We studied 118 consecutive patients with a clinical diagnosis of congestive HF (age 62 ± 10 years, 57 female) with ischemic or non-ischemic aetiology, who were in New York Heart Association (NYHA) functional class I-III, and were referred to the Clinic of Cardiology, University Clinical Centre of Kosovo, between December 2014 and September 2016. At the time of the study all patients were on full cardiac medications, optimized at least 2 weeks prior to enrollment. Patients with NYHA class IV, those with limited physical activity due to factors other than cardiac symptoms (e.g. arthritis), with more than mild renal or hepatic failure, with chronic obstructive pulmonary disease, with recent acute coronary syndrome, stroke, psychological or psychiatric disorders, or those with severe anemia, were excluded from the study. All patients signed a written informed consent to participate in the study, which was approved by the Ethics Committee of the Medical Faculty, University of Prishtina. This study was supported and monitored by Kosovo Society of Cardiology [27], which is trying to implement European Society of Cardiology guidelines and other current diagnostic and therapeutic recommendations.

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

The MLHFQ contains 21 questions, whose aim is to determine how HF affects the physical, psychological and socioeconomic conditions of the patients (Additional file 1 Table S1). The questions refer to the signs and symptoms of HF, social relationships, physical and sexual activity, work and emotions [14] and assesses how HF affected the patient’s life during the previous month. The MLHFQ has a scoring range of 0 for no impairment to 105 for maximum impairment. The questions cover symptoms and signs relevant to HF, physical activity, social interaction, sexual activity, work, and emotions. Three scores were determined: an overall score (21 items, 0–105), the physical dimension (8 items, 0–40), and the emotional dimension (5 items, 0–25), with the highest scores reflecting the worse QoL. The scale of answers to each question ranges from 0 (none) to 5 (very much), where 0 represented no limitation and 105 represented maximal limitation.

A single operator performed all echocardiographic examinations using a Philips Intelligent E-33 system with a multi-frequency transducer, and harmonic imaging as appropriate. Using conventional landmarks and recommendations of the American Society of Echocardiography and European Association of Echocardiography [28, 29] we obtained all measurements including, interventricular septal (IVS) thickness, posterior wall (PW) thickness, and LV dimensions, LV volumes and EF using the modified Simpson’s method and left ventricular mass (LVM) using Devereux formula [30].

Ventricular long axis motion was also studied using conventional methods previously described [31], from which the following measurements were obtained; total amplitude as the mitral annular plane systolic excursion (MAPSE) and the tricuspid plane systolic excursion (TAPSE), and long axis myocardial velocities in systole (s’), early (e’) and late (a’) diastole. Mean value of the lateral and septal e’ velocities was also calculated. LV diastolic function was assessed from spectral Doppler recordings, from which LV early (E wave), late (A wave) diastolic velocities, E/A ratio and E/e’ (mean lateral and septal) ratio were all calculated. Finally, LV isovolumic relaxation time (IVRT) was measured. LV filling pattern was considered ‘restrictive’ when E/A ratio was >2.0, E wave deceleration time < 140 ms and the LA trasverse diameter was >40 mm [33]. LA diameter and volumes were measured, according to the guidelines of the American Society of Echocardiography and European Association of Echocardiography [29], maximal volume (LAV max) at the end systole and LA minimal volume (LAV min) at end diastole. LA total emptying fraction was calculated using the formula [32]:

Indirect assessment of LV dyssynchrony was obtained by measuring total isovolumic time (t-IVT), Tei Index and LV-RV pre-ejection time delay, a spreviously described [33] using total LV filling time and ejection times. Total isovolumic time (t-IVT) was calculated as 60 - (total ejection time + total filling time) and was expressed in s/min [34]. Tei index was calculated as the ratio between t-IVT and ejection time [35].

Mitral and tricuspid regurgitation severity were 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 (LA) in line with the recommendations of the American Society of Echocardiography [36]. 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). From the pulmonary artery flow recordings pulmonary artery acceleration time (PAAT) [37]. The LV outflow tract (LVOT) diameter and area were measured [38] in order to calculate the average velocity time integral (VTI) and the stroke volume (SV) [39].

Blood was taken from an antecubital vein in the morning, sober and after staying extended for 20 min. Blood samples were collected into tubes containing potassium ethylenediaminetetraacetic acid (EDTA) (1 g/L plasma) and N-terminal proBNP were calculated with the Cobas Elecsys E411 analyzer (range 5–35,000 pg/mL) using chemiluminescent immunoassay kit (Roche Diagnostics, Grenach -Wyhlen, Germany).

Within 24 h of the echocardiographic examination a 6-MWT was performed on a level hallway surface and was administered by a specialized nurse blinded to the results of the echocardiogram. According to the method of Gyatt et al. [40] patients were informed of the purpose and protocol of the 6-MWT, which was conducted in a standardized fashion without interrupting patient’s regular medications [41]. A 15 m flat, obstacle-free corridor was used and patients were instructed to walk as far as they can, turning 180° after they had 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.

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 Chi-square test. Correlations were tested with Pearson coefficients. Predictors 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 [42], and were compared using unpaired Student t-test.

Patients with limited exercise, who walked <300 m during 6-MWT, were older (p = 0.003), had higher NYHA functional class (p = 0.002), faster baseline heart rate (p = 0.006), higher prevalence of smoking (p = 0.015), and higher global, physical and emotional MLHFQ scores (p < 0.001, for all), compared to those with good exercise capacity. Patients with limited exercise also had larger LA diameter (p = 0.001), shorter LV FT (p = 0.027), smaller septal MAPSE (p = 0.037), higher E/e’ ratio (0.020), shorter IVRT (p = 0.028), PAAT (p = 0.005), lower septal a’ (p = 0.019) and s’ (p = 0.023), compared to those with preserved exercise capacity. All other clinical and echocardiographic parameters were not significantly different between two groups.

In the patients’ group as a whole, total MLHFQ score had strong correlation with 6-MWT distance, lateral s’ (p < 0.001 for both), good correlation with LVMI (p = 0.001) and with lateral MAPSE (p = 0.009), and weak correlation with hemoglobin level (p = 0.024). In HFpEF, total MLHFQ score had strong correlation with 6-MWT distance (p < 0.001, Fig. 1), and weak correlation with lateral s’ (p = 0.014), LVMI (p = 0.027) and with hemoglobin level (p = 0.016), whereas in HFrEF patients it has only a weak correlation with lateral s’ (p = 0.03), LVMI (p = 0.027), lateral MAPSE (p = 0.027) and with E/A ratio (p = 0.047).

The results of this study analysis can be summarized as follows: 1) the total scale, physical and emotional MLHFQ subscale scores were not different between HFpEF and HFrEF patients. 2) Patients with limited exercise capacity were older, had higher NYHA functional class, faster baseline heart rate, higher prevalence of smoking and higher global, physical and emotional MLHFQ scores, compared to those with good exercise capacity. 3) Patients with limited exercise capacity, also had larger LA, shorter LV FT, worse longitudinal systolic function and raised LV filling pressures, compared to those with preserved exercise capacity. 4) Total MLHFQ score had strong correlation with 6-MWT distance in the patients group as a whole and in HFpEF subgroup, but not in HFrEF. 5) Total MLHFQ score, age and diabetes were the only independent predictors of limited 6-MWT distance in the whole group of patients and in HFpEF subgroup. It was LA enlargement and age which independently predicted limited exercise capacity in HFrEF.

MLHFQ irrespective of its components; physical or emotional seems to be a good measure of exercise capacity, since it correlated strongly with the 6-MWT distance in the HF group irrespective of EF. Thus, it could be used to reflect the overall cardiac status, when used to evaluate patients’ response to treatment. It however, does not reflect the underlying cardiac structural or functional disturbances, which contribute to the limited exercise capacity in individual patients, and which might need different treatments. Age seemed to be correlating with limited exercise capacity but nothing can be done about it. On the other hand baseline heart rate proved to be an equally important factor but can be managed by beta blockers [43] or other forms of heart rate controlling medications e.g. Ivabridine [44], or the combination of the two [45]. Furthermore, patients with limited exercise capacity proved to have dilated LA [46, 47], the underlying pathophysiology of which is known to be complicated. It proved to be related to the high filling pressures in some [48] and poor LA emptying, as shown be short LV filling time, in others [49]. In addition to the variety of mechanisms of disturbed physiology, the matter is further complicated by the way patients differ in their response to treatment. While the former group usually responds to LA pressure lowering medications i.e. ACE-inhibitors or A2 blockers [50], the latter respond better to cardiac resynchronization therapy [51]. Finally, it seems that predictors of the limited exercise capacity differed fundamentally according to the cardiac physiology. While specifically the causes of LA enlargement; pressure, mitral regurgitation, stiff LV, etc., that limited patients exercise in HFrEF, the respective reasons were multifactorial including age, diabetes, as well as emotional and physical scores that predicted exercise capacity in HFpEF. The latter finding adheres to what is known about HFpEF in terms of its etiology, comorbidities as well as limited benefit when using conventional guidelines-based treatment recommendations [52]. The lack of an acceptable relationship between LA volume and exercise capacity in HFpEF could be explained by either strict early treatment with vasodilators which reduced cavity pressure and hence volume or less myocardial stiffness compared with HFrEF. Also, despite higher AF prevalence in HFrEF patients compared to HFpEF, our analysis suggest that AF was not necessarily a determinant factor for the difference in relationship between left atrial enlargement and 6-MWT. It seems therefore that more than one factor could contribute to the lack of direct relationship between the LA volume and exercise capacity in HFpEF. It was however not feasible to run a number of permutations and combinations in order to identify the additive value of various individual variables in predicting exercise capacity.

Our findings suggest that the MLHFQ correlates with 6MWT distance in heart failure patients as a whole and is able, fairly accurately, to predict those with limited exercise capacity. These findings apply better to patients with HFpEF much more than those with HFrEF in whom clearly signs of raised LA pressures are those which independently determine their limited exercise capacity. These differences support the need for continuing the use of detailed Doppler echocardiographic follow up of heart failure patients in order to better understand the pattern of disturbances that explain symptoms as well as the most accurate treatment option.

Obvious limitations can easily be seen in this study. The small number of patients included in this study limits general application of the findings before results are revalidated in a larger cohort. We consider that further prospective cohort studies with a larger sample size, are undoubtedly needed to strengthen or refute our findings. Speckle tracking ultrasonography to measure the global longitudinal strain, which might be associated with reduced functional capacity in HF patients was not used. However, assessing longitudinal LV function with conventional tools, provided an estimate of other overall longitudinal LV function. We cannot ignore the emotional element in conducting the 6-MWT and patient encouragement to walk faster, although unassisted. We did not assess the reproducibility of the results of the MLHFQ neither the 6-MWT distance, which could have shown significant differences.