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Quantification of left ventricular performance in different heart failure phenotypes by comprehensive ergometry stress echocardiography
International Journal of Cardiology 169 (2013) 311–315
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Quantification of left ventricular performance in different heart failure phenotypes by comprehensive ergometry stress echocardiography Jing Wang a, Fang Fang a, Gabriel Wai-Kwok Yip b, John E. Sanderson a, Wei Feng a, Jun-Min Xie a, Xiu-Xia Luo a, Cheuk-Man Yu a, Yat-Yin Lam a,⁎ a Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, S.H. Ho Cardiovascular Disease and Stroke Centre, Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong b Cardiac Medicine Unit, Grantham Hospital, Hong Kong
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Article history: Received 3 May 2013 Received in revised form 3 August 2013 Accepted 27 September 2013 Available online 3 October 2013 Keywords: Left ventricular performance HFPEF HFREF Stress echocardiography
a b s t r a c t Background: We evaluated the left ventricular (LV) performance in patients with heart failure and preserved ejection fraction (HFPEF) during exercise as compared to those with heart failure and reduced ejection fraction (HFREF) and healthy subjects. Methods: All subjects received echocardiographic (Vivid7, GE Healthcare) examination with symptom-limited exercise testing on a semi-recumbent and tilting bicycle ergometer (Lode BV, Netherlands). The exercise images for 2-dimensional (2D) speckle tracking were acquired with heart rate of 90–100 bpm, while exercise images for tissue Doppler imaging (TDI) and M-mode echocardiography were stored with attainment of N85% of maximal age-predicted heart rate. Results: Stress echocardiographic examinations were performed in 40 HFPEF (aged 65 ± 9 years; 53% male), 40 HFREF (aged 62 ± 9 years; 90% male) and 30 normal controls (aged 56 ± 5 years; 33% male). Trends of progressive decline in 2D global longitudinal, circumferential and radial strains (GLS, GCS and GRS); TDI septal s′ and Sm; and M-mode mitral annular plane systolic excursion (MAPSE) were observed from control, HFPEF to HFREF groups (p b 0.05 for all). LV twist was preserved in HFPEF but reduced in HFREF patients as compared to normal controls (p b 0.05). Diastolic function measured by TDI septal e′, Em and septal E/e′ progressively decreased from controls, HFPEF to HFREF patients (all p b 0.05). Stroke volumes and cardiac indices (LVSI & LVCI) were preserved in HFPEF but deteriorated in HFREF than controls. Conclusions: This study provides the reference values of LV performance during exercise in HFPEF and knowledge about these changes provide important insights for future clinical studies. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction About half of the patients presenting with symptoms and signs of heart failure have a preserved ejection fraction (HFPEF) [1,2]. These patients have severe chronic symptoms, reduced exercise tolerance and mortality comparable to those with heart failure and reduced ejection fraction (HFREF) [1–4]. In contrast to the tremendous resources devoted to evaluate the pathophysiology and treatment of HFREF, HFPEF remains understudied [5,6]. Westermann et al. [7] showed that patients with HFPEF had increased left ventricular (LV) stiffness at rest. Our group, using speckle tracking echocardiography, also [8] revealed a range of global and regional LV systolic and diastolic abnormalities at rest for HFPEF patients.
⁎ Corresponding author. Tel.: +852 2632 1299; fax: +852 2637 3852. E-mail address: [email protected] (Y.-Y. Lam). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.09.010
Both of these studies evaluated LV function at rest despite the primary symptom of HFPEF being breathlessness on exertion. As exercise intolerance is the dominant symptom for HFPEF patients leading to loss of ambulatory ability, evaluating LV performance on exercise may be more relevant to the pathophysiology of HFPEF. New developments in echocardiography enable a more comprehensive assessment of LV systolic and diastolic function, including measurements of myocardial deformation, ventricular twist, annular motion (longitudinal function) and LV suction, which potentially provides better mechanistic insight into ventricular adaptation of HFPEF on exercise [9–11]. There are limited comprehensive data about LV performance during stress in different heart failure phenotypes. We therefore compare the LV systolic and diastolic function on exercise in three groups of subjects: patients with HFPEF, patients with HFREF and health controls using state-of-the-art echocardiography [standard two-dimensional (2D), M-mode, tissue Doppler imaging (TDI) and 2D speckle tracking echocardiography].
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2. Methods 2.1. Study population A prospective cohort of 80 patients with symptoms or signs of congestive heart failure was recruited. Among these patients, forty met the criteria of the Heart Failure and Echocardiography Associations of the European Society of Cardiology for HFPEF with left ventricular ejection fraction (LVEF) ≥50%, and another forty had HFREF with LVEF b50% [12]. Thirty normal healthy subjects with unremarkable clinical assessments and normal echocardiographic findings were included as controls. All eligible patients were carefully screened for non-cardiac causes of heart failure. We excluded patients presenting with acute coronary syndromes or significant coronary artery disease as confirmed by coronary angiography (defined N50% stenosis) or functional cardiac nuclear or magnetic resonance imaging. Patients with HFPEF who has echocardiographic evidence of regional wall motion abnormality were also excluded. Other exclusion criteria include (1) atrial fibrillation, sick sinus syndrome, second or third degree heart block with or without pacemaker, (2) congenital or more-than-mild valvular heart disease, (3) infiltrative, restrictive or hypertrophic cardiomyopathy, (4) obesity by Chinese standard (body mass index N 25 kg/m2, and/or waist circumference N 90 cm for men and N80 cm women) [13], (5) lung diseases such as chronic obstructive pulmonary disease by chest radiography and lung function tests (FEV1/FVC b 0.7) [14], (6) primary renal disease or serum creatinine ≥ 250 μmol/l and/or estimated glomerular filtration rate ≤ 30 ml/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula for Chinese ethnicity, (7) primary hepatic disease or cirrhosis, (8) pregnancy, (9) inability to exercise on an upright bicycle or to withhold cardiovascular medicines for 24 h, and (9) suboptimal echocardiographic image. Beta-blockers were withheld for 24 h and other cardiovascular medications were also withheld on the day of stress test. The study protocol was approved by institution's research ethical committees and informed consent was obtained from all subjects. 2.2. Echocardiography All subjects underwent symptom-limited (fatigue or dyspnea) exercise testing on a semi-recumbent and tilting bicycle ergometer (Lode BV, Netherlands). Their heart rates, blood pressures, symptoms and 12 lead ECG were monitored continuously during exercise. The submaximal heart rate, called pre-peak heart rate, was defined as the achievement of heart rate in the range of 90–100 beats/min, while the maximum heart rate, also called peak heart rate, was defined by attainment of N85% of maximum age-predicted heart rate [85% × (220-age)]. Transthoracic echocardiography (Vivid7, GE Healthcare) was performed using a multi-frequency matrix probe with patients lying left lateral decubitus position during exercise. At least 3 sets of images with loops consisting of 5 consecutive cardiac cycles each were stored for offline analysis with a customized software package (EchoPac, GE Vingmed). Resting LV dimensions were measured and LV mass was estimated and divided by the body surface area (BSA) to derive the LV mass index (LVMI) [15]. LVEF was calculated from apical 2- and 4-chamber views using the modified biplane Simpson's rule [15]. LV sphericity was measured by the LV short-to-long axis dimension ratio in end-diastolic apical 4-chamber view. Left atrial volume was calculated with biplane area–length method from the apical 4- and 2-chamber views and indexed to BSA to derive left atrial volume index (LAVI) [16]. The submaximal exercise echocardiographic images were analyzed offline using 2D speckle tracking echocardiography. The LV apical 4-, 2- and 3-chamber images and parasternal short-axis views at basal, mid-papillary and apical levels were used for assessing 2D LV longitudinal, radial, circumferential strains and rotation with the speckle tracking echocardiography [9–11]. From standard 2D grayscale recordings, myocardial deformation was tracked frame-by-frame automatically within the region of interest bound by endocardial and epicardial borders throughout the cardiac cycle. Global strain was derived from the average of 18 segments in the longitudinal, or radial and circumferential planes—that is, six evenly divided segments in each of the three long-axis or shortaxis views [9–11]. Furthermore, LV twist was calculated as the net difference of peak systolic rotation strain between six basal and six apical segments [17]. The maximal exercise echocardiographic images were analyzed offline with TDI and M-mode echocardiography. The early filling (E), late filling (A) peak velocities, and deceleration time (DT) of early filling were measured from transmitral flow. Stroke volume (SV) was determined by pulse-wave Doppler and indexed by BSA to derive the LV stroke volume index (LVSI). Cardiac index (LVCI) was determined from the product of LVSI and heart rate. The peak systolic (s′), early diastolic (e′) and late diastolic (a′) mitral annular velocities were also measured with pulsed-wave Doppler. The E/e′ ratio was derived from dividing the early mitral inflow velocity by the early diastolic mitral annular velocity [18]. Furthermore, color-coded tissue Doppler images were also acquired over 5 consecutive cardiac cycles for each of the 6 myocardial walls in LV apical views [19]. Systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities were measured by placing a 4 × 4 mm region of interest in the mid-myocardial area of each wall. Additionally, using conventional 2D-guided M-mode echocardiography, mitral annular plane systolic excursion (MAPSE) was estimated from the apical 4-chamber view with the cursor positioned through the septal angle of mitral valve annulus [20]. 2.3. Statistical analysis Sample size was estimated from a pilot study. For LV longitudinal systolic function with anticipated difference in mean of 1.5 and standard deviation (SD) of 2, a sample
size of 30 would provide 90% power with α = 0.01. Statistical analysis was performed with SPSS version 17.0 (Chicago, IL, USA). Continuous variables were expressed as mean ± SD and categorical variables as percentages. Continuous variables between groups during exercise were compared by analysis of covariance in general linear model with LSD post-hoc analysis for subgroup comparisons, adjusted for age, gender and BSA, as well as New York Heart Association (NYHA) class. The p values after adjustment are presented. Categorical variables were compared between groups by the chi-square test. Intraobserver and interobserver variability was calculated as the mean percentage error, defined as the absolute difference between the two sets of measurements divided by the mean of the measurements, using reading from 10 randomly selected patients. In the present study, the intraobserver variability and interobserver variability were 4.7% and 3.2% for TDI parameters, 5.9% and 9.4% for global circumferential strain, 6.1% and 8.1% for global radial strain, 2.3% and 3.1% for global longitudinal strain and 8.2% and 9.8% for twist, respectively. A value of p b 0.05 was considered statistically significant.
3. Results 3.1. Subjects characteristics We screened 126 consecutive subjects. Sixteen patients were excluded: 7 failed to finish the exercise testing and 9 had poor exercise images which were not suitable for offline analyzes. The remaining 110 subjects (40 HFPEF patients, 40 HFREF patients and 30 normal controls) had sufficient exercise images for offline analysis. Patients were older with higher BSA than controls. Both heart failure groups had comparable prevalence of hypertension, diabetes mellitus and anemia except gender sex (Table 1). All patients received similar medications except that calcium channel blockers were used more often in HFPEF patients (p b 0.05). After adjustment for age, gender, BSA and NYHA class, HFPEF and controls had similar resting LV end-diastolic diameter (LVEDD), LVEF, and sphericity index and HFREF patients as expected had significantly dilated left ventricles, reduced LVEF, and increased sphericity as compared with controls. Both heart failure groups had larger LAVI than controls (p b 0.05). The LVMI at rest was highest in HFREF followed by HFPEF and control groups (p b 0.05, Table 1).
Table 1 Clinical characteristics and standard echocardiographic parameters in all subgroups. Group 1 Group 2 Group 3 p value⁎ NC (n = 30) HFPEF (n = 40) HFREF (n = 40) Age Male (%) BSA(m2) NYHA class (I/II/III/IV) Hypertension (%) Diabetes mellitus (%) Anemia (%) ACEI/ARB (%) Beta-blockers (%) Calcium channel blockers (%) Diuretics (%) Statins (%) Digoxin (%) LVEDD (cm) Biplane LVEF (%) LVMI (g/m2) LAVI (ml/m2) Sphericity
56 ± 5 33 1.60 ± 0.14 I 0 0 0 0 0 0
65 ± 9a 53 1.69 ± 0.20a (2/33/5/0) 80 43 3 73 48 55
62 ± 9a 90a,b 1.75 ± 0.18a (0/24/11/5)b 63 38 10 78 63 15b
b0.0005 – 0.020 – – – – – – –
0 0 0 4.4 ± 0.4 65 ± 4 81.2 ± 19.6 23.9 ± 6.4 0.54 ± 0.08
43 63 3 4.7 ± 0.6 63 ± 6 115.0 ± 34.5a 36.7 ± 15.6a 0.56 ± 0.07
28 63 8 5.7 ± 0.8a,b 37 ± 8a,b 147.8 ± 31.7a,b 37.1 ± 12.4a 0.60 ± 0.08a,b
– – – b0.0005 b0.0005 b0.0005 b0.0005 0.005
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BSA, body surface area; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LAVI, left atrial volume index; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; NC, normal control; NYHA, New York Heart Association. a p b 0.05 versus the Group 1. b p b 0.05 versus the Group 2. ⁎ p values for analysis of covariance after adjustment for age, gender, BSA and the NYHA class.
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3.2. LV myocardial deformation and twist When adjusted for age, gender, BSA and NYHA class, there was progressive decrease in global 2D longitudinal, circumferential and radial strains (GLS, GCS and GRS) on exercise from control, HFPEF to HFREF groups (all p b 0.05). Compared with controls, LV twist on exercise was preserved in HFPEF group but were significantly reduced in HFREF group (p b 0.05, Table 2, Fig. 1). 3.3. LV longitudinal systolic function After adjustment for age, gender, BSA and NYHA class, there was a progressive decrease of TDI septal s′, Sm and M-mode MAPSE from controls, HFPEF and HFREF on exercise (all p b 0.05, Table 2). 3.4. LV diastolic function Diastolic function on exercise exhibited a progressive decline of TDI septal e′, Em and septal E/e′ from controls to HFPEF followed by HFREF after adjusting for age, gender, BSA and NYHA class (all pb 0.05, Table 2). Fig. 1. The distribution of twist during exercise in all subgroups. Scatter plot showing the distribution of LV twist in normal controls, patients with heart failure and preserved ejection fraction (HFPEF), and patients with heart failure and reduced ejection fraction (HFREF).
3.5. LV hemodynamic changes In adjusted comparison for age, gender, and BSA as well as NYHA class, both HFPEF and control groups had comparable LVSI and LVCI on exercise, but patients with HFREF had significantly lower LVSI and LVCI than controls (Table 2). 4. Discussion 4.1. Main findings In the current study, we evaluated LV function in HFPEF patients using stress echocardiography, and we have demonstrated a variety of LV global and regional systolic and diastolic abnormalities in these patients during exercise. These include the impairment of global LV circumferential, radial and longitudinal strain, reduced mitral annular velocity and displacement.
Table 2 Exercise echocardiographic parameters in all subgroups.
GLS (%) GCS (%) GRS (%) Twist (°) Sm (cm/s) Em (cm/s) Septal s′ (cm/s) Septal e′ (cm/s) Septal E/e′ MAPSE (mm) LVSI (ml/m2) LVCI (l/min/m2)
Group 1 NC (n = 30)
Group 2 HFPEF (n = 40)
Group 3 HFREF (n = 40)
p value⁎
28.8 ± 5.1 30.4 ± 23.1 46.4 ± 11.9 27.1 ± 6.9 7.5 ± 1.9 12.4 ± 3.0 13.1 ± 2.8 17.9 ± 4.2 7.7 ± 1.4 15.3 ± 1.7 45.2 ± 9.0 5.4 ± 0.9
20.7 ± 4.2a 22.2 ± 4.8a 38.0 ± 12.3a 23.8 ± 9.0 6.4 ± 1.6a 9.2 ± 2.1a 10.9 ± 2.8a 13.4 ± 4.1a 9.8 ± 2.9a 13.3 ± 2.8a 43.2 ± 7.8 4.8 ± 0.9
10.8 ± 4.2a,b 11.7 ± 5.1a,b 18.1 ± 9.4a,b 12.9 ± 5.9a,b 4.5 ± 1.7a,b 7.2 ± 2.4a,b 7.4 ± 3.7a,b 10.9 ± 4.2a,b 12.5 ± 5.0a,b 7.9 ± 2.5a,b 32.3 ± 12.7a,b 3.7 ± 1.3a,b
b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005
Em, early diastolic myocardial velocity; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LVCI, left ventricular cardiac index; LVSI, left ventricular stroke volume index; MAPSE, mitral annular plane systolic excursion; NC, normal control; Septal E/e′, ratio of early mitral diastolic inflow velocity to septal mitral annular early diastolic velocity; Septal e′, septal mitral annular early diastolic velocity; Septal s′, septal mitral annular systolic velocity; Sm, systolic myocardial velocity. a p b 0.05 versus the Group 1. b p b 0.05 versus the Group 2. ⁎ p values for analysis of covariance after adjustment for age, gender, BSA and the NYHA class.
4.1.1. Comprehensive exercise echocardiography for evaluation of heart failure HFPEF is a growing health problem and the relationship between LV adaptation and the development of symptoms remains unclear [21]. As exertion-related symptoms are often the reason why the HFPEF patients are referred for specialist assessment [4], elucidating the abnormalities of LV function during exercise is important. Ergometry stress echocardiography with supine bicycle can be used for a number of cardiac conditions where an assessment of cardiac and hemodynamic response to physiological exercise is needed. This non-invasive and safe method can provide important diagnostic information and improved understanding of underlying pathophysiological mechanisms. 2D speckle tracking echocardiography has allowed assessment of LV myocardial deformation in longitudinal, circumferential, radial and transverse directions, as well as twist. These measurements are angleindependent, and would not be affected by tethering and translation effects seen with TDI [8]. Because of scattering, reflection and interference of the ultrasound beams in myocardial tissue, speckle formations in gray-scale echocardiographic images represent tissue markers and thus the LV global strain was shown to reflect the global systolic performance [10]. In the present study, we demonstrated progressive decline in global LV strain in different directions during exercise from controls to HFPEF followed by HFREF patients, which concurs with the findings of two recent works by Tan et al. [22] and Wang et al. [23]. 4.1.2. Impairment of LV twist during exercise in HFREF but not HFPEF patients The LV twist is a consequence of myocardial fiber orientation, which changes from an approximately longitudinal but a right-handed direction in the subendocardium to a circumferential orientation in the mid layer and to left-handed direction in the subepicardium [24,25]. These myocardial fibers are connected with a smooth transition from subendocardium to mid layer, and then to subepicardium. Contraction of these three layers of fibers causes not only circumferential, radial, and longitudinal movements of the heart, but also contortion of the myocardium [26]. The degree of shortening of myocardial fibers is of the order of 15–20% at most. The myocardial fiber contraction only explains for about a third of the observed LVEF in normal heart while part of the pumping function is contributed by LV twisting motion.
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Myocardial fibers are arranged in a spiral fashion, so when they contract they cause a simultaneous wringing motion resulting in augmented pump function [27]. In addition, LV twisting is also important for storing up energy during systole, which is released during early diastole to accentuate ventricular suction and filling [28]. Therefore, LV twist plays a major role in maintaining myocardial contraction and generating suction in early diastole. In the current study, we found comparable LV twist during exercise in HFPEF patients as compared to controls while it was significantly impaired in HFREF patients. We postulate that the subendocardial fibers are primarily affected in early stage of HFPEF so that the unopposed epicardial fibers will compensate the loss of function by augmenting the apical twist. While all the myocardial fibers are affected at later stage of the disease because of widespread fibrosis, both LV global function and twist would be reduced [22]. 4.1.3. Long axis impairment during exercise in heart failure In the present study, we also confirmed the trends of progressive impairment of the LV longitudinal systolic and diastolic functions from control, HFPEF to HFREF groups during exercise. Of note, the important contribution of longitudinally arranged fibers to overall ventricular function has been recognized for many years. Abnormalities in longitudinal function occur in a variety of pathological conditions, such as heart failure, myocardial hypertrophy, ischemia and so on [29]. The longitudinally arranged fibers dominate in subendocardial layers and papillary muscles, which are highly susceptible to ischemia [30]. In this study, we used septal s′, Sm, MAPSE and septal e′, Em, septal E/e′ to evaluate LV longitudinal systolic and diastolic function respectively. All these parameters derived from TDI and M-mode echocardiography represent mitral annular velocity and displacement. The rapid apical descend of mitral annulus aids in generating the negative intraventricular pressure gradient, LV filling, and facilitates LV fast ejection [31]. Hence, the deterioration in these echocardiographic parameters confirmed a more severe degree of long axis functional impairment during exercise in HFREF than HFPEF. While the extent of long axis impairment during exercise may play a role in terms of symptomatology observe in HFPEF patients, recent work [32,33] already began to study the clinical significance of long axis reserve between rest and exercise in these patients. 5. Study limitations The echocardiographic images were acquired in different levels of exercise according to the study protocol, which may bias the results in our study. Furthermore, echocardiographic parameters have inherently greater variability than invasive methods. This study only included patients with non-ischemic heart failure and the results are not applicable to patients with significant coronary artery diseases. 6. Conclusions We have demonstrated that HFPEF patients have a combination of LV systolic and diastolic abnormalities on exercise including impaired global 2D strain in multi-directions, decreased mitral annular velocity and displacement. This study provides comprehensive reference values for LV performance during exercise in different heart failure phenotypes and such information is crucial for future clinical studies. Acknowledgment This research was funded by the General Research Fund (project # 479509) from the Research Grants Council of Hong Kong. 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;355:251–9.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Quantification of left ventricular performance in different heart failure phenotypes by comprehensive ergometry stress echocardiography Jing Wang a, Fang Fang a, Gabriel Wai-Kwok Yip b, John E. Sanderson a, Wei Feng a, Jun-Min Xie a, Xiu-Xia Luo a, Cheuk-Man Yu a, Yat-Yin Lam a,⁎ a Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, S.H. Ho Cardiovascular Disease and Stroke Centre, Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong b Cardiac Medicine Unit, Grantham Hospital, Hong Kong
a r t i c l e
i n f o
Article history: Received 3 May 2013 Received in revised form 3 August 2013 Accepted 27 September 2013 Available online 3 October 2013 Keywords: Left ventricular performance HFPEF HFREF Stress echocardiography
a b s t r a c t Background: We evaluated the left ventricular (LV) performance in patients with heart failure and preserved ejection fraction (HFPEF) during exercise as compared to those with heart failure and reduced ejection fraction (HFREF) and healthy subjects. Methods: All subjects received echocardiographic (Vivid7, GE Healthcare) examination with symptom-limited exercise testing on a semi-recumbent and tilting bicycle ergometer (Lode BV, Netherlands). The exercise images for 2-dimensional (2D) speckle tracking were acquired with heart rate of 90–100 bpm, while exercise images for tissue Doppler imaging (TDI) and M-mode echocardiography were stored with attainment of N85% of maximal age-predicted heart rate. Results: Stress echocardiographic examinations were performed in 40 HFPEF (aged 65 ± 9 years; 53% male), 40 HFREF (aged 62 ± 9 years; 90% male) and 30 normal controls (aged 56 ± 5 years; 33% male). Trends of progressive decline in 2D global longitudinal, circumferential and radial strains (GLS, GCS and GRS); TDI septal s′ and Sm; and M-mode mitral annular plane systolic excursion (MAPSE) were observed from control, HFPEF to HFREF groups (p b 0.05 for all). LV twist was preserved in HFPEF but reduced in HFREF patients as compared to normal controls (p b 0.05). Diastolic function measured by TDI septal e′, Em and septal E/e′ progressively decreased from controls, HFPEF to HFREF patients (all p b 0.05). Stroke volumes and cardiac indices (LVSI & LVCI) were preserved in HFPEF but deteriorated in HFREF than controls. Conclusions: This study provides the reference values of LV performance during exercise in HFPEF and knowledge about these changes provide important insights for future clinical studies. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction About half of the patients presenting with symptoms and signs of heart failure have a preserved ejection fraction (HFPEF) [1,2]. These patients have severe chronic symptoms, reduced exercise tolerance and mortality comparable to those with heart failure and reduced ejection fraction (HFREF) [1–4]. In contrast to the tremendous resources devoted to evaluate the pathophysiology and treatment of HFREF, HFPEF remains understudied [5,6]. Westermann et al. [7] showed that patients with HFPEF had increased left ventricular (LV) stiffness at rest. Our group, using speckle tracking echocardiography, also [8] revealed a range of global and regional LV systolic and diastolic abnormalities at rest for HFPEF patients.
⁎ Corresponding author. Tel.: +852 2632 1299; fax: +852 2637 3852. E-mail address: [email protected] (Y.-Y. Lam). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.09.010
Both of these studies evaluated LV function at rest despite the primary symptom of HFPEF being breathlessness on exertion. As exercise intolerance is the dominant symptom for HFPEF patients leading to loss of ambulatory ability, evaluating LV performance on exercise may be more relevant to the pathophysiology of HFPEF. New developments in echocardiography enable a more comprehensive assessment of LV systolic and diastolic function, including measurements of myocardial deformation, ventricular twist, annular motion (longitudinal function) and LV suction, which potentially provides better mechanistic insight into ventricular adaptation of HFPEF on exercise [9–11]. There are limited comprehensive data about LV performance during stress in different heart failure phenotypes. We therefore compare the LV systolic and diastolic function on exercise in three groups of subjects: patients with HFPEF, patients with HFREF and health controls using state-of-the-art echocardiography [standard two-dimensional (2D), M-mode, tissue Doppler imaging (TDI) and 2D speckle tracking echocardiography].
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2. Methods 2.1. Study population A prospective cohort of 80 patients with symptoms or signs of congestive heart failure was recruited. Among these patients, forty met the criteria of the Heart Failure and Echocardiography Associations of the European Society of Cardiology for HFPEF with left ventricular ejection fraction (LVEF) ≥50%, and another forty had HFREF with LVEF b50% [12]. Thirty normal healthy subjects with unremarkable clinical assessments and normal echocardiographic findings were included as controls. All eligible patients were carefully screened for non-cardiac causes of heart failure. We excluded patients presenting with acute coronary syndromes or significant coronary artery disease as confirmed by coronary angiography (defined N50% stenosis) or functional cardiac nuclear or magnetic resonance imaging. Patients with HFPEF who has echocardiographic evidence of regional wall motion abnormality were also excluded. Other exclusion criteria include (1) atrial fibrillation, sick sinus syndrome, second or third degree heart block with or without pacemaker, (2) congenital or more-than-mild valvular heart disease, (3) infiltrative, restrictive or hypertrophic cardiomyopathy, (4) obesity by Chinese standard (body mass index N 25 kg/m2, and/or waist circumference N 90 cm for men and N80 cm women) [13], (5) lung diseases such as chronic obstructive pulmonary disease by chest radiography and lung function tests (FEV1/FVC b 0.7) [14], (6) primary renal disease or serum creatinine ≥ 250 μmol/l and/or estimated glomerular filtration rate ≤ 30 ml/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula for Chinese ethnicity, (7) primary hepatic disease or cirrhosis, (8) pregnancy, (9) inability to exercise on an upright bicycle or to withhold cardiovascular medicines for 24 h, and (9) suboptimal echocardiographic image. Beta-blockers were withheld for 24 h and other cardiovascular medications were also withheld on the day of stress test. The study protocol was approved by institution's research ethical committees and informed consent was obtained from all subjects. 2.2. Echocardiography All subjects underwent symptom-limited (fatigue or dyspnea) exercise testing on a semi-recumbent and tilting bicycle ergometer (Lode BV, Netherlands). Their heart rates, blood pressures, symptoms and 12 lead ECG were monitored continuously during exercise. The submaximal heart rate, called pre-peak heart rate, was defined as the achievement of heart rate in the range of 90–100 beats/min, while the maximum heart rate, also called peak heart rate, was defined by attainment of N85% of maximum age-predicted heart rate [85% × (220-age)]. Transthoracic echocardiography (Vivid7, GE Healthcare) was performed using a multi-frequency matrix probe with patients lying left lateral decubitus position during exercise. At least 3 sets of images with loops consisting of 5 consecutive cardiac cycles each were stored for offline analysis with a customized software package (EchoPac, GE Vingmed). Resting LV dimensions were measured and LV mass was estimated and divided by the body surface area (BSA) to derive the LV mass index (LVMI) [15]. LVEF was calculated from apical 2- and 4-chamber views using the modified biplane Simpson's rule [15]. LV sphericity was measured by the LV short-to-long axis dimension ratio in end-diastolic apical 4-chamber view. Left atrial volume was calculated with biplane area–length method from the apical 4- and 2-chamber views and indexed to BSA to derive left atrial volume index (LAVI) [16]. The submaximal exercise echocardiographic images were analyzed offline using 2D speckle tracking echocardiography. The LV apical 4-, 2- and 3-chamber images and parasternal short-axis views at basal, mid-papillary and apical levels were used for assessing 2D LV longitudinal, radial, circumferential strains and rotation with the speckle tracking echocardiography [9–11]. From standard 2D grayscale recordings, myocardial deformation was tracked frame-by-frame automatically within the region of interest bound by endocardial and epicardial borders throughout the cardiac cycle. Global strain was derived from the average of 18 segments in the longitudinal, or radial and circumferential planes—that is, six evenly divided segments in each of the three long-axis or shortaxis views [9–11]. Furthermore, LV twist was calculated as the net difference of peak systolic rotation strain between six basal and six apical segments [17]. The maximal exercise echocardiographic images were analyzed offline with TDI and M-mode echocardiography. The early filling (E), late filling (A) peak velocities, and deceleration time (DT) of early filling were measured from transmitral flow. Stroke volume (SV) was determined by pulse-wave Doppler and indexed by BSA to derive the LV stroke volume index (LVSI). Cardiac index (LVCI) was determined from the product of LVSI and heart rate. The peak systolic (s′), early diastolic (e′) and late diastolic (a′) mitral annular velocities were also measured with pulsed-wave Doppler. The E/e′ ratio was derived from dividing the early mitral inflow velocity by the early diastolic mitral annular velocity [18]. Furthermore, color-coded tissue Doppler images were also acquired over 5 consecutive cardiac cycles for each of the 6 myocardial walls in LV apical views [19]. Systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities were measured by placing a 4 × 4 mm region of interest in the mid-myocardial area of each wall. Additionally, using conventional 2D-guided M-mode echocardiography, mitral annular plane systolic excursion (MAPSE) was estimated from the apical 4-chamber view with the cursor positioned through the septal angle of mitral valve annulus [20]. 2.3. Statistical analysis Sample size was estimated from a pilot study. For LV longitudinal systolic function with anticipated difference in mean of 1.5 and standard deviation (SD) of 2, a sample
size of 30 would provide 90% power with α = 0.01. Statistical analysis was performed with SPSS version 17.0 (Chicago, IL, USA). Continuous variables were expressed as mean ± SD and categorical variables as percentages. Continuous variables between groups during exercise were compared by analysis of covariance in general linear model with LSD post-hoc analysis for subgroup comparisons, adjusted for age, gender and BSA, as well as New York Heart Association (NYHA) class. The p values after adjustment are presented. Categorical variables were compared between groups by the chi-square test. Intraobserver and interobserver variability was calculated as the mean percentage error, defined as the absolute difference between the two sets of measurements divided by the mean of the measurements, using reading from 10 randomly selected patients. In the present study, the intraobserver variability and interobserver variability were 4.7% and 3.2% for TDI parameters, 5.9% and 9.4% for global circumferential strain, 6.1% and 8.1% for global radial strain, 2.3% and 3.1% for global longitudinal strain and 8.2% and 9.8% for twist, respectively. A value of p b 0.05 was considered statistically significant.
3. Results 3.1. Subjects characteristics We screened 126 consecutive subjects. Sixteen patients were excluded: 7 failed to finish the exercise testing and 9 had poor exercise images which were not suitable for offline analyzes. The remaining 110 subjects (40 HFPEF patients, 40 HFREF patients and 30 normal controls) had sufficient exercise images for offline analysis. Patients were older with higher BSA than controls. Both heart failure groups had comparable prevalence of hypertension, diabetes mellitus and anemia except gender sex (Table 1). All patients received similar medications except that calcium channel blockers were used more often in HFPEF patients (p b 0.05). After adjustment for age, gender, BSA and NYHA class, HFPEF and controls had similar resting LV end-diastolic diameter (LVEDD), LVEF, and sphericity index and HFREF patients as expected had significantly dilated left ventricles, reduced LVEF, and increased sphericity as compared with controls. Both heart failure groups had larger LAVI than controls (p b 0.05). The LVMI at rest was highest in HFREF followed by HFPEF and control groups (p b 0.05, Table 1).
Table 1 Clinical characteristics and standard echocardiographic parameters in all subgroups. Group 1 Group 2 Group 3 p value⁎ NC (n = 30) HFPEF (n = 40) HFREF (n = 40) Age Male (%) BSA(m2) NYHA class (I/II/III/IV) Hypertension (%) Diabetes mellitus (%) Anemia (%) ACEI/ARB (%) Beta-blockers (%) Calcium channel blockers (%) Diuretics (%) Statins (%) Digoxin (%) LVEDD (cm) Biplane LVEF (%) LVMI (g/m2) LAVI (ml/m2) Sphericity
56 ± 5 33 1.60 ± 0.14 I 0 0 0 0 0 0
65 ± 9a 53 1.69 ± 0.20a (2/33/5/0) 80 43 3 73 48 55
62 ± 9a 90a,b 1.75 ± 0.18a (0/24/11/5)b 63 38 10 78 63 15b
b0.0005 – 0.020 – – – – – – –
0 0 0 4.4 ± 0.4 65 ± 4 81.2 ± 19.6 23.9 ± 6.4 0.54 ± 0.08
43 63 3 4.7 ± 0.6 63 ± 6 115.0 ± 34.5a 36.7 ± 15.6a 0.56 ± 0.07
28 63 8 5.7 ± 0.8a,b 37 ± 8a,b 147.8 ± 31.7a,b 37.1 ± 12.4a 0.60 ± 0.08a,b
– – – b0.0005 b0.0005 b0.0005 b0.0005 0.005
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BSA, body surface area; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LAVI, left atrial volume index; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; NC, normal control; NYHA, New York Heart Association. a p b 0.05 versus the Group 1. b p b 0.05 versus the Group 2. ⁎ p values for analysis of covariance after adjustment for age, gender, BSA and the NYHA class.
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3.2. LV myocardial deformation and twist When adjusted for age, gender, BSA and NYHA class, there was progressive decrease in global 2D longitudinal, circumferential and radial strains (GLS, GCS and GRS) on exercise from control, HFPEF to HFREF groups (all p b 0.05). Compared with controls, LV twist on exercise was preserved in HFPEF group but were significantly reduced in HFREF group (p b 0.05, Table 2, Fig. 1). 3.3. LV longitudinal systolic function After adjustment for age, gender, BSA and NYHA class, there was a progressive decrease of TDI septal s′, Sm and M-mode MAPSE from controls, HFPEF and HFREF on exercise (all p b 0.05, Table 2). 3.4. LV diastolic function Diastolic function on exercise exhibited a progressive decline of TDI septal e′, Em and septal E/e′ from controls to HFPEF followed by HFREF after adjusting for age, gender, BSA and NYHA class (all pb 0.05, Table 2). Fig. 1. The distribution of twist during exercise in all subgroups. Scatter plot showing the distribution of LV twist in normal controls, patients with heart failure and preserved ejection fraction (HFPEF), and patients with heart failure and reduced ejection fraction (HFREF).
3.5. LV hemodynamic changes In adjusted comparison for age, gender, and BSA as well as NYHA class, both HFPEF and control groups had comparable LVSI and LVCI on exercise, but patients with HFREF had significantly lower LVSI and LVCI than controls (Table 2). 4. Discussion 4.1. Main findings In the current study, we evaluated LV function in HFPEF patients using stress echocardiography, and we have demonstrated a variety of LV global and regional systolic and diastolic abnormalities in these patients during exercise. These include the impairment of global LV circumferential, radial and longitudinal strain, reduced mitral annular velocity and displacement.
Table 2 Exercise echocardiographic parameters in all subgroups.
GLS (%) GCS (%) GRS (%) Twist (°) Sm (cm/s) Em (cm/s) Septal s′ (cm/s) Septal e′ (cm/s) Septal E/e′ MAPSE (mm) LVSI (ml/m2) LVCI (l/min/m2)
Group 1 NC (n = 30)
Group 2 HFPEF (n = 40)
Group 3 HFREF (n = 40)
p value⁎
28.8 ± 5.1 30.4 ± 23.1 46.4 ± 11.9 27.1 ± 6.9 7.5 ± 1.9 12.4 ± 3.0 13.1 ± 2.8 17.9 ± 4.2 7.7 ± 1.4 15.3 ± 1.7 45.2 ± 9.0 5.4 ± 0.9
20.7 ± 4.2a 22.2 ± 4.8a 38.0 ± 12.3a 23.8 ± 9.0 6.4 ± 1.6a 9.2 ± 2.1a 10.9 ± 2.8a 13.4 ± 4.1a 9.8 ± 2.9a 13.3 ± 2.8a 43.2 ± 7.8 4.8 ± 0.9
10.8 ± 4.2a,b 11.7 ± 5.1a,b 18.1 ± 9.4a,b 12.9 ± 5.9a,b 4.5 ± 1.7a,b 7.2 ± 2.4a,b 7.4 ± 3.7a,b 10.9 ± 4.2a,b 12.5 ± 5.0a,b 7.9 ± 2.5a,b 32.3 ± 12.7a,b 3.7 ± 1.3a,b
b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005 b0.0005
Em, early diastolic myocardial velocity; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LVCI, left ventricular cardiac index; LVSI, left ventricular stroke volume index; MAPSE, mitral annular plane systolic excursion; NC, normal control; Septal E/e′, ratio of early mitral diastolic inflow velocity to septal mitral annular early diastolic velocity; Septal e′, septal mitral annular early diastolic velocity; Septal s′, septal mitral annular systolic velocity; Sm, systolic myocardial velocity. a p b 0.05 versus the Group 1. b p b 0.05 versus the Group 2. ⁎ p values for analysis of covariance after adjustment for age, gender, BSA and the NYHA class.
4.1.1. Comprehensive exercise echocardiography for evaluation of heart failure HFPEF is a growing health problem and the relationship between LV adaptation and the development of symptoms remains unclear [21]. As exertion-related symptoms are often the reason why the HFPEF patients are referred for specialist assessment [4], elucidating the abnormalities of LV function during exercise is important. Ergometry stress echocardiography with supine bicycle can be used for a number of cardiac conditions where an assessment of cardiac and hemodynamic response to physiological exercise is needed. This non-invasive and safe method can provide important diagnostic information and improved understanding of underlying pathophysiological mechanisms. 2D speckle tracking echocardiography has allowed assessment of LV myocardial deformation in longitudinal, circumferential, radial and transverse directions, as well as twist. These measurements are angleindependent, and would not be affected by tethering and translation effects seen with TDI [8]. Because of scattering, reflection and interference of the ultrasound beams in myocardial tissue, speckle formations in gray-scale echocardiographic images represent tissue markers and thus the LV global strain was shown to reflect the global systolic performance [10]. In the present study, we demonstrated progressive decline in global LV strain in different directions during exercise from controls to HFPEF followed by HFREF patients, which concurs with the findings of two recent works by Tan et al. [22] and Wang et al. [23]. 4.1.2. Impairment of LV twist during exercise in HFREF but not HFPEF patients The LV twist is a consequence of myocardial fiber orientation, which changes from an approximately longitudinal but a right-handed direction in the subendocardium to a circumferential orientation in the mid layer and to left-handed direction in the subepicardium [24,25]. These myocardial fibers are connected with a smooth transition from subendocardium to mid layer, and then to subepicardium. Contraction of these three layers of fibers causes not only circumferential, radial, and longitudinal movements of the heart, but also contortion of the myocardium [26]. The degree of shortening of myocardial fibers is of the order of 15–20% at most. The myocardial fiber contraction only explains for about a third of the observed LVEF in normal heart while part of the pumping function is contributed by LV twisting motion.
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Myocardial fibers are arranged in a spiral fashion, so when they contract they cause a simultaneous wringing motion resulting in augmented pump function [27]. In addition, LV twisting is also important for storing up energy during systole, which is released during early diastole to accentuate ventricular suction and filling [28]. Therefore, LV twist plays a major role in maintaining myocardial contraction and generating suction in early diastole. In the current study, we found comparable LV twist during exercise in HFPEF patients as compared to controls while it was significantly impaired in HFREF patients. We postulate that the subendocardial fibers are primarily affected in early stage of HFPEF so that the unopposed epicardial fibers will compensate the loss of function by augmenting the apical twist. While all the myocardial fibers are affected at later stage of the disease because of widespread fibrosis, both LV global function and twist would be reduced [22]. 4.1.3. Long axis impairment during exercise in heart failure In the present study, we also confirmed the trends of progressive impairment of the LV longitudinal systolic and diastolic functions from control, HFPEF to HFREF groups during exercise. Of note, the important contribution of longitudinally arranged fibers to overall ventricular function has been recognized for many years. Abnormalities in longitudinal function occur in a variety of pathological conditions, such as heart failure, myocardial hypertrophy, ischemia and so on [29]. The longitudinally arranged fibers dominate in subendocardial layers and papillary muscles, which are highly susceptible to ischemia [30]. In this study, we used septal s′, Sm, MAPSE and septal e′, Em, septal E/e′ to evaluate LV longitudinal systolic and diastolic function respectively. All these parameters derived from TDI and M-mode echocardiography represent mitral annular velocity and displacement. The rapid apical descend of mitral annulus aids in generating the negative intraventricular pressure gradient, LV filling, and facilitates LV fast ejection [31]. Hence, the deterioration in these echocardiographic parameters confirmed a more severe degree of long axis functional impairment during exercise in HFREF than HFPEF. While the extent of long axis impairment during exercise may play a role in terms of symptomatology observe in HFPEF patients, recent work [32,33] already began to study the clinical significance of long axis reserve between rest and exercise in these patients. 5. Study limitations The echocardiographic images were acquired in different levels of exercise according to the study protocol, which may bias the results in our study. Furthermore, echocardiographic parameters have inherently greater variability than invasive methods. This study only included patients with non-ischemic heart failure and the results are not applicable to patients with significant coronary artery diseases. 6. Conclusions We have demonstrated that HFPEF patients have a combination of LV systolic and diastolic abnormalities on exercise including impaired global 2D strain in multi-directions, decreased mitral annular velocity and displacement. This study provides comprehensive reference values for LV performance during exercise in different heart failure phenotypes and such information is crucial for future clinical studies. Acknowledgment This research was funded by the General Research Fund (project # 479509) from the Research Grants Council of Hong Kong. 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;355:251–9.
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