Different determinants of exercise capacity in HFpEF compared to HFrEF

Background Quality of life is as important as survival in heart failure (HF) patients. Controversies exist with regards to echocardiographic determinants of exercise capacity in HF, particularly in patients with preserved ejection fraction (HFpEF). The aim of this study was to prospectively examine echocardiographic parameters that correlate and predict functional exercise capacity assessed by 6 min walk test (6-MWT) in patients with HFpEF. Methods In 111 HF patients (mean age 63 ± 10 years, 47% female), an echo-Doppler study and a 6-MWT were performed in the same day. Patients were divided into two groups based on the 6-MWT distance (Group I: ≤ 300 m and Group II: >300 m). Results Group I were older (p = 0.008), had higher prevalence of diabetes (p = 0.027), higher baseline heart rate (p = 0.004), larger left atrium - LA (p = 0.001), longer LV filling time - FT (p = 0.019), shorter isovolumic relaxation time (p = 0.037), shorter pulmonary artery acceleration time - PA acceleration time (p = 0.006), lower left atrial lateral wall myocardial velocity (a’) (p = 0.018) and lower septal systolic myocardial velocity (s’) (p = 0.023), compared with Group II. Patients with HF and reduced EF (HFrEF) had lower hemoglobin (p = 0.007), higher baseline heart rate (p = 0.005), higher NT-ProBNP (p = 0.001), larger LA (p = 0.004), lower septal s’, e’, a’ waves, and septal mitral annular plane systolic excursion (MAPSE), shorter PA acceleration time (p < 0.001 for all), lower lateral MAPSE, higher E/A & E/e’, and shorter LVFT (p = 0.001 for all), lower lateral e’ (p = 0.009), s’ (p = 0.006), right ventricular e’ and LA emptying fraction (p = 0.012 for both), compared with HFpEF patients. In multivariate analysis, only LA diameter [2.676 (1.242–5.766), p = 0.012], and diabetes [0.274 (0.084–0.898), p = 0.033] independently predicted poor 6-MWT performance in the group as a whole. In HFrEF, age [1.073 (1.012–1.137), p = 0.018] and LA diameter [3.685 (1.348–10.071), p = 0.011], but in HFpEF, lateral s’ [0.295 (0.099–0.882), p = 0.029], and hemoglobin level [0.497 (0.248–0.998), p = 0.049] independently predicted poor 6-MWT performance. Conclusions In HF patients determinants of exercise capacity differ according to severity of overall LV systolic function, with left atrial enlargement in HFrEF and longitudinal systolic shortening in HFpEF as the the main determinants.


Data collection
Detailed history and clinical assessment were obtained in all patients, in whom routine biochemical tests were also performed including hemoglobin, lipid profile, blood glucose level, and kidney function tests. Estimated body mass index (BMI) was calculated from weight and height measurements. Waist, hip measurements were also made and waist/hip ratio was calculated.

Echocardiographic examination
A single operator performed all echocardiographic examinations using a Philips Intelligent E-33 system with a multifrequency transducer, and harmonic imaging as appropriate. Images were obtained with the patient in the left lateral decubitus position and during quiet expiration. Measurements of interventricular septal thickness, posterior wall thickness, and LV dimensions were made at end-diastole and end-systole, as recommended by the American Society of Echocardiography [19]. LV mass (LVM) was calculated LV volumes and EF were calculated from the apical 2 and 4 chamber views using the modified Simpson's method. Ventricular long axis motion was studied by placing the M-mode cursor at the lateral and septal angles of the mitral ring and the lateral angle of the tricuspid ring. Total amplitude of long axis motion was measured as previously described [21] from peak inward to peak outward points. LV and right ventricular (RV) long axis myocardial velocities were also studied using Doppler myocardial imaging technique. From the apical 4-chamber view, longitudinal velocities were recorded with the sample volume placed at the basal part of LV lateral and septal segments as well as RV free wall. Systolic (s'), as well as early and late (e' and a') diastolic myocardial velocities were measured with the gain optimally adjusted. Mean value of lateral and septal LV velocities were calculated.
Left atrial diameter was measured from aortic root recordings with the M-mode cursor positioned at the level of the aortic valve leaflets. LA volumes were measured using area-length method from the apical four chamber views, according to the guidelines of the American Society of Echocardiography and European Association of Echocardiography [22]. Left atrial maximal volume (LAV max) was measured at the end of LV systole, just before the opening of the mitral valve, LA minimal volume (LAV min) was measured at end diastole, right after mitral valve closure. LA emptying fraction (LA EF) was calculated with the formula [22,23]: Diastolic LV and RV function was assessed from filling velocities using spectral pulsed wave Doppler with the sample volume positioned at the tips of the mitral and tricuspid valve leaflets, respectively, during a brief apnea. Peak LV and RV early (E wave) and late (A wave) diastolic velocities were measured and E/A ratios were calculated. E wave deceleration time (DT) was also measured from peak E wave to the end of its deceleration in all study patients. The E/e' ratio was calculated from the transmitral E wave and the mean lateral and septal segments e' wave velocities. The isovolumic relaxation time was also measured from aortic valve closure to mitral valve opening, on the pulsed wave Doppler recording. LV filling pattern was considered 'restrictive' when E/A ratio was >2.0, E wave deceleration time < 140 ms and the left atrium dilated of more than 40 mm in transverse diameter [24]. Total LV filling time was measured from the onset of the E wave to the end of the A wave and ejection time from the onset to the end of the aortic Doppler flow velocity. Mitral regurgitation severity was assessed by colour and continuous wave Doppler and was graded as mild, moderate, or severe according to the relative jet area to that of the left atrium as well as the flow velocity profile, in line with the recommendations of the American and European Society of Echocardiography [25,26]. Likewise, tricuspid regurgitation was assessed by colour Doppler and continuous-wave Doppler. Retrograde trans-tricuspid pressure drop > 35 mmHg was taken as an evidence for pulmonary hypertension [26,27]. All Mmode and Doppler recordings were made at a fast speed of 100 mm/s with a superimposed ECG (lead II).

Measurement of amino-terminal pro BNP
Fasting venous blood was collected from study participants after they had rested in a supine position for 20 min. Samples were placed in disposable EDTA containers (1 g/L of plasma), and N-terminal proBNP was measured by a Cobas Elecsys E 411 analyzer (measuring range 5-35000 pg/mL) using a chemiluminescent immunoassay kit (Roche Diagnostics, Grenach-Wyhlen, Germany).

Six minute walk test
Within 24 h of the echocardiographic examination a 6-MWT was performed on a level hallway surface, administered by a specialized nurse who was blinded to the results of the echocardiogram. According to the method of Gyatt et al. [28] patients were informed of the purpose and protocol of the 6 MWT which was conducted in a standardized fashion while patients on their regular medications [29,30]. A 15 m flat, obstacle-free corridor was used and patients were instructed to walk as far as they can, turning 180°after they have reached the end of the corridor, during the allocated time of 6 min. Patients walked unaccompanied so not to influence walking speed. At the end of the 6 min the supervising nurse measured the total distance walked by the patient.
Using the norm-reference equation developed by Troosters [31] for the prediction of 6MWT distance   according to age, height, weight, and gender that has been proposed for healthy patients, we derived the percentage of the predicted value (PPV). PPV is computed by dividing the actual 6MWT distance by the expected value of 6MWT distance and then multiplying by 100. Troosters' equation is as follows: Predicted 6MWT distance = 218 + 5.14 height (cm) − 5.32 age (years) −1.8 weight (kg) + 51.31 sex (1-male, 0-female).

Statistical analysis
Data are presented as mean ± SD or proportions (% of patients). Continuous data was compared with two-tailed unpaired Student's t test and discrete data with Chisquare test. Correlations were tested with Pearson coefficients. Determinants of 6 MWT distance were identified with univariate analysis and multivariate logistic regression was performed using the step-wise method. A significant difference was defined as p < 0.05 (2-tailed). Patients were divided according to their ability to walk >300 m into good and limited exercise performance groups [30], and were compared using unpaired Student t-test. Also, patients with HFpEF (>45%) were compared with those with HFrEF (<45%) using unpaired t-test.

Results
Patients with Limited vs. Good 6 MWT performance (Table 1) Patients with limited exercise capacity were older (p = 0.008) and had higher prevalence of diabetes (p = 0.027) compared with those with good exercise capacity. Patients with limited 6-MWT had larger left atrium (p = 0.001), increased LVMI (p = 0.006), shorter LV filling time (p = 0.019), shorter isovolumic relaxation time (p = 0.037) and shorter PA acceleration time (p = 0.006), lower septal a' (p = 0.018) and s' (p = 0.023), compared to those with good 6-MWT performance. The rest of the clinical and echocardiographic indices were not different between groups.
Patients with HFpEF vs. HFrEF (Table 2) The whole group of study patients walked a distance of 310 ± 116 m during 6-MWT. Patients with HFrEF walked significantly shorter distance compared those with HFpEF (p = 0.01, Fig. 1).

Findings
The results of this study show that in general HF patients with limited exercise capacity are older and have worse left ventricular function and raised filling pressures than those with satisfactory exercise performance. However, determinants of exercise capacity differed significantly according to ejection fraction. While patients with reduced ejection fraction have the enlarged left atrium and advanced age as the independent determinants of exercise capacity, it was the low hemoglobin and reduced lateral s' the respective determinants in those with preserved ejection fraction.

Data interpretation
Patients with heart failure due to reduced ejection fraction are known to have worse segmental and overall ventricular function, with additional signs of myocardial stiffness and raised filling pressures in many of them [32]. These perpetual changes result in left atrial enlargement due to the raised pressure, either because of venous hypertension, additional mitral regurgitation or the combination of both [33]. Indeed left atrial enlargement has previously been shown to be the most important prognostic marker in heart failure patients, irrespective of the development of atrial fibrillation [34]. It has also been taken as a reflection of the severity of LV myocardial stiffness, which is an endstage dysfunction, thus an irreversible damage. On the other hand, many factors contribute to the pathophysiology of heart failure with preserved ejection fraction [35], including atrial fibrillation, hypertension and kidney disease. Although none of our patients was in atrial fibrillation, the low hemoglobin levels were the main determinant of compromised exercise capacity. This reflects the need for acknowledging differences in the strategic management of these patients when compared with those of HFrEF. Finally, our findings discard ejection fraction, as the commonest marker of ventricular function as a determinant of exercise capacity.

Limitations
The main limitation of our study is that we did not investigate the response of echocardiographic measurements to exercise, at the time of symptoms development. However the objective of this study was to determine determinants of ordinary walking exercise limitation rather than heavy exercise in HF patients. The other limitation was the lack of invasive measurements of left atrial pressures, but the study was based on Doppler measurements which have been shown to be reproducible and correlate closely with invasive pressure measurements [36]. The small sample size was another limitation, but we believe that future studies with larger sample size should strength our findings.

Clinical implications
Patients with HF have significantly limited exercise tolerance. Although ejection fraction is considered as the most useful index of LV function and the corner stone for recruiting patients for various treatment modalities, the other echo parameters should be considered as part of the conventional protocol of the follow-up of such patients, depending on overall LV systolic function: enlarged left atrium in HFrEF and impaired longitudinal systolic shortening and reduced hemoglobin in those with HFpEF. While management of patients with HFrEF could be standardized, and follow one protocol, that of patients with HFpEF is likely to be individualized.

Conclusions
In HF patients determinants of exercise capacity differ according to severity of overall LV systolic function, with left atrial enlargement in HFrEF and longitudinal systolic shortening and low hemoglobin in HFpEF as the the main determinants.