Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations.

Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients' death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration. To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1A4V or hSOD1G85R). We demonstrate that pan-neuronal expression of the hSOD1A4V or hSOD1G85R pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected. The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.

Could the Combination of eGFR and mGPS Facilitate the Differential Diagnosis of Age-Related Renal Decline from Diseases? A Large Study on the Population of Western Sicily.

The assessment of renal function is critical to diagnosing and managing renal age-related decline, disease (KD), and failure, which are prevalent in the elderly population. The glomerular filtration rate (GFR) is widely used as an indicator of kidney function, but its direct measurement is challenging, as are its age and gender caveats. This makes difficult the differential diagnosis between age-related physiological decline and KD and/or failure. Currently, the inflammation-based modified Glasgow prognostic score (mGPS) is emerging as a promising biomarker of several inflammatory acute/chronic diseases. In this study, the large variability of eGFR with age and gender was evaluated as the association of eGFR values with mGPS levels. A population of 57,449 adult participants (age ≥ 18 years) was enrolled. Appropriate circulating biomarkers were measured to detect eGFR and mGPS values. The data obtained demonstrated a significant decrease in eGFR in men vs. women across the four selected age classes (18-40, 40-60, 60-80, 80-100 years); eGFR classes were significantly associated with mGPS (p < 0.001), as were age classes and gender with mGPS categories. Accordingly, the percentage of people having an mGPS score = 2 significantly increased across the eGFR classes: with an 11% in the G1/eGFR class needed to achieve 44% in G5/eGFR. Thus, the combination of mGPS with eGFR could represent the best benchmark risk model for the differential diagnosis of kidney disease from the age-related eGFR reduction.

Effects of Sacubitril/Valsartan on Exercise Capacity in Patients with Heart Failure with Reduced Ejection Fraction and the Role of Percentage of Delayed Enhancement Measured by Cardiac Magnetic Resonance in Predicting Therapeutic Response: A Multicentre Study.

Background: This study aims to evaluate the cardiopulmonary effects of sacubitril/valsartan therapy in patients with heart failure with reduced ejection fraction (HFrEF), investigating a possible correlation with the degree of myocardial fibrosis, as assessed by cardiac magnetic resonance. Methods: A total of 134 outpatients with HFrEF were enrolled. Results: After a mean follow-up of 13.3 ± 6.6 months, an improvement in ejection fraction and a reduction in E/A ratio, inferior vena cava size and N-terminal pro-B-type natriuretic peptide levels were observed. At follow-up, we observed an increase in VO2 peak of 16% (p<0.0001) and in O2 pulse of 13% (p=0.0002) as well as an improvement in ventilatory response associated with a 7% reduction in the VE/VCO2 slope (p=0.0001). An 8% increase in the ΔVO2/Δ work ratio and an 18% increase in exercise tolerance were also observed. Multivariate logistic regression analysis showed that the main predictors of events during follow-up were VE/VCO2 slope >34 (OR 3.98; 95% CI [1.59-10.54]; p=0.0028); ventilatory oscillatory pattern (OR 4.65; 95% CI [1.55-16.13]; p=0.0052); and haemoglobin level (OR 0.35; 95% CI [0.21-0.55]; p<0.0001). In patients who had cardiac magnetic resonance, when delayed enhancement >4.6% was detected, a lower response after sacubitril/valsartan therapy was observed as expressed by improvement in ΔVO2 peak, O2 pulse, LVEF and N-terminal pro-B-type natriuretic peptide. No significant differences were observed in ΔVO2/Δ work and VE/VCO2 slope. Conclusion:Sacubitril/valsartan improves cardiopulmonary functional capacity in HFrEF patients. The presence of myocardial fibrosis on cardiac magnetic resonance is a predictor of response to therapy.

Delineating Purinergic Signaling in Drosophila.

Simplistic models can aid in discovering what is important in the context of normal and pathological behavior. First recognized as a genetic model more than 100 years ago, to date, fruit flies (Drosophila melanogaster) still remain an astonishingly good laboratory stand-in for scientists to study development and physiology and to investigate the molecular mechanisms of human diseases. This is because fruit flies indeed represent a simplistic model. Furthermore, about 75% of human disease-related genes have their counterparts in the Drosophila genome, added to the fact that fruit flies are inexpensive and extremely easy to maintain, being invertebrates and, moreover, lacking any ethical concern issues. Purinergic signaling is, by definition, mediated by extracellular purinergic ligands, among which ATP represents the prototype molecule. A key feature that has progressively emerged when dissecting the purinergic mechanisms is the multilayer and dynamic nature of the signaling sustained by purinergic ligands. Indeed, these last are sequentially metabolized by several different ectonucleotidases, which generate the ligands that simultaneously activate several different purinergic receptors. Since significant purinergic actions have also been described in Drosophila, the aim of the present work is to provide a comprehensive picture of the purinergic events occurring in fruit flies.

First Computed Tomography Evidence of Pulmonary Cavitated Lipoma: Diagnosis and Management.

Lipomas are the most common form of benign soft tissue tumors in humans, occurring infrequently in visceral organs. Pulmonary lipomas are seen rarely and can occur such as an endobronchial (80%) or peripheral parenchymal (20%) lesion. Less than 10 cases of lung peripheral lipoma are described in literature, none cavitated. We report the clinical case of a 51-year-old emphysematous smoker man with a peripheral intrapulmonary middle-lobe cavitating lipoma, revealed during a routine chest X-ray for emphysema, subsequently confirmed by high-resolution computed tomography (HRCT) and positron emission tomography (PET)-CT. Some hypotheses are made about the origin of cavitation. Biopsy and surgery were not done due to the fully benign nodular features at imaging. The nodule was unchanged till 2 years, last follow-up with low-dose HRCT. It is probably useful to choose a conservative approach with a follow-up, if there is a high suspicion of benignity.

Iatrogenic superior vena cava syndrome with concomitant deep vein thrombosis of azygos and hemiazygos veins.

Iatrogenic superior vena cava syndrome (SVCs) represents an emergent diagnostic entity and its correlation with deep vein thrombosis is extremely rare. Recently, the increased use of indwelling lines, pacemakers and intracardiac devices has led to more cases of SVC syndrome also associated with a higher frequency of DVT. We report an unusual complication in a 74-year-old female, who has been undergoing hemodialysis via CVC for 14 years, who referred at our Emergency Department complaining of shortness of breath, headache, face and neck swelling. She underwent chest Computed Tomography Angiography (CTA), that showed a thrombus extending from the superior vena cava to the azygos and hemiazygos veins. Acute SVCs should be suspected in emergency settings in symptomatic patients with indwelling central lines, catheters and pacemakers. CTA represents an accurate and quick imaging modality for the diagnosis and the assessment of the extension of the thrombus.

Mutual relationship between heart failure and atrial fibrillation.

Atrial fibrillation (AF) and heart failure (HF) are evolving epidemies, together responsible for substantial human suffering and health-care expenditure. The simultaneous co-hexistence of the two conditions is associated with mortality rates higher than those observed in individuals with only one or none of them. Patients with concomitant HF and AF suffer from even worse symptoms and poorer prognosis, yet evidence-based evaluation and management of this group of patients is lacking. In this review, we evaluate the common mechanisms for the development of AF in HF patients and vice versa, focusing on the evidence for potential treatment strategies. Recent data have suggested that these patients may respond differently if compared to those with HF or AF alone. These results highlight the clear clinical need to identify and treat these diseases according to best evidence, in order to prevent adverse outcomes and reduce the huge burden that HF and AF are expected to have on global healthcare systems in the future.

The MECKI score initiative: Development and state of the art.

The high morbidity and poor survival rates associated with chronic heart failure still represent a big challenge, despite improvements in treatments and the development of new therapeutic opportunities. The prediction of outcome in heart failure is gradually moving towards a multiparametric approach in order to obtain more accurate models and to tailor the prognostic evaluation to the individual characteristics of a single subject. The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was developed 10 years ago from 2715 patients and subsequently validated in a different population. The score allows an accurate evaluation of the risk of heart failure patients using only six variables that include the evaluation of the exercise capacity (peak oxygen uptake and ventilation/CO2 production slope), blood samples (haemoglobin, Na+, Modification of Diet in Renal Disease) and echocardiography (left ventricular ejection fraction). Over the following years, the MECKI score was tested taking into account therapies and specific markers of heart failure, and it proved to be a simple, useful tool for risk stratification and for therapeutic strategies in heart failure patients. The close connection between the centres involved and the continuous updating of the data allow the participating sites to propose substudies on specific subpopulations based on a common dataset and to put together and develop new ideas and perspectives.

New Ultrasound Technologies for Ischemic Heart Disease Assessment and Monitoring in Cardiac Rehabilitation.

Owing to its ease of application, noninvasive nature, and safety, echocardiography is an essential imaging modality to assess cardiac function in patients affected by ischemic heart disease (IHD). Over the past few decades, we have witnessed a continuous series of evolutions in the ultrasound field that have led to the introduction of innovative echocardiographic modalities which allowed to better understand the morphofunctional abnormalities occurring in cardiovascular diseases. This article offers an overview of some of the newest echocardiographic modalities and their promising application in IHD diagnosis, risk stratification, management, and monitoring after cardiac rehabilitation.

Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. METHODS: Patients with HFrEF admitted to outpatients' services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. RESULTS: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = -0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = -0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = -0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = -2.065, SE = 0.354, p < 0.001). CONCLUSIONS: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.

[A strange case of acute respiratory failure: the platypnea-orthodeoxia syndrome]. / Un insolito caso di insufficienza respiratoria acuta: la sindrome platipnea-ortodeossia.

Platypnea-orthodeoxia syndrome is a rare disorder characterized by dyspnea and oxygen desaturation in upright position, with improvement of symptoms and blood oxygenation in supine position. Basically a right-to-left shunt (intracardiac or pulmonary) or a ventilation/perfusion mismatch are necessary to develop platypnea-orthodeoxia syndrome. Atrial septal defects, including patent foramen ovale (PFO), are known to be a frequent cause of platypnea-orthodeoxia syndrome. We describe herein the case of a 79-year-old woman with platypnea-orthodeoxia syndrome and PFO who developed a refractory worsening respiratory failure. Only the "rescue" emergency closure of PFO allowed the patient a clinical turning point with immediate and sustained respiratory improvement.

Association between Very Low-Density Lipoprotein Cholesterol (VLDL-C) and Carotid Intima-Media Thickness in Postmenopausal Women Without Overt Cardiovascular Disease and on LDL-C Target Levels.

BACKGROUND: atherosclerotic process inexorably advances in patients reaching low-density lipoprotein cholesterol (LDL-C) targets. An attractive hypothesis is that lipoprotein particles (very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL)), could contribute to residual risk. The present study aims to investigate the relationship between carotid intima-media thickness (IMT) and different lipoprotein subfractions in a cohort of healthy postmenopausal women. METHODS: 75 postmenopausal women, at LDL-C target levels without overt cardiovascular disease, underwent biochemical analyses (including subfraction assay of plasma lipoproteins) and carotid ultrasound examination. RESULTS: a statistically significant correlation between VLDL and carotid IMT (p < 0.001) was found. No significant correlation was found between carotid IMT and LDL-C (p = 0.179), IDL-C (p = 0.815), high-density lipoprotein (HDL) (p = 0.855), and LDL score (p = 0.240). Moreover, IMT is significantly correlated to LDL particle diameter (p = 0.044). After adjusting for age, systolic blood pressure, body mass index, smoking habits, glucose plasma concentration, and Lipoprotein(a) (Lpa) levels, multivariate analysis showed that women in the third tertile of VLDL-C, compared with those in the first tertile, were significantly associated to the highest IMT (p = 0.04). CONCLUSIONS: in this cohort of postmenopausal women, VLDL-C was significantly associated to carotid IMT, independent of main cardiovascular risk factors. These findings pave the way for targeting circulating concentrations of VLDL-C to reduce cardiovascular events in patients with target LDL-C levels.

Clinical Evidence for Q10 Coenzyme Supplementation in Heart Failure: From Energetics to Functional Improvement.

Oxidative stress and mitochondrial dysfunction are hallmarks of heart failure (HF). Coenzyme Q10 (CoQ10) is a vitamin-like organic compound widely expressed in humans as ubiquinol (reduced form) and ubiquinone (oxidized form). CoQ10 plays a key role in electron transport in oxidative phosphorylation of mitochondria. CoQ10 acts as a potent antioxidant, membrane stabilizer and cofactor in the production of adenosine triphosphate by oxidative phosphorylation, inhibiting the oxidation of proteins and DNA. Patients with HF showed CoQ10 deficiency; therefore, a number of clinical trials investigating the effects of CoQ10 supplementation in HF have been conducted. CoQ10 supplementation may confer potential prognostic advantages in HF patients with no adverse hemodynamic profile or safety issues. The latest evidence on the clinical effects of CoQ10 supplementation in HF was reviewed.

Effect of intravenous iron replacement therapy on exercise capacity in iron deficient anemic patients after cardiac surgery.

Iron deficiency (ID) is recognized as an important comorbidity in patients undergoing cardiac surgery; however, it still remains under-diagnosed and under-treated in clinical practice. This study aims at comparing efficacy and the effects on exercise capacity of intravenous ferric carboxymaltose (FCM) versus ferric gluconate (FG) in patients with ID anemia (IDA) resulting from cardiac surgery. We retrospectively analyzed data from our records of in-hospital patients with IDA after cardiac surgery undergoing cardiac rehabilitation. Group I was treated with FG, group II with FCM. Efficacy measures included changes (baseline vs discharge) in hemoglobin (Hb) and in distance traveled at six-minutes walking test (6MWT). Data from 74 in-patients (mean age 67.5±10.4 years, 43% women) were analyzed. At discharge, patients treated with FCM showed higher levels of Hb (11.1±1.2g/dl vs 10.2±1.1 g/dl; p=0.001), greater distance traveled at 6MWT (279.2±108.8 meters vs 236.3±72.7 meters; p=0.048), and lower in-hospital rehabilitation length of stay (20.3±7 vs 25.3±11.7 days; p=0.043) as compared to FG group. At multivariate analysis, the most powerful predictors of Hb increase >1 g/dl at discharge were transferrin levels (p=0.019) and treatment with FCM (p<0.001). FCM replacement therapy and iron serum levels were the most powerful predictors of 6MWT distance improvement (>100 meters) at discharge (p=0.13 and p=0.003, respectively). In patients with IDA following cardiac surgery, intravenous FCM is effective in restoring Hb levels and in improving exercise capacity after cardiac surgery.

Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction.

AIMS: Ventilation vs. carbon dioxide production (VE/VCO2 ) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. METHODS AND RESULTS: We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13-83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2-year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). CONCLUSIONS: The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.

The Effects of Sacubitril/Valsartan on Clinical, Biochemical and Echocardiographic Parameters in Patients with Heart Failure with Reduced Ejection Fraction: The "Hemodynamic Recovery".

BACKGROUND: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However, knowledge of the impact on cardiac performance remains limited. We sought to evaluate the effects of sacubitril/valsartan on clinical, biochemical and echocardiographic parameters in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Sacubitril/valsartan was administered to 205 HFrEF patients. RESULTS: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow-up of 10.49 (2.93 ± 18.44) months, the percentage of patients in New York Heart Association (NYHA) class III changed from 40% to 17% (p < 0.001). Median N-Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p = 0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p = 0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p < 0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p = 0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p = 0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p < 0.014). CONCLUSIONS: Sacubitril/valsartan induce "hemodynamic recovery" and, consistently with reduction in Nt-proBNP concentrations, improve NYHA class despite diuretic dose reduction.

Post-exercise high-sensitivity troponin T levels in patients with suspected unstable angina.

BACKGROUND: Previous studies showed that troponin blood levels may increase after exercise. In this study we assessed whether, among patients admitted with suspected unstable angina, the increase in high-sensitive troponin T (hs-TnT) levels after exercise stress test (EST) might help identify those with obstructive coronary artery disease (CAD) and predict symptom recurrence during short term follow-up. METHODS: Maximal treadmill EST was performed in 69 consecutive patients admitted to the emergency room with a suspicion of unstable angina (acute chest pain but confirmed normal serum levels of cardiac troponins) was measured before and 4 hours after EST. Coronary angiography was performed in 22 patients (32.8%). RESULTS: hs-TnT increased after EST compared to baseline in the whole population (from 0.84±0.65 to 1.17±0.87 ng/dL, p<0.001). The increase was similar in patients with positive (n = 14) and negative (n = 55) EST (p = 0.72), and was also similar in patients with (n = 12) and without (n = 10) obstructive CAD at angiography (p = 0.91). The achievement of a heart rate at peak EST ≥85% of that predicted for age was the variable mainly associated with the post-EST hs-TnT increase at multivariable linear regression analysis (p = 0.005). The change after EST of hs-TnT did not predict the recurrence of symptoms or readmission for chest pain at 6-month follow-up. CONCLUSIONS: Our data show that hs-TnT increased after EST in patients with suspected unstable angina, which seemed largely independent of most clinical and laboratory variables. Thus, hs-TnT assessed after EST does not seem to be helpful to identify patients with obstructive CAD in this kind of patients.

Early Effects of Sacubitril/Valsartan on Exercise Tolerance in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Sacubitril/valsartan in heart failure (HF) with reduced ejection fraction (HFrEF) was shown to be superior to enalapril in reducing the risk of death and hospitalization for HF. Our aim was to evaluate the cardiopulmonary effects of sacubitril/valsartan in patients with HFrEF. METHODS: We conducted an observational study. Ninety-nine ambulatory patients with HFrEF underwent serial cardiopulmonary exercise tests (CPET) after initiation of sacubitril/valsartan in addition to recommended therapy. RESULTS: At baseline, 37% of patients had New York Heart Association (NYHA) class III. After a median follow-up of 6.2 months (range 3⁻14.9 months) systolic blood pressure decreased from 117 ± 14 to 101 ± 12 mmHg (p < 0.0001), left ventricular ejection fraction (LVEF) increased from 27 ± 6 to 29.7 ± 7% (p < 0.0001), peak oxygen consumption (VO2) improved from 14.6 ± 3.3 (% of predicted = 53.8 ± 14.1) to 17.2 ± 4.7 mL/kg/min (% of predicted = 64.7 ± 17.8) (p < 0.0001), minute ventilation/carbon dioxide production relationship (VE/VCO2 Slope) decreased from 34.1 ± 6.3 to 31.7 ± 6.1 (p = 0.006), VO2 at anaerobic threshold increased from 11.3 ± 2.6 to 12.6 ± 3.5 mL/kg/min (p = 0.007), oxygen pulse increased from 11.5 ± 3.0 to 13.4 ± 4.3 mL/kg/min (p < 0.0001), and ∆VO2/∆Work increased from 9.2 ± 1.5 to 10.1 ± 1.8 mL/min/watt (p = 0.0002). CONCLUSION: Sacubitril/valsartan improved exercise tolerance, LVEF, peak VO2, and ventilatory efficiency at 6.2 months follow-up. Further studies are necessary to better clarify underlying mechanisms of this functional improvement.

Testosterone treatment in chronic heart failure. Review of literature and future perspectives.

Mounting evidence suggests that hormonal deficiencies (HD) have an important role in chronic heart failure (CHF). In particular, androgen depletion is common in men with CHF and is associated with increased morbidity and mortality. This review summarizes the current understanding of the complex relationship between CHF and testosterone, focusing on evidence derived from clinical trials that have investigated the role of testosterone in the treatment of CHF. A greater comprehension of this area will allow researchers and clinicians to plan future studies that improve current strategies to reduce mortality in this high-risk population. Online databases PubMed (Medline), Web of Science, and Scopus were searched for manuscripts published prior to June 2018 using key words "heart failure" AND "testosterone" OR "anabolism" OR "hormone" OR "replacement treatment". Manuscripts were collated, studied and carried forward for discussion where appropriate. In summary, findings from the literature demonstrate that testosterone treatment in CHF is a promising topic that requires further investigation.

The impairment of the Growth Hormone/Insulin-like growth factor 1 (IGF-1) axis in heart failure: A possible target for future therapy.

Hormonal abnormalities are quite common in chronic heart failure (CHF). The most studied hormonal axis in CHF is the impairment of Growth Hormone (GH)/Insulin Growth Factor-1(IGF-1), which in turn is defined either by a blunted response to GH stimulation test or low serum IGF-1 values.  Several independent groups reported that the presence of an abnormal GH/IGF-1 status in CHF is associated with a more severe disease, impaired functional capacity and reduced Survival rates. After the first encouraging results, double -blind controlled trials showed a neutral effect of the GH administration in patients. However, further studies reported positive results, when a GH-therapy is implemented only in those patients presenting a GH deficiency (replacement therapy).