Borlaug, Barry A.

Abstract Funding Acknowledgements Type of funding sources: None. Background Aortic valve stenosis (AS) and heart failure with preserved ejection fraction (HFpEF) present with similar cardiac alterations, but their overlap is poorly understood.(1–3). Purpose To study left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, hemodynamics, and exercise capacity according to HFpEF status versus AS severity. Methods Patients (n=206) with at least moderate AS (aortic valve area ≤0.85 cm2/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the H2FPEF score [0–5 (AS/HFpEF-) vs. 6–9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Results Mean age was 73±10 years with 40% women. Stratification yielded 41 AS/HFpEF+ (20%) versus 165 AS/HFpEF- (80%) and 139 Severe (67%) versus 67 Moderate (33%) AS patients. AS/HFpEF+ patients had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction compared to AS/HFpEF- patients. The mean pulmonary arterial pressure-cardiac output (mPAP/CO) slope was significantly higher in AS/HFpEF+ versus AS/HFpEF- (5.4±3.1 vs. 3.9±2.2 mmHg/L/min, respectively; p = 0.003), mainly driven by impaired cardiac output (CO) reserve and chronotropic incompetence, with signs of right ventricular-pulmonary arterial (RV-PA) uncoupling. AS/HFpEF+ versus AS/HFpEF- was associated with a lower peak aerobic capacity (11.5±3.7 vs. 15.9±5.9 mL/min/kg, respectively; p<0.0001), but did not differ between Moderate and Severe AS (14.7±5.5 vs. 15.2±5.9mL/min/kg, respectively; p = 0.6). Conclusions A high H2FPEF score is associated with a reduced exercise capacity and adverse hemodynamics in patients with moderate to severe AS. Both exercise performance and hemodynamics correspond better with intrinsic cardiac dysfunction than AS severity itself.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasingly common clinical syndrome with diagnostic challenges and no effective treatment. The high heterogeneity of HFpEF clinical syndrome demands novel technologies to distinguish from heart failure with reduced ejection Fraction (HFrEF). Currently, invasive hemodynamic exercise testing is performed to evaluate for HFpEF with right heart catheterization. Hypothesis: We hypothesize that a deep learning model can noninvasively detect patients with HFpEF using phonocardiogram (PCG). Methods: Eligible patients undergoing right heart catheterization were recruited after IRB approval. Eko duo stethoscope was used to record simultaneous ECG & PCG at the mitral area on the patients prior to right heart catheterization at baseline. Each recording was 30 seconds in length with a frequency range between 250 - 5000 Hz. R-wave peak detection was performed & beat to beat PCG annotations were performed. The annotated PCG signals were converted into Mel-frequency cepstral coefficients (MFCC) and padded to account for the difference in lengths. Deep Learning model was developed using a Sequential Neural Network with 80% data to train and validate the model and 20% hold out data was used for testing accuracy of the model. Receiver operating curve (ROC) was obtained to estimate area under the curve (AUC) for performance analysis. Results: 42 patients were enrolled with 25 patients diagnosed as HFpEF by right heart catheterization and 17 were reported as controls. 2544 & 1771 individual PCG annotations for HFpEF and controls were used for model training/validation and testing. The model performed reasonably well with accuracy of 0.89, F1 score of 0.88, precision of 0.80 and recall of 0.97 on the test data. ROC was obtained with AUC of 0.94. Conclusions: The results demonstrate the ability of the deep learning model to noninvasively detect HFpEF using PCG. Larger study is needed to validate these findings.

Abstract Aims It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF. Methods and results Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation <94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar–arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO2), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO2, and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7–5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01–3.96; p = 0.046). Conclusion Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF.

Objective: Limited evidence is available regarding the impact of workload-indexed hypertensive response to exercise (HRE) in patients at different stages of the heart failure (HF) spectrum. We evaluated the prevalence, pathophysiologic and prognostic correlates of HRE, evaluated by the systolic blood pressure (SBP)/Workload slope, across the HF spectrum as defined by the American College of Cardiology/American Heart Association. Design and method: We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) and either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. We recorded two SBP measurements for each patient: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles, using sex-specific cut-off values; HRE was defined as the highest SBP/Workload slope tertile in each HF stage. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome. Results: The median SBP/Workload slope was 0.53 (interquartile range 0.36 - 0.72) mmHg/W and was steeper in women than men in all subgroups. After adjusting for age and sex, SBP/Workload slope in controls was similar to HFrEF but significantly lower than Stages A-B and HFpEF. In all HF stages, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81 - 5.18). Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B and HFpEF, but not HFrEF. After adjusting for clinical and echocardiographic variables, patients in the highest SBP/Workload tertile had a 47% higher risk of the primary outcome than subjects in the lowest tertile. Conclusions: HRE is associated with peculiar pathophysiological features and possibly worse prognosis in patients in the earliest stages of cardiovascular disease and in those with HFpEF.

Background: Heart failure patients with preserved ejection fraction (HFpEF) exhibit exercise intolerance and exertional dyspnea. The underlying pathophysiology is complex and involves multiple physiological systems. To this point, HFpEF patients exhibit pulmonary abnormalities at rest and during exercise. For example, HFpEF patients have higher work of breathing during exercise due to greater inspiratory and expiratory resistive work of breathing. Importantly, this greater resistive work of breathing is not associated with higher inspiratory and expiratory flow rates suggesting pulmonary resistance is elevated in HFpEF patients. One potential explanation for the increase in resistive work of breathing during exercise in HFpEF patients is smaller luminal area of the airways. Purpose: The purpose of this study was to determine if differences exist in the luminal area of the large conducting airways in HFpEF patients compared to controls. We hypothesized that HFpEF patients will exhibit smaller luminal areas of the large conducting airways compared to controls. Methods: HFpEF patients (n=9; 67±7 yrs; 30±3 kg/m2) and controls (n=8; 62±9 yrs; 24±3 kg/m2) were enrolled. All participants performed pulmonary function testing and a thoracic computerized tomographic (CT) scan (assessed at total lung capacity). The airway luminal area was quantified from three-dimensional reconstructions from the high-resolution CT scans. The luminal areas of the large conducting airways were measured at three discreet points (corresponding to the beginning, middle, and end of the airway), averaged, and indexed to height. Results: The luminal area of the trachea was not different between groups (p=0.95). HFpEF patients had smaller luminal area of the right main bronchus (control: 1.38±0.21 vs. HFpEF: 1.18±0.13 mm2/cm) and left main bronchus (control: 0.98±0.20 vs. HFpEF: 0.79±0.15 mm2/cm) (both, p<0.04) than controls. HFpEF patients also had smaller luminal area of the bronchus intermedius (control: 0.82±0.14 vs. HFpEF: 0.67±0.15 mm2/cm) and left lower lobe bronchus (control: 0.48±0.13 vs. HFpEF: 0.36±0.07 mm2/cm) compared to controls (both, p<0.04). No differences were present between groups in the right and left upper lobe bronchi (both, p>0.40). Conclusion: HFpEF patients have smaller luminal areas of some, but not all large conducting airways compared to controls. These findings provide support for smaller large conducting airways in HFpEF contributing to the pulmonary abnormalities during exercise in these patients. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract Funding Acknowledgements Type of funding sources: None. Background Conflicting data exist regarding the prognostic significance of hypertensive response to exercise (HRE), commonly defined according to absolute peak systolic blood pressure (SBP) values. Limited evidence is available regarding the impact of workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the haemodynamic, functional and prognostic correlates of HRE. Methods We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C); among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded the first (i.e., within the first minute of exercise) and last (i.e., at peak effort) BP measurement during the ramp protocol. The SBP/Workload slope (Figure 1) was calculated as the ratio of the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile in each HF stage. The primary outcome was a composite of all-cause mortality and hospitalization for cardiovascular reasons. Results Median SBP/Workload slope was 0.53 mmHg/W, interquartile range 0.36-0.72 mmHg/W; the slope was 39% steeper in women than in men (p&lt;0.0001). After adjusting for age and sex, SBP/Workload slope in controls (0.43, 0.35-0.57 mmHg/W) was similar to HFrEF (0.47, 0.30-0.63 mmHg/W) but significantly lower than Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W). In all HF stages, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p=0.005) and HFpEF (p&lt;0.001), but not HFrEF. After adjusting for age, sex, body mass index, rest and peak SBP, rest and peak cardiac output, and rest and peak left ventricular ejection fraction, patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusion HRE, as evaluated by the SBP/Workload slope, is associated with distinct pathophysiological features and impaired functional capacity across the HF spectrum, especially in Stages A-B and in patients with HFpEF. Patients with HRE in these subgroups may be at increased risk of adverse cardiovascular outcomes.

BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P <0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0–8.1]; P =0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P =0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P =0.01; P interaction =0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously ( P interaction =0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all P interaction values nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02653482 and NCT03030235.