BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

• MeSH
• glukagonu podobné peptidy * MeSH
• kvalita života * MeSH
• lidé MeSH
• natriuretický peptid typu B MeSH
• obezita farmakoterapie   MeSH
• srdeční selhání * diagnóza   farmakoterapie   MeSH
• tepový objem MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

• MeSH
• benzhydrylové sloučeniny * terapeutické užití   farmakologie   MeSH
• glifloziny * terapeutické užití   farmakologie   MeSH
• glukosidy * terapeutické užití   farmakologie   MeSH
• hmotnostní úbytek * účinky léků   MeSH
• lidé MeSH
• peptid YY * metabolismus   MeSH
• srdeční selhání * farmakoterapie   patofyziologie   MeSH
• tepový objem * fyziologie   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

• MeSH
• funkce pravé komory srdeční * fyziologie   MeSH
• lidé MeSH
• plicní hypertenze * patofyziologie   etiologie   terapie   MeSH
• plicní oběh * fyziologie   MeSH
• srdeční selhání * patofyziologie   komplikace   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I-III (body mass index (BMI) 30.0-34.9 kg m-2, 35.0-39.9 kg m-2 and ≥40 kg m-2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511 .

• MeSH
• C-reaktivní protein MeSH
• hmotnostní úbytek MeSH
• lidé MeSH
• obezita komplikace   farmakoterapie   MeSH
• srdeční selhání * MeSH
• tělesná hmotnost MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

OBJECTIVES: The authors hypothesized that quantitative computed tomography (QCT) imaging would reveal subclinical increases in lung congestion in patients with heart failure and preserved ejection fraction (HFpEF) and that this would be related to pulmonary vascular hemodynamic abnormalities. BACKGROUND: Gross evidence of lung congestion on physical examination, laboratory tests, and radiography is typically absent among compensated ambulatory patients with HFpEF. However, pulmonary gas transfer abnormalities are commonly observed and associated with poor outcomes. METHODS: Patients referred for invasive hemodynamic exercise testing who had undergone chest computed tomography imaging within 1 month were identified (N = 137). A novel artificial intelligence QCT algorithm was used to measure pulmonary fluid content. RESULTS: Compared with control subjects with noncardiac dyspnea, patients with HFpEF displayed increased mean lung density (-758 HU [-793, -709 HU] vs -787 HU [-828, -747 HU]; P = 0.002) and a higher ratio of extravascular lung water to total lung volume (EVLWV/TLV) (1.25 [0.80, 1.76] vs 0.66 [0.01, 1.03]; P < 0.0001) by QCT imaging, indicating greater lung congestion. EVLWV/TLV was directly correlated with pulmonary vascular pressures at rest, with stronger correlations observed during exercise. Patients with increasing tertiles of EVLWV/TLV demonstrated higher mean pulmonary artery pressures at rest (34 ± 11 mm Hg vs 39 ± 14 mm Hg vs 45 ± 17 mm Hg; P = 0.0003) and during exercise (55 ± 17 mm Hg vs 59 ± 17 mm Hg vs 69 ± 22 mm Hg; P = 0.0003). CONCLUSIONS: QCT imaging identifies subclinical lung congestion in HFpEF that is not clinically apparent but is related to abnormalities in pulmonary vascular hemodynamics. These data provide new insight into the long-term effects of altered hemodynamics on pulmonary structure and function in HFpEF.

• MeSH
• hemodynamika MeSH
• lidé MeSH
• plíce diagnostické zobrazování   MeSH
• plicní edém * diagnostické zobrazování   etiologie   MeSH
• prediktivní hodnota testů MeSH
• srdeční selhání * komplikace   diagnostické zobrazování   MeSH
• tepový objem MeSH
• umělá inteligence MeSH
• zátěžový test MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: A warmup period of priming exercise has been shown to improve peripheral oxygen transport in older adults. We sought to determine the acute effects of priming exercise on central hemodynamics at rest and during a repeat exercise in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This is a post hoc analysis from 3 studies. Patients with HFpEF (n = 42) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise (20 W for 5 minutes, priming exercise). Measurements were then repeated at rest and during a second bout of exercise at a 20-W workload (second exercise). During the priming exercise, patients with HFpEF displayed dramatic increases in biventricular filling pressures and exercise-induced pulmonary hypertension. After the priming exercise at rest, biventricular filling pressures and pulmonary artery (PA) pressures were lower and lung tidal volume was increased. During the second bout of exercise, biventricular filling (PA wedge pressure, 29 ± 8 mm Hg at second exercise vs 32 ± 7 mm Hg at first exercise, P = .0003) and PA pressures were lower, and PA compliance increased. CONCLUSIONS: This study shows that short duration, submaximal priming exercise attenuates the pathologic increases in filling pressures, improving pulmonary vascular hemodynamics at rest and during repeat exercise in patients with HFpEF.

• MeSH
• funkce levé komory srdeční MeSH
• hemodynamika MeSH
• lidé MeSH
• senioři MeSH
• srdeční selhání * terapie   MeSH
• tepový objem MeSH
• tolerance zátěže MeSH
• zátěžový test MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Identification of elevated pulmonary artery pressures during exercise has important diagnostic, prognostic and therapeutic implications. Stress echocardiography is frequently used to estimate pulmonary artery pressures during exercise testing, but data supporting this practice are limited. This study examined the accuracy of Doppler echocardiography for the estimation of pulmonary artery pressures at rest and during exercise. METHODS: Simultaneous cardiac catheterisation-echocardiographic studies were performed at rest and during exercise in 97 subjects with dyspnoea. Echocardiography-estimated pulmonary artery systolic pressure (ePASP) was calculated from the right ventricular (RV) to right atrial (RA) pressure gradient and estimated RA pressure (eRAP), and then compared with directly measured PASP and RAP. RESULTS: Estimated PASP was obtainable in 57% of subjects at rest, but feasibility decreased to 15-16% during exercise, due mainly to an inability to obtain eRAP during stress. Estimated PASP correlated well with direct PASP at rest (r=0.76, p<0.0001; bias -1 mmHg) and during exercise (r=0.76, p=0.001; bias +3 mmHg). When assuming eRAP of 10 mmHg, ePASP correlated with direct PASP (r=0.70, p<0.0001), but substantially underestimated true values (bias +9 mmHg), with the greatest underestimation among patients with severe exercise-induced pulmonary hypertension (EIPH). Estimation of eRAP during exercise from resting eRAP improved discrimination of patients with or without EIPH (area under the curve 0.81), with minimal bias (5 mmHg), but wide limits of agreement (-14-25 mmHg). CONCLUSIONS: The RV-RA pressure gradient can be estimated with reasonable accuracy during exercise when measurable. However, RA hypertension frequently develops in patients with EIPH, and the inability to noninvasively account for this leads to substantial underestimation of exercise pulmonary artery pressures.

• MeSH
• arteria pulmonalis * diagnostické zobrazování   MeSH
• cvičení MeSH
• dopplerovská echokardiografie MeSH
• lidé MeSH
• plicní hypertenze * diagnostické zobrazování   MeSH
• zátěžová echokardiografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

AIMS: Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. METHODS AND RESULTS: Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001). CONCLUSION: Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. CLINICAL TRIAL REGISTRATION: NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

• MeSH
• arteria pulmonalis fyziologie   MeSH
• arteriální tlak fyziologie   MeSH
• atriální natriuretický faktor krev   MeSH
• cvičení fyziologie   MeSH
• echokardiografie metody   MeSH
• endotelin-1 krev   MeSH
• hemodynamika fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty krev   MeSH
• plicní hypertenze etiologie   metabolismus   patofyziologie   MeSH
• prospektivní studie MeSH
• průřezové studie MeSH
• senioři MeSH
• spotřeba kyslíku fyziologie   MeSH
• srdeční selhání komplikace   patofyziologie   MeSH
• studie případů a kontrol MeSH
• tepový objem fyziologie   MeSH
• tolerance zátěže fyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

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 31P 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.

• MeSH
• acidóza metabolismus   patofyziologie   MeSH
• bérec MeSH
• biologické markery krev   MeSH
• časové faktory MeSH
• deficit železa MeSH
• dospělí MeSH
• energetický metabolismus * účinky léků   MeSH
• intravenózní podání MeSH
• isometrická kontrakce * MeSH
• izotopy fosforu * MeSH
• kosterní svaly účinky léků   metabolismus   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• maltosa aplikace a dávkování   analogy a deriváty   MeSH
• prediktivní hodnota testů MeSH
• senioři MeSH
• srdeční selhání diagnóza   farmakoterapie   metabolismus   patofyziologie   MeSH
• studie případů a kontrol MeSH
• výsledek terapie MeSH
• zátěžový test * MeSH
• železité sloučeniny aplikace a dávkování   MeSH
• železo krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Aims: Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Little is known about the impact of PVD on the pathophysiology of exercise intolerance. Methods and results: Heart failure with preserved ejection fraction patients (n = 161) with elevated pulmonary capillary wedge pressure (≥15 mmHg) at rest were classified into three groups: non-PH-HFpEF (n = 21); PH but no PVD (isolated post-capillary PH, IpcPH; n = 95); and PH with PVD (combined post- and pre-capillary PH, CpcPH; n = 45). At rest, CpcPH-HFpEF patients had more right ventricular (RV) dysfunction and lower pulmonary arterial (PA) compliance compared to all other groups. While right atrial pressure (RAP) and left ventricular transmural pressure (LVTMP) were similar in HFpEF with and without PH or PVD at rest, CpcPH-HFpEF patients demonstrated greater increase in RAP, enhanced ventricular interdependence, and paradoxical reduction in LVTMP during exercise, differing from all other groups (P < 0.05). Lower PA compliance was correlated with greater increase in RAP with exercise. During exercise, CpcPH-HFpEF patients displayed an inability to enhance cardiac output, reduction in forward stroke volume, and blunted augmentation in RV systolic performance, changes that were coupled with marked limitation in aerobic capacity. Conclusion: Heart failure with preserved ejection fraction patients with PVD demonstrate unique haemodynamic limitations during exercise that constrain aerobic capacity, including impaired recruitment of LV preload due to excessive right heart congestion and blunted RV systolic reserve. Interventions targeted to this distinct pathophysiology require testing in patients with HFpEF and PVD.

• MeSH
• arteria pulmonalis * MeSH
• lidé MeSH
• nemoci cév etiologie   MeSH
• senioři MeSH
• srdeční selhání komplikace   patofyziologie   MeSH
• tepový objem * MeSH
• venae pulmonales * MeSH
• zátěžový test * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH