise27 results in deterioration of LV diastolic function without worsening systolic function. Similar changes in response to stress have been demonstrated in patients with HFNEF.43
Pharmacological stress used in this study may differ qualitatively from exercise. This choice permitted us to investigate patients who were elderly with poor exercise capacity and mobility. The problem of inadequate image quality because of the increased rate and depth of breathing, after exercise stress, was eliminated. The lack of diagnostic gold standard for diastolic HF made diagnosis difficult. The diastolic blood flow and annular velocities were measured at submaximal heart rates to avoid the problem of fusion of these velocities at peak stress. This strategy was reasonable considering that these breathless patients were unlikely to generate maximal heart rates during daily living. The E/Ea ratio measured was higher than previously reported.12,13 This is because myocardial velocities measured by cTDI in this study are lower than that measured by pulsed TDI.44 The left atrial diameter measured in the parasternal long-axis view may not have reflected the true increase in LA size that often occurs in the apicobasal direction in patients with HFNEF. The study group was heterogeneous comprising patients with ischemic heart disease, MI, hypertension, and diabetes, all of which may have influenced LV relaxation. The study involved small number of patients, and the findings need to be confirmed on a larger population.
Stress does not commonly induce systolic dysfunction in patients with HFNEF. It is unlikely that exercise intolerance is due to global regional or long-axis systolic dysfunction or other noncardiac causes. Abnormalities in diastolic function are often induced or exacerbated by stress in these patients, whether the final diagnosis is thought to be diastolic HF. Stress-induced impairment of early diastolic relaxation with consequent rise in the LV end-diastolic pressure is the likely cause of exercise intolerance. This study suggests that routine stress echocardiography may be useful in fully evaluating these patients. However, the use of the test is uncertain till it is shown to predict symptoms, morbidity, mortality, and effects of treatment.
Sources of Funding
This work was supported by British Heart Foundation Grant PG/2001/1088.
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The genesis of symptoms of breathlessness in patients with heart failure and normal ejection fraction has been poorly elucidated. Although most of these patients are breathless only on exertion, most investigations of heart failure and normal ejection fraction have focused on cardiac function at rest. We attempted to characterize the pathophysiological basis of this exercise-induced breathlessness by use of dobutamine stress echocardiography and tissue Doppler imaging. The study suggests that exercise intolerance, as measured by the 6-minute walk distance, in patients with heart failure and normal ejection fraction is due to a stress-induced impairment in the diastolic relaxation of the left ventricle with resultant increase in the left ventricular end-diastolic pressure. Overt global or regional systolic dysfunction because of stress-induced ischemia was not seen in our patients. The mitral annular systolic velocity at rest is lower in these patients, suggesting an impaired long-axis function. However, this increases with stress similar to controls. Dobutamine stress echocardiography unmasked the diastolic abnormality and excluded significant inducible ischemia as the cause of these symptoms. Thus, routine stress echocardiography may be useful in fully evaluating these patients. Exercise may be more appropriate stressor than dobutamine.