The primary outcome of the study is the change in VO2peak after 12 weeks. VO2peak is the gold standard for assessing cardiovascular fitness and is a strong prognostic indicator in HF patients.14 VO2peak will be evaluated through the maximal CPET testing on a treadmill (Medisoft, Model 870C). The testing protocol will be chosen according to the patient's physical activity (PA) level and orthopedic/musculoskeletal condition (modified Naughton or Bruce). The CPET will be conducted under medical supervision, with electrocardiography continually monitored throughout the protocol. Using a stationary metabolic cart system (Geratherm® Respiratory Ergostik, under BLUE CHERRY®), respiratory gas exchange measurements will be obtained breath-by-breath and recorded every 30 seconds. Heart rate and blood pressure will be recorded at regular intervals throughout the test. During CPET testing, patients will be strongly encouraged to achieve a Borg rating of perceived exertion score >17 on the 6 to 20 scale, and a respiratory exchange ratio >1.10. Peak VO2 will be determined as the highest VO2 achieved during exercise.

All subjects will undergo venous blood sampling drawn from an antecubital vein at baseline and after 12 weeks. Alterations in disease-related biomarkers, such as N-terminal pro b-type natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP) and Troponin T (TnT) will be assessed using the standard protocol of our hospital laboratory. The circulating levels of other important functional biomarkers in HF, including galectin-3 (Gal-3), fibroblast growth factor 21 (FGF-21), and angiopoietin-2 (Ang2), will be quantified using commercially available ELISA kits. Nitric oxide (NO) will be indirectly measured by the quantification of nitrate and nitrite using a total NO assay kit. All the measurements will be performed in duplicate according to the respective manufacturer's instructions.

NTproBNP has great prognostic significance in these patients.4 hsCRP is a nonspecific marker of the inflammatory response; in HF patients, higher levels are associated with a worst outcome.15 Elevation in TnT is a predictor of adverse outcomes in hospitalized as well as stable ambulatory patients with HF.16 Gal-3 can be used as a prognostic biomarker to monitor the progression and risk of mortality in chronic HF patients.17 Despite the mechanisms underlying the effects of FGF-21 in HF are not fully understood, it has been shown that FGF-21 levels are elevated in HF, and have good predictive values for adverse cardiac events within 1 year.18 Ang2 had been mostly associated with acute cardiovascular events.19 However, higher levels of Ang2 in serum were also seen in chronic HF patients of increasing severity.20 In HF, endothelial function is compromised due to higher levels of inflammation and oxidative stress, which will impair NO production.21

Changes in physical fitness levels will be evaluated by the Senior Fitness Test battery.22 Physical fitness in HF patients is related with better QoL and, an improvement in physical fitness may be associated with a reduction in cardiac rehospitalization and all-cause mortality.23

Six-minute walking test (6MWT): it will be performed in an indoor corridor with a course of 25 m, marked every 5 m with cones. Baseline oxygen saturation, heart rate, brachial arterial blood pressure and the Borg scale rating will be recorded. During the test, the participants must walk as fast as they can, and they are allowed to stop or slow down if they feel like doing it. At the end of the test, the Borg scale for dyspnea and fatigue and heart rate will be measured. The number of laps and the additional distance covered will be recorded.

30-Second chair stand: this test assesses lower body strength. To perform the test, patients will be required to stand up and sit down quickly and as safely as possible. The number of repetitions performed in 30 seconds, with the arms crossed over the chest, will be registered.

30-Second arm curl: this test assesses upper body strength. Sitting in a chair, the patient should flex the forearm with a 2.27 kg weight for women and 3.63 kg for men for 30 seconds. The number of repetitions performed during the 30s will be registered.

Chair sit-and-reach: this test assesses lower body flexibility. From a sitting position in front of a chair, the patient tries to reach the toes with the leg straight in the knee joint. The distance between extended fingers and the tip of the toe (+ or −), in centimeters, will be recorded and the best value will be taken for analysis.

Back scratch: this test assesses upper body (shoulder) flexibility. The patient tries to join the hands behind the back, leading one hand from the top, and the other from the bottom. The result is the distance between the middle fingers (+ or −), in centimeters. The best value of two repetitions will be taken for analysis.

Eight-foot up-and-go test (8FUG): the test assesses agility and dynamic balance. The patient starts the test in a sitting position. After a signal, the patient must stand up, walk 2.44 meters, make a turn around a cone, and return to the initial position as fast as possible. The patients will perform the test twice and the best time will be considered.

Handgrip strength: strength (kg) will be measured with an isometric hand dynamometer (Lafayette Model 78010, 78011, Indiana, USA). Both arms will be measured 3 times while patients were seated, with the shoulder adducted and neutrally rotated, the elbow flexed at 90̊, and the forearm and wrist in a neutral position. The best attempt will be used as the final score.

Physical activity will be measured through a questionnaire and a triaxial accelerometer copulate to the Polar M200. Self-reported PA will be assessed with the short form of the International Physical Activity Questionnaire (IPAQ-SF)24 through a personal interview to identify time spent in specific behaviours. Total weekly PA in METs will be estimated using the instrument's scoring protocol (3.3 METs to walking, 4.0 METs to moderate, and 8.0 METs to vigorous activity).

PA will be evaluated objectively using the Polar M200 (Polar Electro Ltd) to measure time spent in light, moderate and vigorous physical activity, time spent sitting and lying, and the number of daily steps. Minutes spent in each activity type will be summed to a total day score. Patients will be instructed to wear the watch device during 24 hours for a period of 7 consecutive days.

Changes in QoL will be evaluated through the Minnesota Living with HF Questionnaire (MLHFQ),25 a disease-specific questionnaire for patients with HF. The MLHFQ encompasses 21 questions, whose purpose is to determine how the disease affects the physical, psychological, and socioeconomic conditions of the patients during the previous month. The MLHFQ total score range from 0 to 105 (no impairment to maximum impairment). Higher MLHFQ score means worse QoL. Two other scores can be determined: the physical dimension (8 items, 0–40), and the emotional dimension (5 items, 0–25). Answers options range from 0 (none) to 5 (very much), where 0 represented no limitation and 105 represented maximal limitation.

This will be evaluated by the Hospital Anxiety and Depression Scale (HADS).26 The questionnaire is composed of 14 questions on a four-point (0–3) scale. The possible scores ranged from 0 to 21 for anxiety and 0 to 21 for depression. A score of 0–7 for either subscale will be regarded as being in the normal range, a score of 11 or higher indicates the probable presence of the mood disorder and a score of 8–10 is just suggestive of the presence of the respective state.

The dietary habits will be evaluated by the 14-Item Mediterranean Diet Assessment Tool (MEDAS-14) questionnaire.27 The answer to each of the 14 items is scored with 1 in the case of meeting the criteria defined as typical of this type of food (range of possible variation 0–14 points). A total score ≥10 represents a good adherence to the Mediterranean diet.

Dyspnea symptoms will be evaluated by the Dyspnea-12 (D-12) questionnaire.28 It provides an overall score for breathlessness severity that incorporates seven physical items and five affective items. The D-12 consists of 12 descriptor items on a scale of none (0), mild (1), moderate (2), or severe (3) symptoms. Total scores from the D-12 range from 0 to 36, with higher scores corresponding to greater severity.

Protein aggregates will be analysed using a diagonal two-dimensional (D2D) SDS-PAGE assay with mass spectrometry to identify and characterize detergent-resistant protein aggregates in plasma pre-cleared from albumin and immunoglobulin in a subgroup of 20 patients. Protein homeostasis (proteostasis) is frequently impaired in HF. The overload of protein degradation pathways and collapse of protein quality control will halt protein turnover and is associated with the formation of toxic protein aggregates and misfolded/dysfunctional proteins that contribute to the pathophysiology of the disease.29

To compare the cost-effectiveness of centre-based versus home-based CR intervention, we will use a 5-dimension questionnaire, the EQ-5D, to measure health-related QoL. We will differentiate between cardiac health care costs, noncardiac health care costs, and non-health care costs. The following information related with the cost of the resources used will be collected: type and the number of visits (urgent and non-urgent visits), procedures and medication associated to the visits and length of stay in case of hospitalization. A survey will be conducted to estimate the patients travel time and costs, work status, hours of absenteeism from work, and the time that each health professional spends with the patients during the CR program. We intend to calculate the costs from a societal perspective, which include medical direct costs, non-medical direct costs, and indirect costs, mainly those related with losses in productivity. We will estimate the incremental cost-effectiveness ratio, that is, ratio between the difference of average costs for home-based exercise programs and the control exercise approach program and the difference between average quality-adjusted life years (QALYs) of the two exercise programs.