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

Overview

The heart is a pump that must both fill and empty effectively to move blood; if it cannot move enough, heart failure may ensue. Approximately half of all adults living with heart failure have a form where the heart stiffens, which impairs its ability to fill. This form of heart failure particularly affects females and older adults. When people exercise, extra blood returns to the heart. The healthy heart can easily fill and move this extra blood to the muscles. However, when the heart's ability to fill is impaired, the extra blood can back up and pool in the lungs. Blood pooling in the lungs makes people feel breathless, although the investigators do not fully understand why, and this form of heart failure has a high risk of hospitalization and death, but few effective treatments are available. Exercise is one of the few treatments that works well if enough exercise is performed regularly. However, many people with this form of heart failure can only tolerate a small amount before stopping due to severe breathlessness, which can put them off from exercising regularly. The study's goal is to help these people perform more exercise. The investigators will use a novel form of stationary cycling with a plastic chamber around the lower body that seals at the waist. The chamber can apply suction to the lower body during exercise which will reduce how much extra blood returns and prevent the heart and lungs from being overloaded. Participants will attend 5 visits, including 3 where they will perform a submaximal exercise test for as many minutes as possible with or without light suction. In each of these tests, the investigators will record how long they exercise and ask them to rate how breathless they feel. The investigators will also study their breathing pattern, using a mouthpiece and pressure sensor, and heart function, using ultrasound imaging. This work will help adults living with heart failure exercise more and improve their health, and help researchers understand what causes breathlessness and develop new treatments.

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 1. 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. 2. 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.