Goran Loncar

Metabolism and the heart: An overview of muscle, fat, and bone metabolism in heart failure

PURPOSE OF REVIEW To review original research studies and reviews that present data on changes of body compartments and its mutual cross-talk with respect to the failing heart predominantly in non-cachectic patients with chronic heart failure (HF). RECENT FINDINGS Thanks to the integrative approach considering the whole organism, several recent studies suggested a complex network of communication between body compartments in respect to failing heart during the natural course of body wasting in non-cachectic patients with HF. Interestingly, recent studies suggest that failing heart trough secretion of natriuretic peptides acts on fat metabolism by inducing adiponectin secretion and lipolytic actions. Soluble myostatin released from the failing heart may induce skeletal muscle wasting in HF through an endocrine-like mechanism, as well. The likelihood that adipocyte-derived hormones influence bone status has been recently proven. Increased serum adiponectin was independently associated with reduced bone mass in elderly patients with non-cachectic HF. SUMMARY The concept of body compartments cross-talk in respect to failing heart provides a very interesting paradigm of integrative physiology. Better understanding of body compartments changes and its complex biochemical interplay may provide more efficacious and forehand treatment to prevent and/or postpone disability and improve quality of life in patients with chronic HF.

Cardiac cachexia: hic et nunc

Cardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.

Relationship of reduced cerebral blood flow and heart failure severity in elderly males

Introduction. Brain detrimental effects are under-recognised complication of chronic heart failure (CHF). One of the major causes may be cerebral hypoperfusion. This study was designed to investigate the relationship between cerebral blood flow (CBF) and severity of CHF as well as to evaluate its determinants among different parameters of cardiac dysfunction. Methods. Seventy-one CHF males with NYHA class II and III and 20 control subjects age ≥ 55 years were recruited. CBF was evaluated by colour duplex sonography of extracranial arteries. Echocardiography, 6-min walk test, quality of life and endothelial function were also assessed. Serum NT-pro-BNP and adipokines levels (adiponectin and leptin) were measured. Results. CBF was significantly reduced in elderly patients with CHF compared to healthy controls (677 ± 170 vs 783 ± 128 ml/min, p = 0.011). Reduced CBF was associated with reduced left ventricular ejection fraction (LVEF) (r = 0.271, p = 0.022), lower 6-min walk distance (r = 0.339, p = 0.004), deteriorated quality of life (r = −0.327, p = 0.005), increased serum adiponectin (r = −0.359, p = 0.002), and NT-pro-BNP levels (r = −0.375, p = 0.001). In multivariate regression analysis, LVEF and adiponectin were independently associated with reduced CBF in CHF patients (R2 = 0.289). Conclusion. CBF was reduced in elderly males with mild-to-moderate CHF, and was associated with factors that represent the severity of CHF including high serum adiponectin and NT-pro-BNP levels, decreased LVEF, impaired physical performance, and deteriorated quality of life.

Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged >55 yr were recruited. PTH, 25-hydroxyvita-min D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77±33 vs 40±11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17±9 vs 10±2 µg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NT-pro-BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Association of adiponectin with peripheral muscle status in elderly patients with heart failure

BACKGROUND Reduced peripheral muscle mass was demonstrated in patients with chronic heart failure (HF). Adipokines may have potent metabolic effects on skeletal muscle. The associations between adipokines, peripheral muscle mass, and muscle function have been poorly investigated in patients with HF. METHODS We measured markers of fat and bone metabolism (adiponectin, leptin, 25-hydroxy vitamin D, parathyroid hormone, osteoprotegerin, RANKL), N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in 73 non-cachectic, non-diabetic, male patients with chronic HF (age: 68 ± 7 years, New York Heart Association class II/III: 76/26%, left ventricular ejection fraction 29 ± 8%) and 20 healthy controls of similar age. Lean mass as a measure of skeletal muscle mass was measured by dual energy X-ray absorptiometry (DEXA), while muscle strength was assessed by hand grip strength measured by Jamar dynamometer. RESULTS Serum levels of adiponectin, parathyroid hormone, osteoprotegerin, RANKL, and NT-pro-BNP were elevated in patients with chronic HF compared to healthy controls (all p<0.0001), while no difference in serum levels of leptin, testosterone or SHBG was noted. Levels of 25-hydroxy vitamin D were reduced (p=0.002) in HF group. Peripheral lean mass and hand grip strength were reduced in patients with HF compared to healthy subjects (p=0.006 and p<0.0001, respectively). Using backward selection multivariable regression, serum levels of increased adiponectin remained significantly associated with reduced arm lean mass and muscle strength. CONCLUSIONS Our findings may indicate a cross-sectional metabolic association of increased serum adiponectin with reduced peripheral muscle mass and muscle strength in non-cachectic, non-diabetic, elderly HF patients.

Relationship Between High Circulating Adiponectin With Bone Mineral Density and Bone Metabolism in Elderly Males With Chronic Heart Failure

BACKGROUND The aim of the study was to investigate the associations of adiponectin and leptin to bone mass and bone specific surrogates in elderly males with chronic heart failure (CHF). METHODS AND RESULTS Seventy-three males (mean age 68 +/- 7 years) with stable mild to moderate CHF and 20 healthy individuals age- and body mass index-matching underwent dual energy x-ray absorptiometry measurements (bone mineral density (BMD) at hip and lumbar spine, total bone mineral content, and body composition); echocardiography; 6-minute walk test; grip strength; and biochemical assessment including adiponectin, leptin, bone specific surrogates (osteocalcin, beta-CrossLaps, osteoprotegerin [OPG], receptor activator of nuclear factor kappaB ligand [RANKL]), parathyroid hormone, 25-hydroxy vitamin D, testosterone, sex hormone-binding globulin, and NT-pro-BNP. Serum adiponectin, osteocalcin, beta-CrossLaps, OPG, RANKL, and parathyroid hormone were significantly increased in CHF patients, whereas 25-hydroxy vitamin D was significantly lower compared to healthy controls. The significant positive association was found between adiponectin level with osteocalcin, beta-CrossLaps, OPG, and RANKL among CHF patients. In multivariate regression analysis, adiponectin was a significant determinant of total hip BMD, although the variance was small (r(2) = 0.239), whereas leptin was determinant for total bone mineral content (r(2) = 0.469) in patients with CHF. CONCLUSIONS Serum adiponectin is an independent predictor of BMD in elderly males with mild to moderate CHF, and showed a positive correlation to bone specific surrogates. Adiponectin, as cardioprotective hormone, seems to be able to exert a negative effect on bone mass in chronic heart failure. Further research is needed to confirm the potential for adipokines in the crosstalk between bone and energy metabolism in CHF patients.

Heart rate following short‐term beta‐blocker titration predicts all‐cause mortality in elderly chronic heart failure patients: insights from the CIBIS‐ELD trial

Beta‐blockers (BBs) improve outcomes in heart failure. Results from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS‐ELD) trial previously demonstrated the feasibility of heart rate, not maximum dose, as a treatment goal. In this pre‐specified analysis, we investigated the prognostic value of achieved heart rate after BB optimization on long‐term mortality.

Emerging Biomarkers in Heart Failure and Cardiac Cachexia

Biomarkers are objective tools with an important role for diagnosis, prognosis and therapy optimization in patients with heart failure (HF). To date, natriuretic peptides are closest to optimal biomarker standards for clinical implications in HF. Therefore, the efforts to identify and test new biomarkers in HF are reasonable and justified. Along the natural history of HF, cardiac cachexia may develop, and once at this stage, patient performance and prognosis is particularly poor. For these reasons, numerous biomarkers reflecting hormonal, inflammatory and oxidative stress pathways have been investigated, but only a few convey relevant information. The complex pathophysiology of HF appears far too complex to be embraced by a single biomarker; thus, a combined approach appears reasonable. With these considerations, we have reviewed the recent developments in the field to highlight key candidates with diagnostic, prognostic and therapy optimization properties, either alone or in combination.

Effect of beta blockade on natriuretic peptides and copeptin in elderly patients with heart failure and preserved or reduced ejection fraction: Results from the CIBIS-ELD trial☆ , ☆☆

BACKGROUND We sought to investigate the effect of beta-blocker (BB) up-titration on serum levels of NT-proBNP and copeptin in patients with heart failure (HF) with reduced (HFREF) or preserved ejection fraction (HFPEF). METHODS Serial measurements of NT-proBNP and copeptin were obtained after initiation of BB up-titration in 219 elderly patients with HFREF or HFPEF. RESULTS After initial increasing trend of NT-proBNP at 6 weeks in HFREF patients, there was a subsequent decrease at 12 weeks of BB treatment up-titration (p=0.003), while no difference was found compared to baseline levels. In contrast to NT-proBNP, there was a continuous decreasing trend of copeptin in HFREF patients (at 12 weeks: p=0.026). In HFPEF patients, NT-proBNP significantly decreased (p=0.043) compared to copeptin after 12 weeks of BB up-titration. CONCLUSIONS After 12 weeks of BB optimization copeptin might reflect successful up-titration faster than NT-proBNP in HFREF, while the opposite was found in patients with HFPEF.

Should procalcitonin be measured routinely in acute decompensated heart failure

AIM To elucidate the prognostic role of procalcitonin (PCT) in patients with acute decompensated heart failure (ADHF) without clinical signs of infection at admission. MATERIALS & METHODS Serial measurements of PCT and NT-proBNP were performed in 168 patients, aged 68 ± 10 years with ADHF followed by 3-month outcome evaluation. RESULTS Cox regression analysis demonstrated significant predictive value of baseline PCT for all-cause death/hospitalization (area under the curve: 0.67; p = 0.013) at 90th day. The patients with persistently elevated PCT or with an increase during the first 72 h of hospitalization had the worst prognosis (p = 0.0002). CONCLUSION Baseline and serial in-hospital measurements of PCT have significant prognostic properties for 3-month all-cause mortality/hospitalization in patients with ADHF without clinical signs of infection at admission.