Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

Sex differences in transthyretin cardiac amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to cardiac dysfunction. Recent evidence suggests that sex differences may play a significant role in various steps of ATTR-CA, including clinical presentation, diagnostic challenges, disease progression, and treatment outcomes. ATTR-CA predominantly affects men, whereas women are older at presentation. Women generally present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. When indexed, left ventricular (LV) wall thickness is equal, or even increased, than men. Women also have smaller LV cavities, more preserved ejection fractions, and apparently a slightly worse right ventricular and diastolic function. Given the under-representation on women in clinical trials, no data regarding sex influence on the treatment response are currently available. Finally, it seems there are no differences in overall prognosis, even if premenopausal women may have a certain level of myocardial protection. Genetic variations, environmental factors, and hormonal changes are considered as potential contributors to observed disparities. Understanding sex differences in ATTR-CA is vital for accurate diagnosis and management. By considering these differences, clinicians can improve diagnostic accuracy, tailor treatments, and optimize outcomes for both sexes with ATTR-CA.

Valvular heart disease in patients with cardiac amyloidosis.

Cardiac amyloidosis (CA) is an underdiagnosed condition caused by the deposition of misfolded proteins, namely immunoglobulin light chains and transthyretin, in the extracellular spaces of the heart. Any cardiovascular structure can be affected by amyloid infiltration, including the valves. Amyloid accumulation within the cardiac valves may lead to their structural and functional impairment, with a profound impact on patients' prognosis and quality of life. The most common forms of valvular disease in CA are aortic stenosis (AS), mitral regurgitation (MR), and tricuspid regurgitation (TR). CA and AS share similar risk factors, disease mechanisms, and remodeling patterns, which make their diagnosis particularly challenging. Patients with both CA and AS experience worse outcomes than CA or AS alone, and transcatheter aortic valve replacement may represent a useful therapeutic strategy in this population. Data on MR and TR are quite limited and mainly coming from case reports or small series. This review paper will summarize our current understanding on the epidemiology, disease mechanisms, echocardiographic features, clinical implications, and therapeutic options of AS, MR, and TR in patients with CA.

Pathophysiology of Cardiac Amyloidosis.

Amyloidosis refers to a heterogeneous group of disorders sharing common pathophysiological mechanisms characterized by the extracellular accumulation of fibrillar deposits consisting of the aggregation of misfolded proteins. Cardiac amyloidosis (CA), usually caused by deposition of misfolded transthyretin or immunoglobulin light chains, is an increasingly recognized cause of heart failure burdened by a poor prognosis. CA manifests with a restrictive cardiomyopathy which progressively leads to biventricular thickening, diastolic and then systolic dysfunction, arrhythmias, and valvular disease. The pathophysiology of CA is multifactorial and includes increased oxidative stress, mitochondrial damage, apoptosis, impaired metabolism, and modifications of intracellular calcium balance.

Management of heart failure with preserved ejection fraction: from neurohormonal antagonists to empagliflozin.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with multifaceted pathophysiology. All approaches to neurohormonal modulation were shown not to improve survival in HFpEF, despite their well-established efficacy in heart failure with reduced ejection fraction (HFrEF). This might be attributed to suboptimal study design, inadequate diagnostic criteria, or statistical power, but is also likely to reflect a lack of consideration for its clinical heterogeneity. The attention then shifted to the phenotypic heterogeneity of HFpEF, with the ultimate goal of developing therapies tailored to individual patient phenotypes. Recently, the sodium-glucose co-transporter-2 inhibitor (SGLT2i) empagliflozin has been found to reduce the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF, a result driven by a reduction in HF hospitalizations. This paper recapitulates the journey from the failure of trials on neurohormonal antagonists to the attempts of personalized approaches and the new perspectives of SGLT2i therapy for HFpEF.

Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis.

Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. "Amyloid seeds" are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in ß-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.

Pirfenidone as a novel cardiac protective treatment.

Myocardial fibrosis is a common feature of several heart diseases. The progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. Some drugs (like renin-angiotensin-aldosterone system inhibitors) have been shown to reduce extracellular matrix deposition, but no primarily anti-fibrotic medications are currently used to treat patients with heart failure (HF). Pirfenidone is an oral antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. Although its exact mechanism of action is not fully understood, pirfenidone might reduce the expression of profibrotic factors such as transforming growth factor-ß (TGF-ß), and proinflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-4, and IL-13, which could modulate the inflammatory response and inhibit collagen synthesis in lung tissue. There is some evidence that pirfenidone has antifibrotic activity in various animal models of cardiac disease. Furthermore, the positive results of the PIROUETTE trial, evaluating pirfenidone in patients with HF with preserved ejection fraction, have been very recently announced. This review summarizes the data about pirfenidone as a potential cardioprotective treatment.

The place of vericiguat in the landscape of treatment for heart failure with reduced ejection fraction.

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.

Subclinical cardiac damage in cancer patients before chemotherapy.

Cancer and cardiovascular diseases, including heart failure (HF), are the main causes of death in Western countries. Several anticancer drugs and radiotherapy have adverse effects on the cardiovascular system, promoting left ventricular dysfunction and ultimately HF. Nonetheless, the relationship between cancer and HF is likely not unidirectional. Indeed, cancer and HF share common risk factors, and both have a bidirectional relationship with systemic inflammation, metabolic disturbances, and neurohormonal and immune activation. Few studies have assessed the impact of untreated cancer on the heart. The presence of an active cancer has been associated with elevated cardiac biomarkers, an initial impairment of left ventricular structure and function, autonomic dysfunction, and reduced exercise tolerance. In turn, these conditions might increase the risk of cardiac damage from chemotherapy and radiotherapy. HF drugs such as beta-blockers or inhibitors of the renin-angiotensin-aldosterone system might exert a protective effect on the heart even before the start of cancer therapies. In this review, we recapitulate the evidence of cardiac involvement in cancer patients naïve from chemotherapy and radiotherapy and no history of cardiac disease. We also focus on the perspectives for an early diagnosis and treatment to prevent the progression to cardiac dysfunction and clinical HF, and the potential benefits of cardioactive drugs on cancer progression.

Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis.

BACKGROUND: Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients' quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient-reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease. DESIGN: Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis. RESULTS: Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF-36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7). CONCLUSIONS: Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials.

Shared and unique characteristics of metabolic syndrome in psychotic disorders: a review.

Introduction: People with psychosis spectrum disorders (PSD) face an elevated risk of metabolic syndrome (MetS), which may reduce their life expectancy by nearly 20%. Pinpointing the shared and specific characteristics and clinical implications of MetS in PSD is crucial for designing interventions to reduce this risk, but an up-to-date review on MetS across the psychosis spectrum is lacking. Methods: This narrative review fills this gap by examining the clinical literature on characteristics and implications of MetS in both distinct PSD and transdiagnostically, i.e., across traditional categorical diagnoses, with a focus on psychiatric and cardio-metabolic management. Results: We discuss common and specific characteristics of MetS in PSD, as well as factors contributing to MetS development in PSD patients, including unhealthy lifestyle factors, genetic predisposition, pro-inflammatory state, drugs consumption, antipsychotic medication, and psychotic symptoms. We highlight the importance of early identification and management of cardio-metabolic risk in PSD patients, as well as the existing gaps in the literature, for instance in the screening for MetS in younger PSD patients. We compare hypotheses-generating clinical associations and characteristics of MetS in different PSD, concluding by reviewing the existing recommendations and challenges in screening, monitoring, and managing MetS in PSD. Conclusion: Early identification and management of MetS are crucial to mitigate the long-term cardio-metabolic toll in PSD patients. Interventions should focus on healthy lifestyle and appropriate pharmacological and behavioral interventions. Further translational and clinical research is needed to develop targeted interventions and personalized treatment approaches for this vulnerable population, aiming at improving physical health and overall well-being.

Safety and efficacy of levosimendan in patients with cardiac amyloidosis.

BACKGROUND: Patients with cardiac amyloidosis (CA) often experience heart failure (HF) episodes. No evidence is available on inotropic therapy. This study aims to fill this gap by examining the safety and efficacy of levosimendan. METHODS: We retrieved all HF patients receiving ≥1 levosimendan infusion from 2013 to 2023. CA patients were matched with HF patients without CA (controls) based on sex, age, and left ventricular ejection fraction (LVEF). The response to levosimendan was measured as changes in daily urinary output, body weight, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). RESULTS: CA patients (median age 77 years, 73% men, 59% with ATTR-CA) and controls were compared. Levosimendan infusion was stopped because of hypotension in 2 cases with CA and (in 1 case) worsening renal function, and in 2 controls because of ventricular tachycardia episodes and (in 1 case) hypotension. CA patients showed a trend toward increased daily urinary output (p = 0.078) and a significant decrease in body weight (p < 0.001), without significant changes in NT-proBNP (p = 0.497) and eGFR (p = 0.732). Both CA patients and controls displayed similar changes in urinary output, weight, and eGFR, but NT-proBNP decreased more significantly among controls (p < 0.001). No differences were noted in rehospitalization rates, but CA patients experienced higher mortality at 6 and 12 months (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Levosimendan appears safe for CA patients needing inotropic support. The diuretic response and weight decrease during hospitalization were comparable between CA patients and matched HF patients, despite the greater mortality of CA patients after discharge.

Tetrameric Transthyretin as a Protective Factor Against Alzheimer's Disease.

Transthyretin (TTR) is a tetrameric protein traditionally recognized for its role in transporting thyroxine and retinol. Recent research has highlighted the potential neuroprotective functions of TTR in the setting of Alzheimer's disease (AD), which is the most common form of dementia and is caused by the deposition of amyloid beta (Aß) and the resulting cytotoxic effects. This paper explores the mechanisms of TTR protective action, including its interaction with Aß to prevent fibril formation and promote Aß clearance from the brain. It also synthesizes experimental evidence suggesting that enhanced TTR stability may mitigate neurodegeneration and cognitive decline in AD. Potential therapeutic strategies such as small molecule stabilizers of TTR are discussed, highlighting their role in enhancing TTR binding to Aß and facilitating its clearance. By consolidating current knowledge and proposing directions for future research, this review aims to underscore the significance of TTR as a neuroprotective factor in AD and the potential implications for future research.

Assessing cardiac mechanics through left ventricular haemodynamic forces.

Haemodynamic forces (HDFs), which represent the forces exchanged between blood and surrounding tissues, are critical in regulating the structure and function of the left ventricle (LV). These forces can be assessed on cardiac magnetic resonance or transthoracic echocardiography exams using specialized software, offering a non-invasive alternative for measuring intraventricular pressure gradients. The analysis of HDFs can be a valuable tool in improving our understanding of cardiovascular disease and providing insights beyond traditional diagnostic and therapeutic approaches. For instance, HDF analysis has the potential to identify early signs of adverse remodelling and cardiac dysfunction, which may not be detected by standard imaging methods such as bidimensional or speckle-tracking echocardiography. This review aims to summarize the principles of HDF analysis and to reappraise its possible applications to cardiac disorders.

Screening the health status of people working in a university.

BACKGROUND: We aimed to evaluate the physical and mental well being of people working in our academic institution. METHODS: This online survey targeted professors ( n  = 108), researchers ( n  = 78), technical and administrative staff ( n  = 279) working in the Scuola Superiore Sant'Anna (Pisa, Italy). Twenty-four multiple-choice questions explored the physical and mental health status, the main cardiovascular risk factors and levels of physical activity, the risk of cancer, and eating and drinking habits. RESULTS: Over 1 week, 112 participants out of 465 (24%) completed the survey [69% women, median age 43 years (interquartile range 33-53)]. The physical and mental health were judged as 'poor' by 5% and 13%. Many individuals had at least one cardiovascular risk factor (diabetes, 4%; hypertension, 10%; family history of coronary artery disease before 40 years, 21%; hypercholesterolemia, 24%; current or former smoking habit, 39%), and 6% had all of them. Many participants were rather sedentary: for example, 44% never or hardly ever walked at a quick pace for ≥20 min. As for eating and drinking habits, 36% ate sweets five or six times a week or every day, 15% drank beer and/or wine at least five or six times a week, and 5% drank spirits three or four times a week. CONCLUSIONS: A small but not negligeable proportion of responders complained of 'poor' health, and 65% had at least one cardiovascular risk factor. The global levels of physical activity and eating and drinking habits were globally suboptimal. Educational and screening activities to improve the wellbeing of people working in academia are advisable.

Echocardiography-Derived Forward Left Ventricular Output Improves Risk Prediction in Systolic Heart Failure.

BACKGROUND: Although it is widely used to classify patients with heart failure (HF), the prognostic role of left ventricular ejection fraction (LVEF) is debated. The aim of this study was to test the hypothesis that echocardiographic measures of forward left ventricular (LV) output, being more representative of cardiac hemodynamics, might improve risk prediction in a large cohort of patients with HF with systolic dysfunction. METHODS: Consecutive stable patients with HF with LVEF <50% on guideline-recommended therapies undergoing echocardiography including the evaluation of forward LV output (i.e., LV outflow tract [LVOT] velocity-time integral [VTI], stroke volume index [SVi], and cardiac index) over a 6-year period were selected and followed for the end point of cardiac and all-cause death. RESULTS: Among the 1,509 patients analyzed (mean age, 71 ± 12 years; 75% men; mean LVEF, 35 ± 9%), 328 (22%) died during a median follow-up period of 28 months (interquartile range, 14-40 months), 165 (11%) of cardiac causes. On multivariable regression analysis, LVOT VTI (P < .001), SVi (P < .001), and cardiac index (P < .001), but not LVEF (P > .05), predicted cardiac and all-cause death. The optimal prognostic cutoffs for LVOT VTI, SVi, and cardiac index were 15 cm, 38 mL/m2, and 2 L/min/m2, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (P < .001). Among the different measures of forward LV output, cardiac index was less accurate than LVOT VTI and SVi. CONCLUSIONS: The echocardiographic evaluation of forward LV output improves risk prediction in patients with HF across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.

Eligibility for vericiguat in a real-world, contemporary heart failure population.

AIMS: Vericiguat is a soluble guanylate cyclase stimulator and improves survival in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and an increased risk of decompensation. As real-world data on how many patients could be eligible for vericiguat therapy derive from outdated registries, we aimed to assess eligibility in a prospective cohort of patients with HF. METHODS AND RESULTS: Data from consecutive HF patients undergoing an elective ambulatory visit at five university hospitals from 3 July to 28 July 2023 were collected. Independent investigators assessed which patients (i) met the eligibility criteria of the VICTORIA trial, (ii) complied with HF guideline recommendations, (iii) met regulatory agency criteria, or (iv) met criteria for refundability according to the Italian regulatory agency. Patients (n = 346, 72% men, median age 69 years) had HFrEF in 57% of cases, left ventricular ejection fraction < 45% in 68%, and New York Heart Association class II-IV symptoms in 76%. Patients meeting the eligibility criteria of the VICTORIA trial or European and American HF Guideline recommendations were 9% and 13%, respectively. Patients meeting Food and Drug Administration (FDA) or European Medicines Agency (EMA) label criteria were 19% and 17%, respectively. Drug costs would be covered by the Italian National Health System in 10% of patients [if a sodium-glucose cotransporter-2 inhibitor (SGLT2i) is not mandatory] or in 8% (if an SGLT2i is requested). CONCLUSIONS: In a real-world study, 9% of patients met the eligibility criteria of the VICTORIA trial, but up to 13% complied with guideline recommendations and up to 19% met FDA or EMA criteria. In Italy, drug costs would be covered by up to 10% of patients.

The Fondazione Toscana Gabriele Monasterio app: a digital health system to improve wellbeing of inpatients with heart or lung disease.

BACKGROUND: An app providing material for education and entertaining is a possible way to support patients and healthcare providers in achieving person-centered care. METHODS: An app tailored on the Fondazione Toscana Gabriele Monasterio (FTGM), a research hospital treating cardiac and lung disorders, was created. A pilot evaluation project was conducted on consecutive patients hospitalized for heart or lung disorders. Patients were asked to complete an assessment questionnaire. RESULTS: The FTGM app provides information on diagnostic and therapeutic investigations, hospital and healthcare personnel, and includes content for entertainment and learning. It was tested on 215 consecutive patients (75% men, 66% aged >60 years, and 40% with a primary or middle school degree). Sixty-nine percentage of patients used the FTGM app, including 67% of patients aged >80 years and 65% of those with an elementary education (65%). Patients gave positive feedback on the app layout. Many (76%) looked for information on doctors and nurses in the 'People' section. Sixty-five percent of responders had used at least one of the sections called 'Music' and 'Museum visits'. The app helped many patients perceive the hospital as a more liveable place (68%), and to feel less anxious (76%), and more engaged in the diagnostic and therapeutic workup (65%). Overall, the majority of responders (87%) rated the app as 'excellent' or 'good', and almost all (95%) would have recommended other patients to use the app. CONCLUSIONS: The FTGM app is a possible tool to improve patient wellbeing during hospitalization.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

AIMS: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. METHODS AND RESULTS: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. CONCLUSION: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Pathophysiological Rationale and Clinical Evidence for Neurohormonal Modulation in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between cardiac diseases, comorbidities and ageing. HFpEF is characterised by the activation of neurohormonal axes, namely of the renin-angiotensin-aldosterone system and the sympathetic nervous system, although to a lesser extent compared with heart failure with reduced ejection fraction. This provides a rationale for neurohormonal modulation as a therapeutic approach for HFpEF. Nonetheless, randomised clinical trials have failed to demonstrate a prognostic benefit from neurohormonal modulation therapies in HFpEF, with the sole exception of patients with left ventricular ejection fraction in the lower range of normality, for whom the American guidelines suggest that such therapies may be considered. In this review, the pathophysiological rationale for neurohormonal modulation in HFpEF is summarised and the clinical evidence on pharmacological and nonpharmacological approaches backing current recommendations discussed.