Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of HFpEF

This study was designed as a prospective, controlled, randomized, four-armed, efficacy trial of patients with the diagnosis of HFpEF and New York Heart Association functional class II-III/IV, diagnosed according to criteria of the European Society of Cardiology. A computer-generated randomization scheme was used to allocate participants (in a 1:1:1:1 ratio) to receive: 1) a home-based 12-week program of inspiratory muscle training (IMT) or; 2) a 12-week program of functional electrical stimulation (FES) of lower limb muscles or; 3) standard treatment (ST) alone or; 4) combination of IMT and FES. The study is being conducted in a single center in Spain. Independently of staggered entry, the minimum duration of a patient's participation is 6 months (from first to last visit). All patients will provide signed informed consent and the protocol has been approved by the research ethics committee of our center in accordance with the principles of the Declaration of Helsinki and national regulations.

Study population Candidate patients are selected from the outpatient's clinics of HF of the Hospital Clínico Universitario of Valencia.

Study objectives The primary endpoint of the study is a clinical endpoint of three and six months change in peak oxygen uptake (peak VO2).

Secondary endpoints are three and six month changes in echocardiogram parameters, QoL and prognostic biomarkers. The investigators also will specifically focus on number of episodes of worsening HF at 6 months:

• Change in E/e' after three and six months.
• Change in left atrial volume index after three and six months.
• Change in health-related QoL measured by the Minnesota Living With Heart Failure Questionnaire (MLHF) after three and six months.
• Change in natriuretic peptide (NT-proBNP) after three and six months.
• Change in minute ventilation/carbon dioxide production (VE/VCO2) slope after three and six months.
• Number of episodes of acute HF hospitalizations and number of episodes of worsening HF not requiring hospitalization at 6 months.

Intervention

Eligibility assessment and screening visit After reviewing the inclusion/exclusion criteria and signing the informed consent form, a comprehensive medical history, physical examination, anthropometry and examination tests will be performed. The examination tests include: electrocardiogram (ECG) echocardiography, cardiopulmonary exercise testing (CPET), 6-minute walk test (6-MWT), inspiratory muscle function test, QoL assessment by the Minnesota Living With Heart Failure Questionnaire (MLHF) and blood samples for a panel of baseline biomarkers.

Finally, patients are randomized (1:1:1:1) to four groups: 1) ST alone or; 2) a home-based 12-week program of IMT or; 3) a 12-week program of FES or; 4) combination of IMT and FES (IMT+FES) during 12 weeks.

12-week and six months visits All patients will be evaluated after 12-week supervised training, and six months after randomization. Evaluation will include medical history, physical examination, anthropometry and functional and QoL assessment tests (ECG, CPET, 6-MWT, inspiratory muscle function test, MLHF and blood tests).

Inclusion criteria

• Previous history of symptomatic heart failure NYHA (New York Heart Association )functional class ≥II with Normal left ventricular ejection fraction:

• ejection fraction >0.50 by Simpson method
• end-diastolic diameter <60 mm
• Structural heart disease:

• left ventricle hypertrophy/left atrial enlargement and/or
• diastolic dysfunction estimated by 2D echocardiography
• Previous admission for acute heart failure
• Clinical stability, without hospital admissions in the past 3 month

Exclusion criteria

• Perform a valid baseline exercise test
• Significant primary moderate to severe valvular disease
• Acute coronary syndrome or cardiac surgery within the previous three months
• Signs of ischemia during cardiopulmonary exercise testing
• Significant primary pulmonary disease; including pulmonary arterial hypertension, chronic thromboembolic pulmonary disease or chronic obstructive pulmonary disease
• Any other comorbidity with an expectancy of life less than one year