Omar, Massar

Abstract Aims Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. Methods and results Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV–PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch. Conclusions Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV–PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.

Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the SGLT2 (sodium–glucose cotransporter-2) favorably affects SBV. We investigated the effect of empagliflozin on estimated SBV in patients with heart failure and reduced ejection fraction compared with placebo. Methods: This was a post hoc analysis of an investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in estimated SBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. Results: Patients with heart failure and reduced ejection fraction, mean age, 57 years and mean ejection fraction 27%, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on estimated SBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (−198.4 mL [95% CI, −317.4 to −79.3] P =0.001), a 9% decrease. The decrease in estimated SBV by empagliflozin was significantly correlated with the decrease in PCWP ( R =−0.33, P <0.0001). The effect of empagliflozin was consistent across subgroup analysis. Conclusions: Empagliflozin treatment significantly reduced SBV compared with placebo after 12 weeks of treatment in patients with stable chronic heart failure and reduced ejection fraction during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03198585.

Abstract Background Patient-worn accelerometer is increasingly used in patients with heart failure and reduced ejection fraction (HFrEF) to assess daily activity and and as surrogate endpoint. We examined the association between cardiac physiology and daily activity by patient-worn accelerometer recordings in stable HFrEF patients. Methods In this descriptive study, physical average daily accelerometer units (PADA) and total average daily accelerometer unit (TADA) were assessed by a accelerometer recordings. Sixty three stable ambulatory patients with HFrEF, mainly men (92%), mean age 58±10 years, and ejection-fraction 26±4% underwent hemodynamic exercise testing, and accelerometry (Table 1). Patients were divided by PADA in a low and high activity level groups based on counts per minute physical activity. Results Patients in the low activity group were older and more frequently treated with diuretics. At rest, the low activity group was characterized by a lower cardiac index (CI) (2.2±0.4 vs. 2.4±0.4 l/min/m2, p=0.01), Stroke volume (SV) (70±19 vs. 81±17 ml, p=0.02) but not pulmonary capillary wedge pressure (PCWP) (12±5 vs. 11±5 mmHg, p=0.3) (Figure 1). Low activity group reached a lower CI (4.8±1.7 vs. 6.6±1.7 l/min/m2, p&lt;0.001) and SV (94±32 vs. 121±29 ml, p&lt;0.001), but not in PCWP (31±12 vs. 27±8 mmHg, p=0.2) or arterial-venous O2 content difference (A-VO2 diff) (13.00±2.32 vs. 12.96±1.65 ml O2/dl, p=0.9) at peak exercise. The attenuated increase was associated with attenuated increase in SV rther than increase in heart rate (42±23 vs. 52±21 bpm, p=0.07). Finally, CI at peak exercise was the only independent variable associated with PADA after adjusting for age, gender, and BMI (p&lt;0.0001). The PADA and TADA were associated to functional assessments using Kansas City Cardiomyopathy Questionnaire, but not with New York Heart Association class or N-terminal pro brain natriuretic peptide (NT-proBNP) (Table 1). Conclusion Accelerometer-assessed activity in patients with HFrEF are associated with impairments in LV performance, SV reserve and cardiac output during exercise, to a greater extent than changes in arterial-venous O2 content difference or pulmonary vascular pressures. Accelerometer data may provide information about the functional status that we do not nessecary find in the widely used tools in both research and daily clinical practice. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the Danish Heart Foundation [grant numbers 17-R116-A7714-22076, 18-R124-A8573-22107]; Steno Diabetes Center Odense, Denmark [grant number 3363] and A.P. Møller Foundation for the Advancement of Medical Science [grant number 17-L-0339]. Table 1. Baseline and regression analysisFigure 1. Change in PCWP and CI by exercise