Videbæk, Lars

Abstract Introduction To investigate the effect of empagliflozin on right ventricular (RV) function in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricular (LV) remodelling in HFrEF. The impact on RV function remains uncertain. Methods The Empire HF trial was an investigator-initiated, double-blind, randomized, placebo-controlled trial of 190 participants with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I−III symptoms. Participants were randomized to receive either empagliflozin (at a dose of 10 mg once daily) or placebo, on top of recommended therapy for 12 weeks. The primary endpoint of this exploratory substudy was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in tricuspid annular plane systolic excursion (TAPSE) and RV S’ velocity. Results Between June 2017 and September 2019, a total of 190 patients were enrolled, of whom 160 were included in this substudy. Baseline characteristics were balanced between the groups (mean age of 64 ± 11 years, 86% male, mean LVEF: 29 ± 8%, 79% in NYHA Class II, 83 patients (52%) had an implanted cardiac device, and tricuspid valve regurgitation was absent/trace in 136 (85%) and mild in 24 (15%)). A high proportion of the population were on optimal medical treatment for HFrEF, and device therapy remained unchanged during follow-up. The overall mean RVFWS was −16.7 ± 6.1%, with the empagliflozin group at −16.4 ± 6.2% and the placebo group at −16.9 ± 5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: −2.9% [95% CI: −5.0 to −0.3]; P = .027). This finding was independent of LVEF, plasma volume, and weight loss, and remained unchanged after additional adjustment for LV remodelling and the presence of resynchronization therapy. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’. Conclusion This exploratory substudy of the Empire HF, treatment with empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration ClinicalTrials.gov, Unique Identifier: NCT03198585

Background: The relationship between blood volume and pressure in the vascular system can be described in terms of unstressed and stressed blood volume. Stressed blood volume determines venous pressure and provides preload back to the heart, which regulates the generation of cardiac output (CO) via the Frank-starling mechanism. Whether sodium-glucose cotransporter-2 (SGLT2i) favorably modifies stressed blood volume is not known. Hypothesis: To investigate the effect of SGLT2i (empagliflozin) on the hemodynamic estimated stressed blood volume (eSBV) in HFrEF patients compared to placebo. Methods: A post hoc analysis of investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin of 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. Outcome was change in eSBV after 12 weeks of empagliflozin treatment at each level of exercise. We conducted computer-modelling simulations based on invasive hemodynamic assessment to measure eSBV. Results: HFrEF patients with mean age was 57 years, mean ejection fraction 27%, 47 (71%) on diuretics were randomized. After 12 weeks treatment exercise eSBV was significantly reduced at 0 watt, 25 watt and 25 % of maximal exercise watt, compared to placebo [(0 watt; –258 mL, 95% CI –476 to –39, p=0.021); (25 watt; –301 mL, 95% CI –561 to –40, p=0.024); and (25% of peak exercise watt; –262 mL, 95% CI –490 to –34, p=0.024)]. There was no effect on rest, or at peak exercise eSBV [(Rest; –75 ml, 95% confidence interval [CI] –279 to 130; p=0.47); and (Peak; –96 mL, 95% CI –444 to 251, p=0.59)]. This was consistent among patients with and without type 2 diabetes, etiology of HFrEF, and diuretic usage (Figure 1). Conclusion: Empagliflozin may contribute to shift blood from the effective circulatory beds to the venous reservoir in reducing filling pressure and eSBV, but maintaining CO.

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<0.001) and SV (94±32 vs. 121±29 ml, p<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<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

Background— In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. Methods and Results— In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P =0.002), presented less often with atrial fibrillation (13% versus 24%; P =0.05) and chronic obstructive pulmonary disease (2% versus 19%; P <0.001), and had a lower prevalence of hypertension (73% versus 40%; P <0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m 2 ; P <0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P <0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P <0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m 2 ; P =0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. Conclusions— The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.

Background Plasma fibulin‐1 levels have been associated with N‐terminal pro–B‐type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. Methods and Results One hundred twenty‐five patients with severe aortic stenosis who were scheduled for aortic valve replacement ( AVR ) were evaluated with preoperative echocardiography and their plasma fibulin‐1 levels were determined with ELISA . The cohort was followed for a median of 4 years after AVR . Increased restrictive left ventricular ( LV ) filling pattern was observed with increased plasma fibulin‐1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin‐1 tertile groups, P =0.004). Likewise, reduced longitudinal systolic LV function (6.6±1.1 versus 6.1±1.3 versus 5.7±1.5 cm/s, P =0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin‐1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13±4 versus 15±5 versus 16±6 in the fibulin‐1 tertile groups, P =0.04). Conclusions In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin‐1 is associated with restrictive filling of the LV , decreased longitudinal systolic function of the LV , and increased LV filling pressures. Clinical Trial Registration URL: www.clinicaltrial.gov with Identifier: NCT00294775

Background— Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. Methods and Results— A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P =0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02–1.25), P =0.04. Comparing the overall log likelihood χ 2 of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. Conclusions— In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.