Borlaug, Barry A.

Abstract Aims Prevalent right ventricular (RV) dysfunction (RVD) is associated with increased mortality in patients with heart failure with preserved ejection fraction (HFpEF), but no study has characterized long-term changes in RV structure and function within the same patient. Methods and results Patients with unequivocal HFpEF defined by either invasive haemodynamics or hospitalization for pulmonary oedema (n = 271) underwent serial echocardiographic evaluations >6 months apart. Clinical, structural, functional, and haemodynamic characteristics were examined. Over a median of 4.0 years (interquartile range 2.1–6.1), there was a 10% decline in RV fractional area change and 21% increase in RV diastolic area (both P < 0.0001). These changes greatly exceeded corresponding changes in the left ventricle. The prevalence of tricuspid regurgitation increased by 45%. Of 238 patients with normal RV function at Exam 1, 55 (23%) developed RVD during follow-up. Development of RVD was associated with both prevalent and incident atrial fibrillation (AF), higher body weight, coronary disease, higher pulmonary artery and left ventricular filling pressures, and RV dilation. Patients with HFpEF developing incident RVD had nearly two-fold increased risk of death (adjusted hazard ratio 1.89, 95% confidence interval 1.01–3.44; P = 0.04). Conclusion While previous attention has centred on the left ventricle in HFpEF, these data show that right ventricular structure and function deteriorate to greater extent over time when compared with changes in the left ventricle. Further study is required to evaluate whether interventions targeting modifiable risk factors identified for incident RVD, including abnormal haemodynamics, AF, coronary disease, and obesity, can prevent RVD and thus improve outcomes.

Aims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension. Methods and results: Male Sprague–Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (Ppa) that were associated with a rapid fall in PaO2, and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling. Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.

Background: Heart failure (HF) is often associated with iron deficiency (ID). Skeletal muscle abnormalities are common in HF, but the potential role of ID in this phenomenon is unclear. In addition to hemopoiesis, iron is essential for muscle bioenergetics. We examined whether energetic abnormalities in skeletal muscle in HF are affected by ID and if they are responsive to intravenous iron. Methods and Results: Forty-four chronic HF subjects and 25 similar healthy volunteers underwent 31 P magnetic resonance spectroscopy of calf muscle at rest and during exercise (plantar flexions). Results were compared between HF subjects with or without ID. In 13 ID-HF subjects, examinations were repeated 1 month after intravenous ferric carboxymaltose administration (1000 mg). As compared with controls, HF subjects displayed lower resting high-energy phosphate content, lower exercise pH, and slower postexercise PCr recovery. Compared with non-ID HF, ID-HF subjects had lower muscle strength, larger PCr depletion, and more profound intracellular acidosis with exercise, consistent with an earlier metabolic shift to anaerobic glycolysis. The exercise-induced PCr drop strongly correlated with pH change in HF group ( r =−0.71, P <0.001) but not in controls ( r =0.13, P =0.61, interaction: P <0.0001). Short-term iron administration corrected the iron deficit but had no effect on muscle bioenergetics assessed 1 month later. Conclusions: HF patients display skeletal muscle myopathy that is more severe in those with iron deficiency. The presence of ID is associated with greater acidosis with exercise, which may explain early muscle fatigue. Further study is warranted to identify the strategy to restore iron content in skeletal muscle.

Background Cardiac resynchronization therapy results in improved ejection fraction in patients with heart failure. We sought to determine whether these effects were mediated by changes in contractility, afterload, or volumes. Methods and Results In 610 patients with New York Heart Association class I/ II heart failure from the Re synchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction ( REVERSE ) study, we performed detailed quantitative echocardiography assessment prior to and following cardiac resynchronization therapy. We derived measures of contractility (the slope [end‐systolic elastance] and the volume intercept of the end‐systolic pressure–volume relationship, stroke work, and preload recruitable stroke work), measures of arterial load and ventricular–arterial coupling, and measures of chamber size (volume intercept, end‐systolic and end‐diastolic volumes). At 6 and 12 months, cardiac resynchronization therapy was associated with a reduction in the volume intercept and end‐systolic and end‐diastolic volumes ( P <0.01). There were no consistent effects on end‐systolic elastance, stroke work, preload recruitable stroke work, or ventricular–arterial coupling. In the active cardiac resynchronization therapy population, baseline measures of arterial load were associated with the clinical composite score (odds ratio 1.30, 95% CI 1.04 to 1.63, P =0.02). The volume intercept was associated with mortality (hazard ratio 1.90, 95% CI 1.01 to 3.59, P =0.047) and more modestly with the combined end point of mortality or heart failure hospitalization (hazard ratio 1.48, 95% CI 0.8 to 2.25, P =0.06). In contrast, end‐systolic elastance, stroke work, preload recruitable stroke work, and ventricular–arterial coupling were not associated with any outcomes. Conclusion In patients with NYHA Class I/ II heart failure, cardiac resynchronization therapy exerts favorable changes in left ventricular end‐systolic and end‐diastolic volumes and the volume intercept. The volume intercept may be useful to gain insight into prognosis in heart failure. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00271154.

Background Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects. Methods and Results REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg; P =0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg; P =0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP) baseline ( r 2 =0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP) baseline ( P =0.001). Hemodynamics of patients with EF ≥50% and those with EF <50% responded similarly to IASD. Conclusions In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01913613.

Abstract Aims Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown. Methods and results The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo. The primary outcome for this post hoc analysis was the change in weight from baseline to last study visit. We conducted an ‘on-treatment’ analysis of patients with at least one follow-up visit on study drug (123 on liraglutide and 124 on placebo). The median age was 61 years, 21% were female, and 69% of patients had New York Heart Association functional Class III or IV symptoms. The median ejection fraction was 25% (25th, 75th percentile 19–32%). Liraglutide use was associated with a significant weight reduction [liraglutide −1.00 lbs vs. placebo 2.00 lbs; treatment difference −4.10 lbs; 95% confidence interval (CI) −7.94, −0.25; P = 0.0367; percentage treatment difference −2.07%, 95% CI −3.86, −0.28; P = 0.0237]. Similar results were seen after multivariable adjustments. Liraglutide also significantly reduced triglyceride levels (liraglutide 7.5 mg/dL vs. placebo 12.0 mg/dL; treatment difference −33.1 mg/dL; 95% CI −60.7, −5.6; P = 0.019). Conclusions Liraglutide is an efficacious weight loss agent in patients with HFrEF. These findings will require further exploration in a well-powered cardiovascular outcomes trial.