Osteoanabolic therapy for osteoporosis in women.

Therapy to activate bone formation is required to reverse and restore the damaged bone architecture found in women with postmenopausal osteoporosis. The osteoanabolic drugs include teriparatide, which has been available for several years, and abaloparatide and romosozumab, novel osteoanabolic drugs that have become available more recently. By stimulating bone formation, these drugs produce greater increases in bone mass and bone strength, and they do so more quickly compared to the commonly used anti-remodeling (also called antiresorptive) drugs such as bisphosphonates. In head-to-head trials, teriparatide and romosozumab reduce fracture risk more effectively than do oral bisphosphonates in women with osteoporosis and high fracture risk. Osteoanabolic drugs have little role in the prevention of bone loss during early menopause, but they have an important place in the treatment of women at very high risk of fracture or who remain at high fracture risk after a course of bisphosphonate therapy. Primarily because of the high cost of the drugs, these therapies are initiated by specialists rather than primary-care physicians in most countries. This review will present the evidence for efficacy and safety of these drugs so that clinicians may discern their appropriate use when caring for postmenopausal women with osteoporosis.

Integrin α1ß1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling.

OBJECTIVE: To investigate the role of integrin α1ß1 in the progression of post-traumatic osteoarthritis (PTOA), and elucidate the contribution of epidermal growth factor receptor (EGFR) signalling to the mechanism by which integrin α1ß1 might control PTOA. We hypothesised that integrin α1ß1 plays a protective role in the course of PTOA and that the effect of PTOA (e.g., synovitis, loss of cartilage and growth of osteophytes) would be exacerbated in mice lacking integrin α1ß1 at every time point post destabilisation of medial meniscus (DMM). METHODS: DMM or sham surgery was performed on integrin α1-null and wild type (WT) mice and the progression of PTOA analysed at 2, 4, 8 and 12 weeks post-surgery (PS) using micro-computed tomography (microCT), histology, and immunohistochemistry. In addition, the effects of EGFR blockade were examined by treating the mice with the EGFR inhibitor erlotinib. RESULTS: Integrin α1-null female, but not male, mice showed earlier cartilage degradation post DMM surgery compared to WT controls. Furthermore, erlotinib treatment resulted in significantly less cartilage damage in integrin α1-null but not WT mice. Independent of genotype, erlotinib treatment significantly mitigated the effects of PTOA on many tissues of female mice including meniscal and fabella bone volume, subchondral bone thickness and density and cartilage degradation. In contrast, reduced EGFR signalling had little effect on signs of PTOA in male mice. CONCLUSION: Integrin α1ß1 protects against PTOA-induced cartilage degradation in female mice partially via the reduction of EGFR signalling. Furthermore, reduction of EGFR signalling protects against the development of PTOA in female, but not male mice.

Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven. OBJECTIVES: To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). SEARCH STRATEGY: We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. SELECTION CRITERIA: We selected trials including pregnant women between 24 and 36(6/7)  weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. DATA COLLECTION AND ANALYSIS: The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. MAIN RESULTS: Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01). CONCLUSION: Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. TWEETABLE ABSTRACT: Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.

Telemonitoring in heart failure: Big Brother watching over you.

Heart failure (HF) is a leading cause of hospitalisations in older people. Several strategies, supported by novel technologies, are now available to monitor patients' health from a distance. Although studies have suggested that remote monitoring may reduce HF hospitalisations and mortality, the study of different patient populations, the use of different monitoring technologies and the use of different endpoints limit the generalisability of the results of the clinical trials reported, so far. In this review, we discuss the existing home monitoring modalities, relevant trials and focus on future directions for telemonitoring.

Integrin α1ß1 differentially regulates cytokine-mediated responses in chondrocytes.

OBJECTIVE: To elucidate the role of integrin α1ß1 in chondrocyte responses to inflammatory interleukin-1α (IL-1) and anabolic transforming growth factor-ß1 (TGF-ß1) in the knee. METHODS: Intracellular calcium transient responses to IL-1 and TGF-ß1 were measured in wild type and integrin α1-null chondrocytes using real time ex vivo confocal microscopy, and immunohistochemistry was performed to analyze TGF-ß1-mediated activation of Smad2/3 in tibial and femoral chondrocytes. RESULTS: Loss of integrin α1ß1 reduces intracellular calcium transient response to IL-1, while it enhances chondrocyte responses to TGF-ß1 as measured by intracellular calcium transients and activation of downstream Smad2/3. CONCLUSIONS: Integrin α1ß1 plays a vital role in mediating chondrocyte responses to two contrasting factors that are critical players in the onset and progression of osteoarthritis - inflammatory IL-1 and anabolic TGF-ß. Further investigation into the molecular mechanisms by which integrin α1ß1 mediates these responses will be an important next step in understanding the influence of increased expression of integrin α1ß1 during the early stages of osteoarthritis on disease progression.

Are non-invasive estimations of plasma volume an accurate measure of congestion in patients with chronic heart failure?

AIMS: We report associations between different formulae for estimating plasma volume status (PVS) and clinical and ultrasound markers of congestion in patients with chronic heart failure (CHF) enrolled in the Hull Lifelab registry. METHODS AND RESULTS: Cohort 1 comprised patients with data on signs and symptoms at initial evaluation (n = 3505). Cohort 2 included patients with ultrasound assessment of congestion [lung B-line count, inferior vena cava (IVC) diameter, jugular vein distensibility (JVD) ratio] (N = 341). Two formulae for PVS were used: (a) Hakim (HPVS) and (b) Duarte (DPVS). Results were compared with clinical and ultrasound markers of congestion. Outcomes assessed were mortality and the composite of heart failure (HF) hospitalisation and all-cause mortality. In cohort 1, HPVS was associated with mortality [hazard ratio (HR) per unitary increase = 1.02 (1.01-1.03); P < 0.001]. In cohort 2, HPVS was associated with B-line count (HR) = 1.05 [95% confidence interval (CI) (1.01-1.08); P = 0.02] and DPVS with the composite outcome [HR = 1.26 (1.01-1.58); P = 0.04]. HPVS and DPVS were strongly related to haemoglobin concentration and HPVS to weight. After multivariable analysis, there were no strong or consistent associations between PVS and measures of congestion, severity of symptoms, or outcome. By contrast, log[NTproBNP] was strongly associated with all three. CONCLUSION: Amongst patients with CHF, HPVS and DPVS are not strongly or consistently associated with clinical or ultrasound evidence of congestion, nor clinical outcomes after multivariable adjustment. They appear only to be surrogates of the variables from which they are calculated with no intrinsic clinical utility.

Chondrocyte primary cilia shorten in response to osmotic challenge and are sites for endocytosis.

OBJECTIVE: The purpose of this study was to examine the influence of cartilage site and osmolarity on primary cilia incidence, length and orientation in live chondrocytes in undisturbed cartilage. Additionally, we imaged endocytotic markers to test our hypothesis that the ciliary pocket is a site for endocytosis. MATERIALS AND METHODS: We measured primary cilia incidence, length and orientation in the coronal plane using ex vivo live cell confocal imaging of intact murine femoral chondrocytes. Measurements were taken from five regions of the medial and lateral condyles of the left and right femur and also after one minute of osmotic challenge. Transmission electron microscopy and immunocytochemistry were used to characterize the orientation and position of chondrocyte primary cilia in the saggital plane and to determine the colocalization of clathrin coated vesicles, endosomal and lysosomal proteins and CD44 with the ciliary pocket. RESULTS: Chondrocyte primary cilia length decreased significantly after a one minute hypo- or hyper-osmotic challenge and varied between condyles and across the surface of each condyle. The majority of the length of the chondrocyte primary cilia was positioned within a membranous invagination rather than projecting out from the cell membrane and clathrin coated vesicles, endosomal proteins and CD44 colocalised with the ciliary pocket. CONCLUSIONS: We demonstrate that live ex vivo chondrocyte primary cilia are capable of shortening within minutes in response to osmotic challenge and provide subcellular and cellular evidence that chondrocyte primary cilia are deeply invaginated in a ciliary pocket which contains sites for endocytosis.

Re-defining iron deficiency in patients with heart failure.

INTRODUCTION: Iron deficiency (ID) is common in patients with chronic heart failure (CHF) and is associated with worse symptoms and prognosis regardless of whether anemia is also present. However, randomized controlled trials (RCT) of intravenous (IV) iron in patients with CHF have produced inconsistent results. This review considers the past, present, and future of defining and treating ID in patients with CHF. AREAS COVERED: The current guideline definition of ID is a serum ferritin <100 µg/L or serum ferritin 100-299 µg/L and transferrin saturation (TSAT) <20% derived from trials of IV iron in patients with end-stage renal failure. Ferritin synthesis and secretion is promoted by inflammatory cytokines which are raised in patients with CHF; thus, using ferritin to define iron deficiency in patients with CHF may be flawed. Observational data suggest that the current definition of iron deficiency in CHF does not identify a high-risk population. EXPERT OPINION: Alternative indicators of ID such as low serum iron concentrations or TSAT may better identify patients with ID who are at greater risk of adverse outcome and thus, possibly, more likely to benefit from IV iron.

Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF.

AIMS: Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK. METHODS AND RESULTS: Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan-Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272-1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15-1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04-1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14-1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion. CONCLUSION: Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.

Effect of frailty on treatment, hospitalisation and death in patients with chronic heart failure.

BACKGROUND: Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. METHODS: Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. RESULTS: 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin-angiotensin-aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. CONCLUSION: Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV.

Routine exercise-based cardiac rehabilitation does not increase aerobic fitness: A CARE CR study.

BACKGROUND: Recent evidence suggests that routine exercise-based cardiac rehabilitation (CR) may not lead to a substantial increase in estimated peak oxygen uptake (V̇O2peak). This could reduce the potential benefits of CR and explain why CR no longer improves patient survival in recent studies. We aimed to determine whether routine exercise-based CR increases V̇O2peak using gold-standard maximal cardiopulmonary exercise testing (CPET), and to quantify the exercise training stimulus which might be insufficient in patients undertaking CR. METHODS: We studied the effects of a routine, twice weekly, exercise-based CR programme for eight weeks (intervention group) compared with abstention from supervised exercise training (control group) in patients with coronary heart disease. The primary outcome was V̇O2peak measured using CPET. We also measured changes in body composition using dual X-ray absorptiometry, carotid intima-media thickness, hs-CRP and N-terminal pro B-type natriuretic peptide at baseline, 10 weeks and 12 months. We also calculated the Calibre 5-year all-cause mortality risk score. RESULTS: Seventy patients (age 63.1 SD10.0 years; BMI 29.2 SD4.0 kg·m-2; 86% male) were recruited (n = 48 intervention; n = 22 controls). The mean aerobic exercise training duration was 23 min per training session, and the mean exercise training intensity was 45.9% of heart rate reserve. V̇O2peak was 23·3 ml·kg-1·min-1 at baseline, and there were no changes in V̇O2peak between groups at any time point. The intervention had no effect on any of the secondary endpoints. CONCLUSION: Routine CR does not lead to an increase in V̇O2peak and is unlikely to improve long-term physiological outcomes.

Telemonitoring in subjects with newly diagnosed heart failure with reduced ejection fraction: From clinical research to everyday practice.

INTRODUCTION: Heart failure is increasingly common, and characterised by frequent admissions to hospital. To try and reduce the risk of hospitalisation, techniques such as telemonitoring (TM) may have a role. We wanted to determine if TM in patients with newly diagnosed heart failure and ejection fraction <40% reduces the risk of readmission or death from any cause in a 'real-world' setting. METHODS: This is a retrospective study of 124 patients (78.2% male; 68.6 ± 12.6 years) who underwent TM and 345 patients (68.5% male; 70.2 ± 10.7 years) who underwent the usual care (UC). The TM group were assessed daily by body weight, blood pressure and heart rate using electronic devices with automatic transfer of data to an online database. Follow-up was 12 months. RESULTS: Death from any cause occurred in 8.1% of the TM group and 19% of the UC group ( p = 0.002). There was no difference between the two groups in all-cause hospitalisation, either in the number of subjects hospitalised ( p = 0.7) or in the number of admissions per patient ( p = 0.6). There was no difference in the number of heart-failure-related readmissions per person between the two groups ( p = 0.5), but the number of days in hospital per person was higher in the UC group ( p = 0.03). Also, there were a significantly greater number of days alive and out of hospital for the patients in the TM group compared with the UC group ( p = 0.0001). DISCUSSION: TM is associated with lower any-cause mortality and also has the potential to reduce the number of days lost to hospitalisation and death.

Mode of presentation and mortality amongst patients hospitalized with heart failure? A report from the First Euro Heart Failure Survey.

BACKGROUND: Heart failure is heterogeneous in aetiology, pathophysiology, and presentation. Despite this diversity, clinical trials of patients hospitalized for HF deal with this problem as a single entity, which may be one reason for repeated failures. METHODS: The first EuroHeart Failure Survey screened consecutive deaths and discharges of patients with suspected heart failure during 2000-2001. Patients were sorted into seven mutually exclusive hierarchical presentations: (1) with cardiac arrest/ventricular arrhythmia; (2) with acute coronary syndrome; (3) with rapid atrial fibrillation; (4) with acute breathlessness; (5) with other symptoms/signs such as peripheral oedema; (6) with stable symptoms; and (7) others in whom the contribution of HF to admission was not clear. RESULTS: The 10,701 patients enrolled were classified into the above seven presentations as follows: 260 (2%), 560 (5%), 799 (8%), 2479 (24%), 1040 (10%), 703 (7%), and 4691 (45%) for which index-admission mortality was 26%, 20%, 10%, 8%, 6%, 6%, and 4%, respectively. Compared to those in group 7, the hazard ratios for death during the index admission were 4.9 (p ≤ 0.001), 4.0 (p < 0.001), 2.2 (p < 0.001), 2.1 (p < 0.001), 1.4 (p < 0.04) and 1.4 (p = 0.04), respectively. These differences were no longer statistically significant by 12 weeks. CONCLUSION: There is great diversity in the presentation of heart failure that is associated with very different short-term outcomes. Only a minority of hospitalizations associated with suspected heart failure are associated with acute breathlessness. This should be taken into account in the design of future clinical trials.

Added value of frailty and social support in predicting risk of 30-day unplanned re-admission or death for patients with heart failure: An analysis from OPERA-HF.

BACKGROUND: Models for predicting the outcome of patients hospitalized for heart failure (HF) rarely take a holistic view. We assessed the ability of measures of frailty and social support in addition to demographic, clinical, imaging and laboratory variables to predict short-term outcome for patients discharged after a hospitalization for HF. METHODS: OPERA-HF is a prospective observational cohort, enrolling patients hospitalized for HF in a single center in Hull, UK. Variables were combined in a logistic regression model after multiple imputation of missing data to predict the composite outcome of death or readmission at 30 days. Comparisons were made to a model using clinical variables alone. The discriminative performance of each model was internally validated with bootstrap re-sampling. RESULTS: 1094 patients were included (mean age 77 [interquartile range 68-83] years; 40% women; 56% with moderate to severe left ventricular systolic dysfunction) of whom 213 (19%) had an unplanned re-admission and 60 (5%) died within 30 days. For the composite outcome, a model containing clinical variables alone had an area under the receiver-operating characteristic curve (AUC) of 0.68 [95% CI 0.64-0.72]. Adding marital status, support from family and measures of physical frailty increased the AUC (p < 0.05) to 0.70 [95% CI 0.66-0.74]. CONCLUSIONS: Measures of physical frailty and social support improve prediction of 30-day outcome after an admission for HF but predicting near-term events remains imperfect. Further external validation and improvement of the model is required.

Estimated peak functional capacity: an accurate method for assessing change in peak oxygen consumption after cardiac rehabilitation?

OBJECTIVE: Cardiopulmonary exercise testing (CPET) is the 'gold standard' method of determining VO2peak . When CPET is unavailable, VO2peak may be estimated from treadmill or cycle ergometer workloads and expressed as estimated metabolic equivalents (METs). Cardiac rehabilitation (CR) programmes use estimated VO2peak (METs) to report changes in cardiorespiratory fitness (CRF). However, the accuracy of determining changes in VO2peak based on estimated functional capacity is not known. METHODS: A total of 27 patients with coronary heart disease (88·9% male; age 59·5 ± 10·0 years, body mass index 29·6 ± 3·8 kg m-2 ) performed maximal CPET before and after an exercise-based CR intervention. VO2peak was directly determined using ventilatory gas exchange data and was also estimated using the American College of Sports Medicine (ACSM) leg cycling equation. Agreement between changes in directly determined VO2peak and estimated VO2peak was evaluated using Bland-Altman limits of agreement (LoA) and intraclass correlation coefficients. RESULTS: Directly determined VO2peak did not increase following CR (0·5 ml kg-1 min-1 (2·7%); P = 0·332). Estimated VO2peak increased significantly (0·4 METs; 1·4 ml kg-1  min-1 ; 6·7%; P = 0·006). The mean bias for estimated VO2peak versus directly determined VO2peak was 0·7 ml kg-1  min-1 (LoA -4·7 to 5·9 ml  kg-1  min-1 ). Aerobic efficiency (ΔVO2 /ΔWR slope) was significantly associated with estimated VO2peak measurement error. CONCLUSION: Change in estimated VO2peak derived from the ACSM leg cycling equation is not an accurate surrogate for directly determined changes in VO2peak . Our findings show poor agreement between estimates of VO2peak and directly determined VO2peak . Applying estimates of VO2peak to determine CRF change may over-estimate the efficacy of CR and lead to a different interpretation of study findings.

Dynamic risk stratification using serial measurements of plasma concentrations of natriuretic peptides in patients with heart failure.

BACKGROUND: Prognostic models for patients with chronic heart failure are generally based on a single assessment but treatment is often given with the intention of changing risk; re- evaluation of risk is an important aspect of care. The prognostic value of serial measurements of natriuretic peptides for the assessment of changes in risk is uncertain. AIMS: To evaluate the prognostic value of serial measurements of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) during follow-up of out-patients with chronic heart failure (CHF). METHODS: Patients diagnosed with CHF between 2001 and 2014 at a single out-patient clinic serving a local community were included in this analysis. NT-proBNP was measured at the initial visit and serially during follow-up. Only patients who had one or more measurements of NT-proBNP after baseline, at 4, 12 and/or 24 months were included. RESULTS: At baseline, amongst 1998 patients enrolled, the median age was 73 (IQR: 64-79) years, 70% were men, 31% were in NYHA class III/IV, and 77% had NT-proBNP >400 pg/mL. Median follow-up was 4.8 (IQR: 2.5-8.6) years. Serial measurements of NT-proBNP improved prediction of all-cause mortality at 3 years (c- statistic = 0.71) compared with using baseline data only (c-statistic = 0.67; p < 0.001) but a model using only the most recent NT-proBNP had an even higher c-statistic (0.72; p < 0.001). Similar results were obtained based on long-term prediction of mortality using all available follow-up data. CONCLUSIONS: Serial measurement of NT-proBNP in patients with CHF improves prediction of all-cause mortality. However, using the most recent value of NT-proBNP has similar predictive power as using serial measurements.

Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency.

Objective Epidemiological studies suggest that adult-onset growth hormone deficiency (AGHD) might increase the risk of death from cardiovascular causes. Methods This was a 6-month double-blind, placebo-controlled, randomised, cross-over trial followed by a 6-month open-label phase. Seventeen patients with AGHD received either recombinant human growth hormone (rGH) (0.4 mg injection daily) or placebo for 12 weeks, underwent washout for 2 weeks, and were then crossed over to the alternative treatment for a further 12 weeks. Cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary exercise testing were performed at baseline, 12 weeks, 26 weeks, and the end of the open phase (12 months). The results were compared with those of 16 age- and sex-matched control subjects. Results At baseline, patients with AGHD had a significantly higher systolic blood pressure, ejection fraction, and left ventricular mass than the control group, even when corrected for body surface area. Treatment with rGH normalised the insulin-like growth factor 1 concentration without an effect on exercise capacity, cardiac structure, or cardiac function. Conclusion Administration of rGH therapy for 6 to 9 months failed to normalise the functional and structural cardiac differences observed in patients with AGHD when compared with a control group.

Prognostic value of simple frailty and malnutrition screening tools in patients with acute heart failure due to left ventricular systolic dysfunction.

BACKGROUND: Frailty and malnutrition are common in patients with heart failure (HF), and are associated with adverse outcomes. We studied the prognostic value of three malnutrition and three frailty indices in patients admitted acutely to hospital with HF. METHODS: 265 consecutive patients [62% males, median age 80 (interquartile range (IQR): 72-86) years, median NTproBNP 3633 (IQR: 2025-6407) ng/l] admitted with HF between 2013 and 2014 were enrolled. Patients were screened for frailty using the Derby frailty index (DFI), acute frailty network (AFN) frailty criteria, and clinical frailty scale (CFS) and for malnutrition using the geriatric nutritional risk index (GNRI), controlling nutritional status (CONUT) score and prognostic nutritional index (PNI). RESULTS: According to the CFS (> 4), DFI, and AFN, 53, 50, and 53% were frail, respectively. According to the GNRI (≤ 98), CONUT score (> 4), and PNI (≤ 38), 46, 46, and 42% patients were malnourished, respectively. During a median follow-up of 598 days (IQR 319-807 days), 113 patients died. One year mortality was 1% for those who were neither frail nor malnourished; 15% for those who were either malnourished or frail; and 65% for those who were both malnourished and frail. Amongst the malnutrition scores, PNI, and amongst the frailty scores, CFS increased model performance most compared with base model. A final model, including CFS and PNI, increased c-statistic for mortality prediction from 0.68 to 0.84. CONCLUSION: Worsening frailty and malnutrition indices are strongly related to worse outcome in patients hospitalised with HF.

Predicting peak oxygen uptake from 6-min walk test performance in male patients with left ventricular systolic dysfunction.

BACKGROUND: In patients with left ventricular systolic dysfunction (LVSD), peak oxygen uptake (pVO2) has strong predictive power for mortality, and can be used to guide management. However, many patients cannot tolerate standard test protocols. The 6-min walk test (6-MWT) is often used to estimate functional capacity due to its simplicity, cost effectiveness and familiarity to patients with LVSD. The relationship between 6-MWT performance and pVO2 is not certain, but if closely related could allow substitution of an expensive and cumbersome test for a cheaper and more familiar one. METHODS AND RESULTS: 120 male patients with LVSD (LVEF <40%; (mean+/-S.D.) age 68+/-13 years; BMI 28+/-5) performed, in random order, a maximal incremental treadmill exercise test with metabolic gas exchange measurements to derive peak oxygen consumption (pVO2 = 19.8+/-5.8 mL.kg(-1).min(-1)), and a standardised 6-MWT (308+/-142 m; r = 0.44; P = 0.00001). In multivariate models including demographic data, resting blood pressure and heart rate, spirometry, routine blood samples, and walk distance, five variables were independently predictive of peak oxygen consumption. pVO2 = 11.92 + (1.48 x FEV1 (L)) + (1.12 x haemoglobin (g dl(-1))) + (0.016 x distance walked (m)) - (0.33 x BMI) - (0.11 x age (years)). This equation accounted for 48% of the variation in pVO2. CONCLUSIONS: Using these five simple variables, peak oxygen consumption can be estimated with moderate accuracy. In clinical practice, however, when an estimate of peak oxygen consumption is required, incremental exercise testing with metabolic gas exchange measurements cannot be avoided in male patients with LVSD. Further work is needed to assess the relation between estimated pVO2 and outcome.

Clinical determinants of poor six-minute walk test performance in patients with left ventricular systolic dysfunction and no major structural heart disease.

BACKGROUND: The clinical determinants of six-minute walk test (6-MWT) performance in patients with left ventricular systolic dysfunction (LVSD) have rarely been investigated, and it is not clear whether they differ from patients referred for the assessment of symptoms of heart failure who do not have major structural heart disease (MSHD). METHODS AND RESULTS: 571 patients with LVSD enrolled in a chronic disease management programme (79% male; mean age 71+/-10 years; BMI 28+/-5) completed a 6-MWT with a mean distance 337+/-103 m. 688 patients referred with suspected heart failure but in whom MSHD was excluded (49% male; mean age 70+/-11 years; BMI 28+/-6) had a mean 6-MWT distance of 391+/-106 m (P<0.001 compared to patients with LVSD). Relationships with walking distance were determined by calculating odds ratios (ORs) with 95% confidence intervals (CIs) for walking300 m. In patients with LVSD, predictors of poor walking distance (or=75 years (OR=4.0, 95% CI=2.4-6.4); low BMI (<20) (OR=3.4, 95% CI=1.6-7.3); anaemia (OR=2.8, 95% CI=1.8-4.2); resting heart rate>80 beats x min(-1) (OR=2.2, 95% CI=1.3-3.5); and being female (OR=2.0, 95% CI=1.3-3.0). Serum creatinine and NT-proBNP showed dose-response effects, as did self-perceived feelings of depression and anxiety. Determinants of 6-MWT in patients without MSHD were similar including age>or=75 years (OR=6.0, 95% CI=3.4-10.4), anaemia (OR=2.8, 95% CI=1.6-4.9), resting HR>80 beats x min(-1) (OR=2.5, 95% CI=1.4-4.4) and being female (OR=1.6, 95% CI=1.9-2.4). NT-proBNP and self-perceived feelings of depression and anxiety also showed dose-response effects. CONCLUSION: The determinants of poor 6-MWT performance depend on physical-cardiovascular and non-cardiovascular, and psychological factors. Clinical predictors for poor walking performance are similar for patients with LVSD and without MSHD.