Effects of a Multicomponent Training Program on Cardiac Function, Skeletal Muscle Metabolism, Functional Capacity, and Quality of Life in Patients With HFpEF: SENSORFIT-4HEART Study

Changes in peak oxygen consumption between and within groups at 12-week Unit of measure of peak oxygen consumption: mL/kg/min. Maximal functional capacity will be evaluated using incremental and symptom-limited cardiopulmonary exercise testing on a bicycle ergometer, beginning with a workload of 25 W and increasing gradually in a ramp protocol at 25-W increments every 3 minute. We define maximal functional capacity as when the patient stops pedalling because of symptoms and the respiratory exchange ratio (RER) was >1. Gas exchange data and cardiopulmonary variables were averages of values taken every 10 seconds. Peak oxygen consumption (PeakVO2) was defined as the highest value of VO2 during the last 20 seconds of exercise.

Dual-energy X-ray absorptiometry (DXA) body composition measure

Systolic and diastolic blood pressure of participants in fasting condition will be analyzed by electronic tensiometer and reported in mmHg.

Heart rate of participants in fasting condition will be analyzed by electronic tensiometer and reported in pulses/min.

Grip strength of participants will be measured using a manual dynamometer and reported in kg. Pectoral press, bilateral leg-press, knee extension, and back press) will be measured using a eGYM machines and reported in kg

We will use the EuroQol five-dimension five-level questionnaire (EQ-5D-5L) to assess health-related quality of life. The EQ-5D-5L includes five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on a 5-point scale ranging from 1 (no problems) to 5 (extreme problems). The responses are combined into an index value ranging from -0.594 to 1, where higher scores indicate a better health-related quality of life.

Physical activity level objectively measured using Actigraph Accelerometry. This will be worn on the waist and will passively record physical activity and sedentary behavior.

A 19-item self-report questionnaire that assesses subjective sleep quality and disturbances over the past month will be evaluated by Pittsburgh Sleep Quality Index. The global score ranges from 0 to 21, with higher scores indicating poorer sleep quality.

Depression levels will be assessed using the Center for Epidemiological Studies-Depression Scale (CES-D) questionnaire, which is validated and widely employed in cardiometabolic patients. The CES-D consists of 20 items, each rated on a 4-point Likert scale ranging from 0 (rarely or none of the time) to 3 (most or all of the time), assessing the frequency of depressive symptoms during the past week. The total score ranges from 0 to 60, with higher scores indicating greater depressive symptomatology.

Global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a validated screening tool that evaluates multiple cognitive domains, including executive function, memory, attention, language, and visuospatial abilities. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance.

Adherence to the Mediterranean dietary pattern will be assessed using the Mediterranean Diet Adherence Screener (MEDAS), a validated 14-item questionnaire designed to evaluate compliance with key components of the Mediterranean diet. Each item is scored 0 or 1, depending on whether the dietary criterion is met, yielding a total score ranging from 0 to 14, where higher scores indicate greater adherence to the Mediterranean diet.

The Kessler Psychological Distress Scale (K10) will be used to assess nonspecific psychological distress, including symptoms of anxiety and depression, experienced over the past four weeks. The K10 consists of 10 items, each rated on a 5-point Likert scale ranging from 1 (none of the time) to 5 (all of the time), resulting in a total score between 10 and 50. Higher scores indicate greater psychological distress.

Erythrocyte count (×10⁶ cells/µL), haematocrit (%), haemoglobin (g/dL), platelet count (×10³ cells/µL), leukocyte count (×10³ cells/µL), and erythrocyte mean corpuscular volume (fL) will be quantified using a Coulter haematology analyzer (Brand, City, Country).

Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IFN-γ, TNF-α, IL-1ra, and TNF sRII-α), adipokines (adiponectin, adipsin, resistin, PAI-1 active, insulin, and leptin), and myokines (irisin) will be quantified using Luminex xMAP technology. In addition, biomarkers related to bone metabolism (ACTH, DKK-1, FGF-23, osteocalcin, osteopontin [OPN], osteoprotegerin, PTH, and sclerostin [SOST]) will be measured with the same platform. Each analyte will be reported separately as an independent outcome, with concentrations expressed in pg/mL or ng/mL, as appropriate for the specific biomarker.

Resting energy expenditure is measured in the fasting and fed state by indirect calorimetry

N-terminal pro-B-type natriuretic peptide (NT-proBNP) will be quantified by standardized immunoassay (e.g., electrochemiluminescence immunoassay, ECLIA) following manufacturer's instructions

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Dual-energy X-ray absorptiometry (DXA) body composition measure

Lipidomic will be expressed and analyzed in plasma and serum according to their intensity measured in arbitrary units (UA), which carries a direct relation with its concentration in blood. Performed in a randomly selected sub-sample of approximately 30% of study participants

Mitochondrial O2 flux is measured by high-resolution respirometry in muscle mass tissue. Performed in a randomly selected sub-sample of approximately 30% of study participants

Assessment of changes in proteins profile following intervention in blood. Performed in a randomly selected sub-sample of approximately 30% of study participants. Each outcome will be reported separately, with concentrations expressed in pg/mL or ng/mL, as appropriate for the specific analyte.