BACKGROUND: Right ventricular dysfunction (RVD) is common in patients with heart failure with reduced ejection fraction, and it is associated with poor prognosis. However, no biomarker reflecting RVD is available for routine clinical use. METHODS: Proteomic analysis of myocardium from the left ventricle and right ventricle (RV) of patients with heart failure with reduced ejection fraction with (n=10) and without RVD (n=10) who underwent heart transplantation was performed. Concentrations of 2 ECM (extracellular matrix) proteins with the highest myocardial upregulation in RVD, FMOD (fibromodulin) and FBLN5 (fibulin-5), were assayed in the blood and tested in a separate cohort of patients with heart failure with reduced ejection fraction (n=232) to test for the association of the 2 proteins with RV function and long-term outcomes. RESULTS: Multivariable linear regression revealed that plasma concentrations of both FMOD and FBLN5 were significantly associated with RV function regardless of the RV function assessment method. No association of FMOD or FBLN5 with left ventricular dysfunction, cardiac index, body mass index, diabetes status, or kidney function was found. Plasma levels of FMOD and FBLN5 were significantly associated with patient outcomes (P=0.005; P=0.004). Area under the curve analysis showed that the addition of FBLN5 or FMOD to RV function assessment had a significantly higher area under the curve after 4 years of follow-up (0.653 and 0.631, respectively) compared with RV function alone (0.570; P<0.05 for both). Similarly, the combination of MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score, FBLN5, and FMOD had a significantly larger area under the curve (0.669) than the combination of MAGGIC score+RVD grade (0.572; P=0.02). The Kaplan-Meier analysis demonstrated that patients with the elevation of both FMOD and FBLN5 (ie, FMOD >64 ng/mL and FMOD >27 ng/mL) had a worse prognosis than those with the elevation of either FBLN5 or FMOD (P=0.03) demonstrating the additive prognostic value of both proteins. CONCLUSIONS: Our study proposes that circulating levels of FMOD and FBLN5 may serve as new biomarkers of RVD in patients with heart failure with reduced ejection fraction.

• Klíčová slova
• biomarkers, extracellular matrix, fibromodulin, fibrosis, heart failure,
• MeSH
• biologické markery krev   metabolismus   MeSH
• dysfunkce pravé srdeční komory * patofyziologie   krev   diagnóza   metabolismus   MeSH
• extracelulární matrix - proteiny * krev   MeSH
• fibromodulin * krev   MeSH
• funkce pravé komory srdeční * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• prognóza MeSH
• proteiny vázající vápník * krev   MeSH
• proteomika * metody   MeSH
• senioři MeSH
• srdeční komory metabolismus   patofyziologie   MeSH
• srdeční selhání * patofyziologie   krev   metabolismus   diagnóza   chirurgie   MeSH
• tepový objem MeSH
• transplantace srdce MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• extracelulární matrix - proteiny * MeSH
• fibromodulin * MeSH
• proteiny vázající vápník * 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.

• Klíčová slova
• Drug, Heart failure, Pulmonary hypertension, Therapy, Translational,
• 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

BACKGROUND: Right ventricular (RV) function is currently being evaluated solely according to the properties of RV myocardium. We have tested a concept that in patients with heart failure with reduced ejection fraction (HFrEF), RV assessment should integrate the information about both RV function as well as size. METHODS: A total of 836 stable patients with HFrEF (LVEF 23.6 ± 5.8%, 82.8% males, 68% NYHA III/IV) underwent echocardiographic evaluation and were prospectively followed for a median of 3.07 (IQRs 1.11; 4.89) years for the occurrence of death, urgent heart transplantation or implantation of mechanical circulatory support. RESULTS: RV size (measured as RV-basal diameter, RVD1) was significantly associated with an adverse outcome independent of RV dysfunction grade (p = 0.0002). The prognostic power of RVD1 was further improved by indexing to body surface area (RVD1i, p < 0.05 compared to non-indexed value). A novel parameter named RV global dysfunction score (RVGDs) was calculated as a product of RVD1i and the degree of RV dysfunction (1-4 for preserved RV function, mild, moderate and severe dysfunction, respectively). RVGDs showed a superior prognostic role compared to RV dysfunction grade alone (ΔAUC >0.03, p < 0.0001). In every subgroup of RVGDs (<20, 20-40, 40-60, >60), patients with milder degree of RV dysfunction but more dilated RV had similar outcome as those with more severe degree of RV dysfunction but smaller RV size (all p > 0.50), independent of tricuspid regurgitation severity and degree of pulmonary hypertension. CONCLUSION: RV dilatation is a manifestation of RV dysfunction. The evaluation of RV performance should integrate the information about both RV size and function.

• Klíčová slova
• heart failure, outcome, right ventricular dysfunction, right ventricular function assessment, right ventricular size,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• Biomarker, Exercise, Heart failure, Pulmonary circulation,
• 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
• Názvy látek
• atriální natriuretický faktor MeSH
• C-terminal proendothelin-1 MeSH Prohlížeč
• endotelin-1 MeSH
• midregional pro-atrial natriuretic peptide, human MeSH Prohlížeč
• peptidové fragmenty MeSH

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.

• Klíčová slova
• Atrial fibrillation, HFpEF, Heart failure, Pulmonary hypertension, Right ventricle, Tricuspid regurgitation,
• MeSH
• dysfunkce pravé srdeční komory * MeSH
• echokardiografie MeSH
• fibrilace síní komplikace   MeSH
• hemodynamika MeSH
• hospitalizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční komory diagnostické zobrazování   patologie   MeSH
• srdeční selhání komplikace   mortalita   patologie   patofyziologie   MeSH
• tepový objem * MeSH
• trikuspidální insuficience etiologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let 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

BACKGROUND: The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. METHODS AND RESULTS: In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic β-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome (P=0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L-1, 68-101 mg·dL-1) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L-1, 108-142 mg·dL-1; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P=0.002). CONCLUSIONS: Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.

• Klíčová slova
• cachexia, glucagon/glucagon‐like peptide, glucose, heart failure, insulin, metabolism, obesity paradox, right ventricular dysfunction, starvation,
• MeSH
• biologické markery krev   MeSH
• časové faktory MeSH
• dysfunkce pravé srdeční komory krev   diagnóza   patofyziologie   MeSH
• funkce pravé komory srdeční MeSH
• glukagon krev   MeSH
• glukózový toleranční test MeSH
• homeostáza MeSH
• inzulin krev   MeSH
• kachexie krev   diagnóza   patofyziologie   MeSH
• Kaplanův-Meierův odhad MeSH
• krevní glukóza metabolismus   MeSH
• Langerhansovy ostrůvky metabolismus   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prognóza MeSH
• rizikové faktory MeSH
• senioři MeSH
• srdeční selhání krev   diagnóza   patofyziologie   MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• glukagon MeSH
• inzulin MeSH
• krevní glukóza MeSH

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects. METHODS: Subjects with obese HFpEF (body mass index ≥35 kg/m2; n=99), nonobese HFpEF (body mass index <30 kg/m2; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing. RESULTS: Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563-4333 mL] versus 2772 mL [2555-3133 mL], and 2680 mL [2380-3006 mL]; P<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm, P=0.0005; length, 66±7 versus 61±7 and 61±7 mm, P<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm; P<0.0001), and greater total epicardial heart volume (945 mL [831-1105 mL] versus 797 mL [643-979 mL] and 632 mL [517-768 mL]; P<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both P<0.05) but not in nonobese HFpEF (P≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20; P=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12; P<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (P for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg; P<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve. CONCLUSIONS: Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.

• Klíčová slova
• exercise, heart failure, hypertension, pulmonary, obesity, pericardium,
• MeSH
• fenotyp * MeSH
• hemodynamika fyziologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita diagnóza   epidemiologie   patofyziologie   MeSH
• remodelace komor fyziologie   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční selhání diagnóza   epidemiologie   patofyziologie   MeSH
• tepový objem fyziologie   MeSH
• zátěžový test metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH