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Aims: A novel tool for the evaluation of left ventricular (LV) systo-diastolic function through echo-derived haemodynamic forces (HDFs) has been recently proposed. The present study aimed to assess the predictive value of HDFs on (i) 6 month treatment response to sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) patients and (ii) cardiovascular events., Methods and Results: Eighty-nine consecutive HFrEF patients [70% males, 65 ± 9 years, LV ejection fraction (LVEF) 27 ± 7%] initiating sacubitril/valsartan underwent clinical, laboratory, ultrasound and cardiopulmonary exercise testing evaluations. Patients experiencing no adverse events and showing ≥50% reduction in plasma N-terminal pro-B-type natriuretic peptide and/or ≥10% LVEF increase over 6 months were considered responders. Patients were followed up for the composite endpoint of HF-related hospitalisation, atrial fibrillation and cardiovascular death. Forty-five (51%) patients were responders. Among baseline variables, only HDF-derived whole cardiac cycle LV strength (wLVS) was higher in responders (4.4 ± 1.3 vs. 3.6 ± 1.2; p = 0.01). wLVS was also the only independent predictor of sacubitril/valsartan response at multivariable logistic regression analysis [odds ratio 1.36; 95% confidence interval (CI) 1.10-1.67], with good accuracy at receiver operating characteristic (ROC) analysis [optimal cutpoint: ≥3.7%; area under the curve (AUC) = 0.736]. During a 33 month (23-41) median follow-up, a wLVS increase after 6 months (ΔwLVS) showed a high discrimination ability at time-dependent ROC analysis (optimal cut-off: ≥0.5%; AUC = 0.811), stratified prognosis (log-rank p < 0.0001) and remained an independent predictor for the composite endpoint (hazard ratio 0.76; 95% CI 0.61-0.95; p < 0.01), after adjusting for clinical and instrumental variables., Conclusions: HDF analysis predicts sacubitril/valsartan response and might optimise decision-making in HFrEF patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Central apneas (CA) and periodic breathing (PB) are the most common related breathing disorders in heart failure, being observed in up to 50% of patients. Once considered only a sleep-related phenomenon, actually CA/PB occur across the whole 24 h period and their presence in the awake patient even in the upright position and during physical effort has been associated with a worse clinical profile and a greater mortality. Chemoreflex activation, circulatory time delay and altered plant gain are the pathophysiological determinants. While the use of guideline-recommended medical and device treatment represents the first step in the management of CA in heart failure patients, no specific therapy has been demonstrated to reduce CA-related impact on mortality. In particular, the use of non-invasive ventilation has yielded contradictory results in the context of large-scale randomized clinical trials. The design and testing of therapies targeting the pathophysiological triggers of CA, such as chemoreflex sensitivity, may prove valuable in the next future.

Background: Fibroblast growth factor-23 (FGF23) has been associated to left ventricular (LV) hypertrophy and heart failure (HF) severity. We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients., Methods: Patients with stable HF and left ventricular ejection fraction (LVEF) < 50% were prospectively enrolled, managed according to current recommendations and followed over time. iFGF23 was measured at baseline with a fully automated immuno-chemiluminescent assay., Results: We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were < 35.2 pg/mL, 35.2-50.9 pg/mL, and > 50.9 pg/mL. LVEF decreased from the first iFGF23 tertile to the third tertile (p = 0.014). N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased from the first to the third tertile (p = 0.001), while peak oxygen consumption decreased (p < 0.001). Thirty-five patients (23%) experienced the primary endpoint (all-cause death or HF hospitalization at 5 years), and 26 (17%) the secondary endpoint (all-cause death at 5 years). On multivariable analysis, iFGF23 independently predicted the primary endpoint on top of age, gender and LVEF (HR 4.6 [95% CI 2.1-10.3], p < 0.001), age, gender and eGFR (HR 4.1 [95% CI 1.6-10.3], p = 0.003), as well as age, gender and NT-proBNP (HR 3.6 [95% CI 1.6-8.2], p = 0.002). iFGF23 even reclassified patient risk on top of all the 3 models, with NRI values of 0.65 (95% CI 0.30-1.01), 0.55 (95% CI 0.25-0.88), and 0.60 (95% CI 0.24-0.96), respectively (both p < 0.001)., Conclusions: Circulating iFGF23 is associated with disease severity and outcome in HF patients with reduced and mildly reduced ejection fraction., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as one of the most important cell types involved in the fibrotic process. There are currently no drugs with primarily antifibrotic action approved for clinical use, as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of chimeric antigen receptor T cells engineered in vivo using lipid nanoparticles containing mRNA encoding a receptor directed against the fibroblast activation protein, expressed by activated cardiac fibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans.

For decades, cardiologists have largely underestimated the role of the right heart in heart failure due to left heart disease. Nowadays, the importance of evaluating right ventricular (RV) structure and function in left heart failure is well documented and this concept has been emphasized in the most recent heart failure guidelines. However, several relevant questions remain unanswered such as the following: (a) which imaging technique (standard or 3D echocardiography or strain imaging or cardiac magnetic resonance) and, more, which parameters should be used to grade the severity of RV dysfunction? (b) do less widespread and less applied diagnostic tools such as cardiopulmonary stress testing and bioelectrical impedance analysis play a role in this field? (c) are there specific biochemical aspects of RV failure? (d) why notion of pathophysiology of heart and lung interaction are so well appreciated at an academic level but are not applied in the clinical setting? The present review has been prepared by the Heart Failure (HF) working group of the Italian Society of Cardiology and its main objective is to improve our understanding on RV dysfunction in heart failure., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. This study aimed to evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT)., Methods and Results: Patients with suspected CA (n = 1149) underwent a diagnostic work-up in three centres in Italy, France (n = 343, derivation cohort), and United Kingdom (n = 806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP <180 ng/L or hs-TnT <14 ng/L were found in 7% of patients, and ruled out CA without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT-proBNP <180 ng/L or hs-TnT <14 ng/L, and 10% showed both biomarkers below cut-offs (0.5% false negatives). These cut-offs refined CA prediction when added to echocardiographic scores in patients with a haematologic disease or an increased wall thickness. In the validation cohort, the 86 ng/L hs-TnT cut-off ruled in 20% of patients (2% false positives). NT-proBNP and hs-TnT cut-offs retained their rule-out and rule-in performance also in cohorts with CA prevalence of 20%, 10%, 5% and 1% derived from the original cohort through bootstrap analysis., Conclusions: Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP <180 ng/L and hs-TnT <14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL-CA or cardiac (pseudo)hypertrophy., (© 2023 European Society of Cardiology.)

Cardiac amyloidosis (CA) is now recognized as an important cause of heart failure. Increased wall thickness and diastolic dysfunction of the left ventricle are the most easily detectable manifestations of CA, but amyloid accumulates in all cardiac structures. Involvement of the left and right atria may be due to the haemodynamic effects of ventricular diastolic dysfunction, the effects of amyloid infiltration into the atrial wall, and the cardiotoxic damage of atrial cardiomyocytes by amyloid precursors. Atrial amyloidosis is an early manifestation of CA, and is associated with an increased risk of atrial fibrillation and thromboembolic events. Furthermore, atrial amyloidosis can be found even in the absence of systemic disease and ventricular involvement. This condition is named isolated atrial amyloidosis and is due to a local overproduction of atrial natriuretic peptide. In this review we summarize the evidence on the mechanisms and clinical relevance of atrial amyloidosis., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre-determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with -omics-based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved., (© 2022 European Society of Cardiology.)

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin-angiotensin-aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF., (© 2021. The Author(s).)

The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown., (© 2021. The Author(s).)

Recommendations represent the core messages of guidelines, and are particularly important when the body of scientific evidence is rapidly growing, as in the case of heart failure (HF). The main messages from two latest major HF guidelines, endorsed by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA), are partially overlapping, starting from the four pillars of treatment for HF with reduced ejection fraction. Some notable differences exist, in part related to the timing of recent publications (most notably, the Universal Definition of HF paper and the EMPEROR-Preserved trial), and in part reflecting differing views of the natural history of HF (with a clear differentiation between stages A and B HF in the ACC/AHA/HFSA guidelines). Different approaches are proposed to specific issues such as risk stratification and implantable cardioverter defibrillator use for primary prevention in HFrEF patients with non-ischaemic aetiology. The ACC/AHA/HFSA guidelines put a greater emphasis on some issues that are particularly relevant to the US setting, such as the cost-effectiveness of therapies and the impact of health disparities on HF care. A comparison between guideline recommendations may give readers a deeper understanding of the ESC and ACC/AHA/HFSA guidelines, and help them apply sensible approaches to their own practice, wherever that may be in the world. A comparison may possibly also help further harmonization of recommendations between future guidelines, by identifying why some areas have led to conflicting recommendation, even when ostensibly reviewing the same published evidence., (© 2022 European Society of Cardiology.)

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. Circulating biomarkers reflecting pathophysiological pathways involved in HF development and progression may assist clinicians in early diagnosis and management of HF patients. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. The roles of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification in HF have been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the role of NPs as a guide to HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, with independent value to NPs. Other biomarkers evaluated as predictors of adverse outcome are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin, and makers of renal dysfunction. Multi-marker scores and genomic, transcriptomic, proteomic, and metabolomic analyses could further refine HF management., (© 2021. The Author(s).)

Background: Neurohormonal activation has never been investigated in patients with cardiac amyloidosis (CA)., Methods: Forty-seven patients with amyloid light-chain (AL)-CA and 61 with transthyretin (ATTR)-CA were matched to non-amyloidotic heart failure (HF) patients based on age, sex, left ventricular ejection fraction ranges, renal function and HF therapies. N-terminal pro-B-type natriuretic peptide (NT-proBNP), norepinephrine and renin were dosed. The primary and secondary endpoints were 1-year cardiovascular death or HF hospitalisation, and 5-year cardiovascular death, respectively., Results: Patients with AL-CA had a 10-fold higher NT-proBNP than HF patients (6548 ng/L [2059-15,097] vs. 692 [243-2241], p  < 0.001), and slightly higher norepinephrine (595 ng/L [383-869] vs. 416 [250-693], p  = 0.047). Patients with ATTR-CA had higher NT-proBNP (3984 ng/L [2275-9505] vs. 1751 [470-4768], p  = 0.006), norepinephrine (552 ng/L [344-855] vs. 441 [323-601], p  = 0.020), and renin (14 mU/L [8-80] vs. 10 [4-34], p  = 0.017). Patients with AL- or ATTR-CA had more often 2 or 3 neurohormones above the corresponding upper reference limits than matched HF patients. NT-proBNP and aldosterone were univariate predictors of the primary endpoint in patients with ATTR-CA, but not in matched controls. NT-proBNP and renin predicted the secondary endpoint in patients with AL-CA, but not in matched controls., Conclusions: Patients with CA display a neurohormonal activation, with some prognostic significance.

Heart failure (HF) has a complex pathophysiology including neurohormonal activation, inflammation and oxidative stress that, together with comorbidities, promote progressive myocardial damage and cardiac remodeling. Over the years the study of these pathogenic mechanisms has led to the identification of several analytes potentially useful as biomarkers in HF. High-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification of HF, with independent value to natriuretic peptides. Other biomarkers currently being evaluated as predictors of adverse outcome in HF are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin as well as makers of renal dysfunction. The use of multi-marker scores as well as the application of genomics, transcriptomics, proteomics and metabolomics could further refine the management of HF.

Heart failure (HF) is the final common pathway of many cardiovascular diseases and is associated with increased morbidity and mortality. Natural history of HF patients can be improved when early diagnosis is achieved, and a timely treatment is initiated. Circulating biomarkers, reflecting pathophysiological pathways involved in HF development and progression, help clinicians diagnose and manage patients with HF. Natriuretic peptides are cardioprotective hormones released by cardiomyocytes in response to pressure/volume overload. B-type natriuretic peptides, namely B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide, have been widely validated as tools for diagnosis and risk stratification of HF, and their use appears promising also for screening the population at risk and as a guide for preventive measures halting progression towards HF. Conversely, there is conflicting evidence regarding their role as a guidance for HF therapy.

Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the deposition of immunoglobulin light chains (AL) and wild-type or variant transthyretin (ATTRwt/ATTRv). Cardiac involvement is the main determinant of outcome in both AL and ATTR, and cardiac amyloidosis (CA) is increasingly recognized as a cause of heart failure. In CA, circulating biomarkers are important diagnostic tools, allow to refine risk stratification at baseline and during follow-up, help to tailor the therapeutic strategy and monitor the response to treatment. Among amyloid precursors, free light chains are established biomarkers in AL amyloidosis, while the plasma transthyretin assay is currently being investigated as a tool for supporting the diagnosis of ATTRv amyloidosis, predicting outcome and monitor response to novel tetramer stabilizers or small interfering RNA drugs in ATTR CA. Natriuretic peptides (NPs) and troponins are consistently elevated in patients with AL and ATTR CA. Plasma NPs, troponins and free light chains hold prognostic significance in AL amyloidosis, and are evaluated for therapy decision-making and follow-up, while the value of NPs and troponins in ATTR is less well established. Biomarkers can be usefully integrated with clinical and imaging variables at all levels of the clinical algorithm of systemic amyloidosis, from screening to diagnosis and prognosis, and treatment tailoring., (© 2021 European Society of Cardiology.)

The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)-GMP-phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Drugs for neurohormonal antagonism are usually denied to patients with cardiac amyloidosis (CA) because of safety concerns., Methods: Patients diagnosed with CA at a tertiary referral centre from 2009 to 2019 were enrolled. In the absence of contraindications, beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB), and mineralocorticoid receptor antagonists (MRA) were started or up-titrated., Results: 99 patients were evaluated (72% men, age 80 years [72,83], 33% light-chain and 67% transthyretin amyloidosis); 56% were started on or underwent up-titration of a beta-blocker, 25% of ACEi/ARB, and 39% of MRA; beta-blockers were then prescribed to 87% of patients, ACEi/ARB to 75%, and MRA to 63%, with median bisoprolol, ramipril, valsartan, and spironolactone daily equivalent doses of 2.5 mg, 5 mg, 80 mg, and 25 mg, respectively. Patients starting or starting/up-titrating a beta-blocker did not show a higher frequency of hypotension, fatigue, syncope, symptomatic bradycardia, need for pacemaker implantation, or HF hospitalization. Lower stroke volume and cardiac output (CO) predicted HF hospitalization regardless of amyloidosis type; lower left ventricular ejection fraction predicted hypotension, and lower CO and diastolic blood pressure predicted syncope. Patients who had an ACEi/ARB or MRA being started or up-titrated did not experience more adverse events than other patients., Conclusions: ACEi/ARB and MRA can be safely used in CA, provided that no contraindications are present, treatment is started at a low dose and slowly up-titrated, and patients are monitored quite closely. Beta-blocker therapy is less tolerated in patients with AL amyloidosis and/or worse haemodynamic function., Competing Interests: Conflict of interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Both oxidative stress and inflammation are enhanced in chronic heart failure. Dysfunction of cardiac mitochondria is a hallmark of heart failure and a leading cause of oxidative stress, which in turn exerts detrimental effects on cellular components, including mitochondria themselves, thus generating a vicious circle. Oxidative stress also causes myocardial tissue damage and inflammation, contributing to heart failure progression. Furthermore, a subclinical inflammatory state may be caused by heart failure comorbidities such as obesity, diabetes mellitus or sleep apnoeas. Some markers of both oxidative stress and inflammation are enhanced in chronic heart failure and hold prognostic significance. For all these reasons, antioxidants or anti-inflammatory drugs may represent interesting additional therapies for subjects either at high risk or with established heart failure. Nonetheless, only a few clinical trials on antioxidants have been carried out so far, with several disappointing results except for vitamin C, elamipretide and coenzyme Q10. With regard to anti-inflammatory drugs, only preliminary data on the interleukin-1 antagonist anakinra are currently available. Therefore, a comprehensive, deep understanding of our current knowledge on oxidative stress and inflammation in chronic heart failure is key to providing some suggestions for future research on this topic.

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Mutations in either the nuclear or the mitochondrial genome can lead to structural and functional changes within the skeletal muscles. These genetic skeletal myopathies are rare, although not infrequent when their cumulative incidence is considered. Dystrophinopathies (Duchenne and Becker muscular dystrophies) and mitochondrial disease are some of the most frequent clinical entities, and those developing heart failure more frequently. Neurohormonal antagonism represents the cornerstone of heart failure management, even though its role in the prevention and treatment of heart failure in patients with dystrophinopathies or mitochondrial disorders remains undefined. In the present paper we will summarise current available evidence on this topic. Particular attention will be devoted to Duchenne muscular dystrophy, and to the approaches modulating neurohormonal function by targeting the skeletal muscle.