Exercise Lower-body Negative Pressure in Heart Failure With Preserved Ejection Fraction

Heart failure is a major public health issue, affecting >750,000 Canadians and >6 million Americans. Half of all adults with heart failure have a preserved ejection fraction (HFpEF), where left ventricular (LV) diastolic dysfunction (impaired filling) is a key abnormality. These adults have few treatment options other than diuretics and exercise training, but dyspnea (a subjective experience of breathing discomfort) on exertion is a hallmark of HFpEF that causes anxiety, activity avoidance, and a spiral of deconditioning leading to worsening dyspnea and prognosis. Mechanisms of dyspnea on exertion are not well understood in HFpEF, but marked increases in LV filling pressure occur that are associated with lung congestion and interstitial fluid accumulation, which stimulates intrapulmonary afferents and impairs breathing mechanics. During exercise, venous return to the heart increases. This augments stroke volume in health but may overload the LV with diastolic dysfunction and drive lung congestion in HFpEF. As such, attenuating the increase in venous return during exercise may reduce congestion, alleviate dyspnea, and improve exercise tolerance in HFpEF. This concept has been demonstrated by invasively reducing venous return, but the safety and feasibility of invasive approaches is unclear. Lower-body negative pressure (LBNP) is a novel, safe and effective non-invasive means to attenuate venous return that can be applied during cycle exercise and may provide considerable benefit.

Study Aims

• To investigate whether LBNP can improve exercise tolerance assessed as the time to exercise limitation (TLIM) during constant work-rate exercise in adults with HFpEF.
• To investigate whether LBNP can attenuate the sensory and affective dimensions of dyspnea during exercise in HFpEF.

Exploratory: To examine the effects of LBNP on central hemodynamics and breathing mechanics during exercise in HFpEF, to explore their relationship with exercise tolerance and dyspnea, and to investigate sex-related differences in these responses and relationships.

Main Endpoints

Primary: Time to exercise limitation (Tlim) measured in seconds during submaximal constant work-rate exercise.

Secondary: Dyspnea intensity measured in Borg units during submaximal constant work-rate exercise.

Study Design

Prospective, two-group (HFpEF and Control), double-blind cross-over study with randomized repeated-measures

Treatment: Lower-body negative pressure (-15 mmHg or -25 mmHg); Placebo: Lower-body atmospheric pressure (0 mmHg)

Study Visits:

Visit 1 [2.0-2.5 hours]: Screening, Enrolment, Phenotyping, and Baseline Testing including anthropometrics, blood pressure, an echocardiogram, pulmonary function tests, and an incremental cardiopulmonary exercise test with 12-lead electrocardiogram.

Visit 2 [0.5 hours]: Venous blood sample for complete blood count (CBC) and B-type natriuretic peptide (NT-proBNP).

Visits 3-5 [1.0-1.5 hours each]: Submaximal Exercise with or without Lower-body Negative Pressure. Participants will undergo assessments of ventilatory and cardiac function while performing 1 submaximal cycle exercise trial per visit with lower-body pressure applied at 0 mmHg, -15 mmHg, or -25 mmHg.

Statistical Analysis

Statistical analyses will be performed using SPSS Statistics (V.28, IBM Inc). Normality will be assessed by the Kolmogorov-Smirnov test. If all compared groups or conditions approximate a normal distribution, data will be presented as mean ± standard deviation with paired comparisons made using t-tests. Otherwise, data will be presented as median (inter-quartile range) with paired comparisons made using the Mann-Whitney U or Wilcoxon Signed Rank tests. Omnibus testing will be conducted using analysis of variance, the Friedman test, or the Kruskal-Wallis test with significant effects tested post hoc using Bonferroni-adjusted t-tests or Dunn's tests. Categorical variables will be summarized as proportions and between-group comparisons will be made using the χ2 test. A two-tailed p <0.05 will be considered significant.

Inclusion criteria

for the HFpEF Group:

• Adults with a clinical diagnosis of HFpEF (LV ejection fraction ≥50%) measured in the year prior to Visit 1 (and confirmed at Visit 1), who are New York Heart Association Functional Class II-III (mild-moderate symptoms), ambulatory, receiving guideline-directed medical therapy unchanged for ≥2 months, and clinically stable for ≥3 months.
• Symptom(s) of heart failure requiring treatment within the year prior to Visit 1
• NT-proBNP >50 pmol/L (sinus rhythm) or >150 pmol/L (atrial fibrillation in year prior)
• Diastolic dysfunction based on at least one of the following echocardiographic findings:

• Left atrial enlargement (diameter >4 cm or volume index >28 mL/m2); or
• e' <10 cm/s (lateral) or <8 cm/s (septal), or
• E/e' >10 (lateral), or >15 (septal)

Inclusion criteria

for the Healthy Control Group:

• Healthy sedentary or recreationally active adults from the community

Exclusion criteria

for the HFpEF Group:

• Any prior measurement demonstrated LV ejection fraction ≤40%
• Primary pulmonary, metabolic, renal, hepatic, neuromuscular, or malignant disease
• Primary pulmonary vascular, complex congenital, or > mild valvular heart disease
• Documented infiltrative cardiomyopathy
• Documented valvular or coronary disease requiring intervention
• Myocarditis, pericardial effusion, acute coronary syndrome, or revascularization in the last 3 months
• Resting seated systolic blood pressure >160 mmHg or <100 mmHg
• Jugular venous pressure >12 cm
• Inferior vena cava >2 cm with no inspiratory collapse, or severe right ventricular dysfunction by echo
• Ambulatory supplemental oxygen
• Current or recent participation in >150 min. per week of moderate intensity exercise
• Current or recent (within the past 6 months) smoking
• Body mass index >35 kg/m2
• Contraindication to exercise or otherwise unable to perform cycle ergometry
• Poor echocardiographic imaging windows

Exclusion criteria

for the Healthy Control Group

• Current or recent participation in >150 min. per week of moderate intensity exercise
• History of any cardiovascular condition or cardioactive drug use
• History of any respiratory condition including asthma
• History of any metabolic condition including diabetes
• Non-sinus rhythm
• Echocardiographic evidence of significant left ventricular hypertrophy, valvular abnormalities, left ventricular ejection fraction <50%, or diastolic dysfunction as described in HFpEF inclusion criteria.
• Seated blood pressure ≥140/90 mmHg
• Any other chronic systemic illness
• Current or recent (within the past 6 months) smoking
• Body mass index >35 kg/m2
• Contraindication to exercise or otherwise unable to perform cycle ergometry
• Poor echocardiographic imaging windows