Left ventricular markers of global dyssynchrony predict limited exercise capacity in heart failure, but not in patients with preserved ejection fraction

We studied 147 patients (mean age 61 ± 11 years, 50.3% male) with clinical diagnosis of congestive heart failure, and New York Heart Association (NYHA) functional class I-III, secondary to ischemic heart disease or non-ischemic etiology. Patients were referred to the Service of Cardiology, Internal Medicine Clinic, University Clinical Centre of Kosovo, between December 2005 and April 2011. At the time of the study all patients were on optimum cardiac medications, optimized at least 2 weeks prior to enrollment, based on patient’s symptoms and renal function: 81% were receiving ACE inhibitors or ARB, 70% beta-blockers, 11% digoxin, 46% spironolactone, 64% diuretics. Patients with reduced LV EF had ischemic etiology in 42%, hypertensive in 25%, and unknown etiology in 33%. Patients with preserved LV EF had ischemic aetiology in 44% and hypertensive in 56%. All patients were in sinus rhythm. Fifty seven patients had LV EF <45% (HFpEF), and the remaining 90 patients had LV EF ≥45% (Table1). Patients with clinical evidence for cardiac decompensation, limited physical activity due to factors other than cardiac symptoms (e.g. arthritis), more than mild mitral regurgitation, more than mild renal failure, chronic obstructive pulmonary disease (COPD) or those with recent acute coronary syndrome, stroke or anemia were excluded. Patients gave a written informed consent to participate in the study, which was approved by the local Ethics Committee.

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 calculated.

A single operator performed all echocardiographic examinations using a Philips Intelligent E-33 system with a multi-frequency transducer, and harmonic imaging as appropriate. Images were obtained with the patient in the left lateral decubitus position and during quiet expiration. End-systole and end-diastole LV dimensions were made from the left parasternal long axis view with the M-mode cursor positioned by the tips of the mitral valve leaflets. 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[23] 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 the 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.

Diastolic function of the LV and RV 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. The E/e’ ratio was calculated from the transmitral E wave and the mean lateral and septal segments e’ waves. 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].

Indirect assessment of LV dyssynchrony was obtained by measuring total isovolumic time (t-IVT), Tei Index and LV-RV pre-ejection time delay. 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. Total isovolumic time (t-IVT) was calculated as 60 - (total ejection time + total filling time) and was expressed in s/min[25]. Tei index was calculated as the ratio between t-IVT and ejection time[26]. LV and RV pre-ejection times were measured as the time interval between the onset of the q wave and the onset of the aortic and pulmonary forward flow velocities, respectively and the time delay between them was calculated[26].

Mitral regurgitation severity was assessed by color 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 Society of Echocardiography[27]. Likewise, tricuspid regurgitation was assessed by color Doppler and continuous-wave Doppler. Retrograde trans-tricuspid pressure drop > 35 mmHg was taken as an evidence for pulmonary hypertension[28]. All M-mode and Doppler recordings were made at a fast speed of 100 mm/s with a superimposed ECG (lead II).

Within 24 h of the echocardiographic examination a 6-MWT was performed on a level hallway surface for all patients and was administered by a specialized nurse blinded to the results of the echocardiogram. According to the method of Gyatt et al.[29] 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[30, 31]. 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 as not to influence walking speed. At the end of the 6 min the supervising nurse measured the total distance walked by the patient. Pulse and blood pressure were measured before and at the end of the walking test.

Out of the list of Doppler echocardiographic measurements, only markers of global dyssynchrony, t-IVT (r = −0.49, p < 0.001) and Tei index (r = −0.43, p < 0.001) correlated with the 6-MWT distance using Pearson’s correlation model (Figure1 &2).

Hemoglobin (p = 0.03) and smoking (p = 0.04) were the only clinical finding that was different between the two groups of patients with good and limited exercise performance (Table3). Patients with limited 6-MWT performance had lower EF (p = 0.003), larger left atrium (p = 0.02), lower A wave (p = 0.009) and lateral myocardial velocity a’ (p = 0.047), but longer isovolumic relaxation time (p = 0.003) and longer t-IVT (p = 0.03, Table1).

In this study we identified markers of global LV dyssynchrony, measured by t-IVT and Tei index but not pre-ejection time which correlated with the 6 MWT distance in a group of patients with clinically stable HF irrespective of EF. A long t-IVT, a low LV EF and high trans-mitral E/A ratio predicted limited exercise performance in multivariate analysis. Low hemoglobin, a univariate predictor, failed to independently predict limited exercise performance. In a small subgroup of patients with HFpEF none of the clinical parameters or functional echocardiographic measurements predicted limited 6MWT distance.

In the absence of musculoskeletal disorders, increased body weight or chronic obstructive pulmonary disease, limited exercise performance is commonly related to cardiac dysfunction, in the form of reduced systolic function (EF) or raised filling pressures[22, 33]. These two common findings have similar consequences, in the form of raised pulmonary pressure, causing exertional breathlessness. Our studied patients show this disturbed pathophysiology, even partially, having shown reduced LV EF and global LV dyssynchrony as independent predictors of limited exercise performance. Global dyssynchrony in the form of prolonged t-IVT and high Tei index restrict effective phases of the cardiac cycle, required for LV filling and ejection. This results in compromised stroke volume and consequently cardiac output and exercise performance as previously shown[33]. In addition, limited left atrial emptying is bound to increase pulmonary venous pressure and hence breathlessness[34] and limited exercise capacity. In individual patients, a t-IVT cut off value of 12.5 s/m clearly discriminated good from limited exercise capacity, having identified over 50% of patients. It must be mentioned that normal exercise capacity is dictated by limited stroke volume or raised left atrial pressure, based on gender[35]. Theoretically therefore, correcting LV synchronous function in heart failure patients by cardiac resynchronisation therapy (CRT), in the absence of evidence for a need for revascularization, is bound to reverse such disturbed physiology and cardiac symptoms[36]. On the other hand when segregating the cohort into patients with reduced EF and those with HFpEF such predictive power of cardiac measurements for 6MWT distance was lost, suggesting the presence of other mechanisms for breathlessness, even in a minority of patients, which diluted the relationship we found above. It also confirms the lack of uniformity of such patients, currently combined under one diagnosis ‘HFpEF’ as has recently been shown not to respond to one and the same medical protocol[37]. This finding confirms our hypothesis stated in the introduction above.

We did not obtain Doppler echocardiographic measurements at peak exercise, when patients became symptomatic, since the objective of the study was to simply determine predictors of ordinary walking exercise limitation rather than an exercise echocardiogram that should have required a different protocol. We did not have invasive measurements of left atrial pressures but relied on Doppler measurements, which are known to be highly reproducible and to closely correlate with invasive pressure measurements[38]. We avoided using segmental measurements of dyssynchrony, based on the recent doubt of their accuracy[31]. We did not have BNP ant NT-pro-BNP data in our patients. However, as the aim of the study was the assessment of echocardiographic predictors of exercise capacity in heart failure patients, we believe that the lack of these data will not weaken the results.

Patients with HF, particularly those in NYHA class III and IV are known to have significantly limited exercise tolerance. Although EF is the most popular measure of LV function, and is considered the corner stone for recruiting patients for various treatment modalities, markers of global LV dyssynchrony should be considered as part of the conventional protocol of the follow-up of such patients. Despite exertional breathlessness in HF patients is multi-factorial, identifying specific patterns of cardiac dysfunction should guide towards optimum management of individual patients, e.g. vasodilators in patients with raised left atrial pressure and cardiac resynchronisation therapy in those with ventricular dyssynchrony, particularly when there is evidence for irreversible dyssynchrony. Those with HFpEF need individualistic approach in assessing their exercise capacity and management.