Citations

Abstract Aims We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary‐echocardiography exercise stress. Methods and results We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C‐reactive protein in HFrEF, while having a direct association with troponin T and C‐reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO 2 ) and peripheral extraction (AVO 2 diff), regardless of body mass index. EAT was inversely correlated with peak VO 2 and AVO 2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo–arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow‐up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04–1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54–0.91). Conclusion In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.

Abstract Aims We aimed to determine the effect of increasing body weight upon right ventricular (RV) volumes, energetics, systolic function, and stress responses using cardiovascular magnetic resonance (CMR). Methods and results We first determined the effects of World Health Organization class III obesity [body mass index (BMI) > 40 kg/m2, n = 54] vs. healthy weight (BMI < 25 kg/m2, n = 49) upon RV volumes, energetics and systolic function using CMR. In less severe obesity (BMI 35 ± 5 kg/m2, n = 18) and healthy weight controls (BMI 21 ± 1 kg/m2, n = 9), we next performed CMR before and during dobutamine to evaluate RV stress response. A subgroup undergoing bariatric surgery (n = 37) were rescanned at median 1 year to determine the effects of weight loss. When compared with healthy weight, class III obesity was associated with adverse RV remodelling (17% RV end-diastolic volume increase, P < 0.0001), impaired cardiac energetics (19% phosphocreatine to adenosine triphosphate ratio reduction, P < 0.001), and reduction in RV ejection fraction (by 3%, P = 0.01), which was related to impaired energetics (R = 0.3, P = 0.04). Participants with less severe obesity had impaired RV diastolic filling at rest and blunted RV systolic and diastolic responses to dobutamine compared with healthy weight. Surgical weight loss (34 ± 15 kg weight loss) was associated with improvement in RV end-diastolic volume (by 8%, P = 0.006) and systolic function (by 2%, P = 0.03). Conclusion Increasing body weight is associated with significant alterations in RV volumes, energetic, systolic function, and stress responses. Adverse RV modelling is mitigated with weight loss. Randomized trials are needed to determine whether intentional weight loss improves symptoms and outcomes in patients with obesity and heart failure.

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DL CO ) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DL CO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath‐by‐breath pulmonary gas exchange were recorded at rest, 20 W, and symptom‐limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m 2 ) achieved a lower symptom‐limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m 2 ). DL CO was lower in patients with HFpEF compared with controls at rest (DL CO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P <0.01) and symptom‐limited maximal exercise (DL CO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P <0.01) because of a lower alveolar‐capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P <0.01; symptom‐limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P <0.01). DL CO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar‐capillary membrane. DL CO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

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.