Borlaug, Barry A.

Background: Exercise normally enhances LV relaxation with minimal change in filling pressure (P). We hypothesize that exercise in hypertensive (HTN) patients increases LV diastolic P through a direct effect on relaxation and ventricular-vascular coupling. Methods: Patients (n=21) with HTN, normal EF, and no coronary disease underwent simultaneous micromanometer LV P and echo-Doppler measurements at rest and with low level supine exercise (12 bicycle; 9 arm weight). Continuous volume (V) was obtained from mitral Doppler inflow and end-diastolic (ED) and end-systolic (ES) V from 2-D echo. Relaxation-corrected LV diastolic P was used for PV relationship P = α.e β*V ; to account for covariance in α and β, LV capacitance (EDV 20 = Ln[20mmHg/α]/β) was reported. Single beat method was used for LV ES elastance (Ees). Group 1 did not increase mean LV diastolic P (mDP) with exercise, Group 2 increased mDP >6mmHg. Results: LV diastolic P and arterial and LV ES elastance increased with exercise; EDV was stable; EDV 20 decreased. Compared to Group 1, Group 2 had a greater exercise-induced increase in afterload, associated with increase in LV minimal P and impaired augmentation of relaxation rate (Table & Figure ). Conclusions: In patients with HTN, impairment of ventricular relaxation plays a major role in causing LV filling P increase with exercise, which is related to ventricular-vascular coupling.

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

Introduction: Left atrial structure and function (LA) is affected by the presence of heart failure (HF), but the specific impact of HF subtype is poorly characterized. Hypothesis: HF-induced LA remodeling differs between patients with preserved (pEF) or reduced ejection fraction (rEF). Methods: 198 consecutive HF patients referred to Mayo Clinic (51% HFpEF, NYHA 3.1±0.7, 66±13 years, 39% females) and 40 HF-free controls of similar age and gender underwent right heart catheterization (LA pressures), echocardiography (LA volumes) and follow-up. Results: Compared with controls, HF patients had larger atria and more impaired LA reservoir and contractile function (total and active LAEF, all p<0.001). At identical mean LA pressure (20 vs 20 mmHg, p=0.9), HFrEF patients had larger LA volumes (LAVI 50 vs 41 ml/m 2 p<0.001), but HFpEF patients had higher LA peak (V-wave) and lower LA minimal pressures, with higher LA stiffness (0.79 vs 0.48 mmHg.ml -1 , p<0.001, Fig-A) and LA pressure pulsatility (19 vs 13 mmHg, p<0.001). Despite smaller LA size, better LA function (total LAEF 39 vs 35 %, p=0.04, active LAEF 30 vs 22 %, p<0.001) and less mitral regurgitation (grade 1.8 vs 2.5, p<0.001), HFpEF patients had more atrial fibrillation (42 vs 26%, p=0.02). After a median follow-up 350 days, 31 HFpEF and 28 HFrEF patients died. LA function was associated with mortality in HFpEF, but not in HFrEF (Fig-B). Conclusions: HFrEF is characterized by greater eccentric LA remodeling, but HFpEF is associated with increased LA stiffening and greater LA pressure pulsatility which may contribute to greater burden of atrial fibrillation. The observation that LA function is more closely linked to outcome in HFpEF supports the goal to maintain or improve LA function in HFpEF.

Accumulating evidence indicates that the lungs are active participants in the pathogenesis of heart failure (HF). Increases in left ventricular end diastolic pressure (LVEDP) leads to elevated pulmonary capillary pressure (PCP) that causes fluid filtration resulting in dyspnea and, ultimately, frank pulmonary edema (PE). However, the severity of dyspnea does not directly relate to the increase in PCP indicating that the clinical manifestation of HF cannot be solely explained by changes in Starling forces. Acute increases in PCP activate glycocalyx‐dependent signaling (endothelial mechanotransduction) that result in oxidative stress, eNOS activation and endothelial hyper‐permeability. Herein we sought to investigate if glypican‐1, a component of the glycocalyx, contributes to pressure‐dependent hyper‐permeability and PE in a model of acute HF. The isolated perfused lung preparation was used to simulate acute HF in male CD‐1 (wild type, WT) and glypican‐1 knockout (Gpc‐1 KO) mice (6 weeks old). Briefly, mice were anesthetized with isoflurane, tracheostomized and mechanically ventilated. Pulmonary artery and left atria were cannulated and in‐line pressure transducers recorded arterial and left atrial pressure; lungs were perfused at 2 mL/min with a Krebs‐Ringer 3% BSA buffer. Control experiments were done setting left atria pressure (P LA ) at 3 cm H2O for 10 minutes; acute heart failure was simulated by setting P LA at 10 cm H2O for 10 minutes. Lung edema was assessed by lung wet‐to‐dry ratio; reactive oxygen species (ROS) production and eNOS activation were assessed as indices of mechanotransduction activation by lucigenin enhanced chemiluminescence and immunoblotting, respectively. NADPH oxidase activity was measured by dihydroethidium fluorescence in isolated membrane‐fracions. WT and Gpc‐1 KO mice had similar increase in pulmonary artery pressure (from 8 to 10 mmHg). Deletion of glypican‐1 protected mice from pressure‐induced PE (wet‐to dry ratio [high and low pressure, respectfully] in WT: 7.3±0.3 vs 4.9±0.3 and in Gpc‐1 KO: 4.8±0.3 vs 4.8±0.2), prevented pressure‐dependen increase in NADPH oxidase activity (15% increase in WT) and in ROS production (80% increase in WT). Moreover, while WT mice showed increased eNOS activation (2‐fold) during acute HF, Gpc‐1 KO mice showed reduced eNOS activation (0.5 fold) indicating that Gpc‐1 is a determinant for mechanotransduction signaling. Taken together, these results suggest that Gpc‐1 activation by pressure leads to endothelial hyper‐permeability due to ROS and NO‐dependent pathways and contributes to PE in an in situ model of acute HF. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Our lab has demonstrated a lower cardiac output (Q) in patients with heart failure (HF) vs. controls (CTL) using acetylene rebreathing (ACET). This technique may be dependent on lung health, which is altered in HF. Therefore, we examined the relationship between Q from echocardiography (echo) and Q from ACET at rest and during exercise. Additionally, we examined the relationship between stroke volume (SV) estimated from O 2 pulse compared to SV by ACET (SV A ). 26 controls (CTL) and 18 HF patients with preserved ejection fraction (EF) completed an exercise test on a cycle ergometer. Lung conductance was measured by lung diffusion for carbon monoxide (DL CO ). Measures of Q (Q A , Acetylene rebreathe; Q E , transthoracic echo), heart rate (HR, 12‐lead ECG), and oxygen consumption (VO 2 , metabolic cart) were taken at rest and peak exercise. Stroke volume (SV) and O 2 pulse were calculated as Q/HR and VO 2 /HR, respectively. HF patients had lower DL CO compared to CTL (Rest: DL CO =11±0.5 vs 14±0.6 ml/min/mmHg, p<0.05). At rest and exercise, Q E was moderately correlated with Q A in CTL (Rest: r=0.47; Pk Ex: r=0.51, p<0.05) and HF (rest: r=0.47; Pk Ex: r=0.77, p<0.05). O 2 pulse was significantly related to SV A at rest and exercise in CTL (Rest: r=0.76; Pk Ex: r=0.81, p<0.05) and HF (Rest: r=0.81; Pk Ex: r=0.82, p<0.05). Cardiac function assessed via ACET is related to cardiac function by echo and O 2 pulse in patients with HF with preserved EF.

Purpose Oxygen pulse (O 2 pulse) is often used clinically as a surrogate for stroke volume during cardiopulmonary exercise testing; however, little data exists on the validity of this measure in patient populations (e.g. heart failure with preserved ejection fraction – HFpEF). Therefore, the purpose of this study was to examine the relationship between O 2 pulse and stroke volume (SV) measured using an accepted technique, echocardiography, at rest and during exercise. Methods Eighteen HFpEF (EF=62±1%) patients and 26 healthy controls (CTL) completed an exercise test on a cycle ergometer. Average measures of oxygen consumption (VO 2 , metabolic cart), heart rate (HR, 12‐lead ECG), and SV (transthoracic echocardiography) were taken at rest and peak exercise. O 2 pulse was calculated as VO 2 divided by HR. Results O 2 pulse was significantly correlated with SV at rest and at peak exercise in CTL (r=0.60 and r=0.55, p<0.05 for both respectfully). O 2 pulse was similarly significantly correlated with SV at rest in HFpEF (r=0.58, p<0.05) whereas this relationship demonstrated a trend at peak exercise (r=0.44, p=0.06). Conclusion Our results demonstrate a moderate relationship between O 2 pulse and SV measured using echocardiography in healthy control participants at rest and during exercise. There is a similar relationship at rest in patients with HFpEF; however, this relationship is less strong during exercise.

Abstract Aims Associations between growth differentiation factor-15 (GDF-15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP-1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF-15 and change in GDF-15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF-15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF-15 were more likely to be male and have more co-morbidities. After adjustment, an increase in GDF-15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF-15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF-15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF-15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF-15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF-15 trajectory in informing risk of heart failure disease progression.

Abstract Aims Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF. Methods and results Subjects with HFpEF ( n = 62) and non‐cardiac dyspnoea (NCD) ( n = 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward‐shifted central venous pressure–dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P < 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r = 0.77, P < 0.0001) and inversely correlated with right ventricular–pulmonary arterial coupling (r = −0.57, all P < 0.0001). Conclusions Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular–pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity‐related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.