Left atrium decompression devices across the spectrum of ejection fraction in heart failure: an updated systematic review and meta-regression analysis.

BACKGROUND: In patients affected by heart failure (HF) with reduced ejection fraction (HFrEF), pharmacological treatments have been proven to alleviate symptoms and improve prognosis, while no treatment other than sodium-glucose co-transporter-2 inhibitors have demonstrated significant effects in HF with preserved ejection fraction (HFpEF). Left atrium decompression devices (LADd) have been recently investigated as a new interventional approach in patients with HFpEF. OBJECTIVES: To assess the efficacy of LADd on soft endpoints in HF patients across the spectrum of ejection fraction. METHODS: PubMed and Web of Science were searched without restrictions from inception to 28 May 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified main outcomes were the change from baseline in 6-min walking distance (6MWD), NYHA class and health-related quality of life (HRQoL). Secondary outcomes were reduction in HF hospitalizations, echocardiographic, and hemodynamic parameters. RESULTS: Eleven studies, with a total of 547 patients, were included. LADd significantly improved 6MWD by 43.95 m (95% CI 29.64-58.26 m), decreased NYHA class by 0.93 (95% CI 1.20-0.67), and improved HRQoL questionnaire by 20.45 points (95% CI 13.77-27.14) with better results for all outcomes in patients with lower EFs. CONCLUSION: The present meta-analysis suggests that LADd are favorable in improving 6MWD, NYHA class, and HRQoL in HF across a wide spectrum of ejection fraction, with better outcomes in patients with lower EFs. TRIAL REGISTRATION: CRD42022336077, URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=336077 .

123I-MIBG imaging in heart failure: impact of comorbidities on cardiac sympathetic innervation.

PURPOSE: Heart failure (HF) is a primary cause of morbidity and mortality worldwide, with significant impact on life quality and extensive healthcare costs. Assessment of myocardial sympathetic innervation function plays a central role in prognosis assessment in HF patients. The aim of this review is to summarize the most recent evidence regarding the clinical applications of iodine-123 metaiodobenzylguanidine (123I-MIBG) imaging in patients with HF and related comorbidities. METHODS: A comprehensive literature search was conducted on PubMed and Web of Science databases. Articles describing the impact of 123I-MIBG imaging on HF and related comorbidities were considered eligible for the review. RESULTS: We collected several data reporting that 123I-MIBG imaging is a safe and non-invasive tool to evaluate dysfunction of cardiac sympathetic neuronal function and to assess risk stratification in HF patients. HF is frequently associated with comorbidities that may affect cardiac adrenergic innervation. Furthermore, HF is frequently associated with comorbidities and chronic conditions, such as diabetes, obesity, kidney disease and others, that may affect cardiac adrenergic innervation. CONCLUSION: Comorbidities and chronic conditions lead to more severe impairment of sympathetic nervous system in patients with HF, with a negative impact on disease progression and outcome. Cardiac imaging with 123I-MIBG can be a useful tool to reduce morbidity and prevent adverse events in HF patients.

Management of heart failure: similarities and discrepancies between the European Society of Cardiology and the American Heart Association guidelines.

Recommendations are the fundamental elements of guidelines and are especially significant when the amount of scientific data is expanding fast, as is the scenario of heart failure (HF). Beginning with the four pillars of treatment for HF with reduced ejection fraction, the main messages of the two most recent 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), partially overlap. There are notable differences, in part due to the timing of recent publications, like the Universal Definition of HF and the EMPEROR-Preserved trial, and in part due to differing perspectives on the natural history of HF. Specific challenges, such as risk stratification and the use of implanted cardioverter-defibrillators for primary prevention in HFrEF patients with non-ischaemic aetiology, are approached from a variety of perspectives. The ACC/AHA/HFSA recommendations place increased attention on topics that are especially pertinent to the US context, such as the cost-effectiveness of medications and the impact of health inequalities on HF care. A comparison of guideline suggestions may assist readers get a better grasp of the ESC and ACC/AHA/HFSA guidelines and apply logical ways to their own practice, wherever in the world that may be. A comparison may also contribute to the harmonization of future guidelines' recommendations by highlighting the reasons why certain areas have resulted to different recommendations while seemingly analysing the same published information.

Depression in Heart Failure with Reduced Ejection Fraction, an Undervalued Comorbidity: An Up-To-Date Review.

Introduction: Depression is a common and severe comorbidity among individuals with heart failure (HF). Up to a third of all HF patients are depressed, and an even higher proportion have symptoms of depression. Aim: In this review, we evaluate the relationship between HF and depression, explain the pathophysiology and epidemiology of both diseases and their relationship, and highlight novel diagnostic and therapeutic options for HF patients with depression. Materials and Methods: This narrative review involved keyword searches of PubMed and Web of Science. Review search terms included ["Depression" OR "Depres*" OR "major depr*"] AND ["Heart Failure" OR "HF" OR "HFrEF" OR "HFmrEF" OR "HFpEF" OR "HFimpEF"] in all fields. Studies included in the review met the following criteria: (A) published in a peer-reviewed journal; (B) described the impact of depression on HF and vice versa; and (C) were opinion papers, guidelines, case studies, descriptive studies, randomized control trials, prospective studies, retrospective studies, narrative reviews, and systematic reviews. Results: Depression is an emergent HF risk factor and strongly relates with worse clinical outcomes. HF and depression share multiple pathways, including platelet dis-reactivity, neuroendocrine malfunction, inappropriate inflammation, tachi-arrhythmias, and frailty in the social and community setting. Existing HF guidelines urge evaluation of depression in all HF patients, and numerous screening tools are available. Depression is ultimately diagnosed based on DSM-5 criteria. There are both non-pharmaceutical and pharmaceutical treatments for depression. Regarding depressed symptoms, non-pharmaceutical treatments, such as cognitive-behavioral therapy and physical exercise, have shown therapeutic results, under medical supervision and with an effort level adapted to the patient's physical resources, together with optimal HF treatment. In randomized clinical studies, selective serotonin reuptake inhibitors, the backbone of antidepressant treatment, did not demonstrate advantage over the placebo in patients with HF. New antidepressant medications are currently being studied and could provide a chance to enhance management, treatment, and control of depression in patients with HF. Conclusions: Despite the substantial link between depression and HF, their combination is underdiagnosed and undertreated. Considering the hopeful yet unclear findings of antidepressant trials, further research is required to identify people who may benefit from antidepressant medication. The goal of future research should be a complete approach to the care of these patients, who are anticipated to become a significant medical burden in the future.

Cardiorenal syndrome: Pathophysiology as a key to the therapeutic approach in an under-diagnosed disease.

Cardiorenal syndrome is a clinical condition that impacts both the heart and the kidneys. One organ's chronic or acute impairment can lead to the other's chronic or acute dysregulation. The cardiorenal syndrome has been grouped into five subcategories that describe the etiology, pathophysiology, duration, and pattern of cardiac and renal dysfunction. This classification reflects the large spectrum of interrelated dysfunctions and underlines the bidirectional nature of heart-kidney interactions. However, more evidence is needed to apply these early findings in medical practice. Understanding the relationship between these two organs during each organ's impairment has significant clinical implications that are relevant for therapy in both chronic and acute conditions. The epidemiology, definition, classification, pathophysiology, therapy, and outcome of each form of cardiorenal syndrome are all examined in this review.

Aortic thrombosis: the forgotten source of ischemic stroke. A case report and systematic review of the literature.

Ischemic stroke represents one of the most important health problems in industrialized countries, both for epidemiological and socio-economic impact. The presence of thrombi in the aorta is rare and its treatment has not been uniquely defined. Here we report the case of an 82-years-old man with aortic thrombosis and acute ischemic stroke.

[How to interpret subgroup analyses in cardiovascular trials?] / Come leggere le analisi per sottogruppi nei trial cardiovascolari?

Clinical trials provide the best evidence on the effect of a treatment, but they evaluate this effect on the total population of the study as if the effect of the randomized treatment was identical in all possible subgroups of patients (young, elderly, male, female, etc.). Subgroup analyses are an important tool to evaluate the presence of any diversity of the treatment effect concerning specific patient characteristics, if there are practical questions about who to treat and when, or if there are doubts about the benefit/risk profile of a therapy in a specific subpopulation. Subgroup analyses should be defined a priori, biologically plausible, and limited to few clinically important questions. Subgroup analyses have greater relevance in the context of studies that have demonstrated an overall significant difference between treatments. In the case of neutral or negative studies, any significant analyses between subgroups should be considered as essentially exploratory. Post-hoc subgroup analyses should be treated with great caution and considered more credible as the results are consistent with other studies. If significant heterogeneity is expected in specific subgroups of patients when planning a trial, they should have sufficient statistical power to detect the difference in the effect. In this review, we propose a critical approach for interpreting subgroup analyses in cardiovascular trials.

Novel potassium binders to optimize RAASi therapy in heart failure: A systematic review and meta-analysis.

AIMS: Hyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. METHODS AND RESULTS: PubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4-26%), decreased hyperkalemia events by 29% (95% CI: 55-92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18-0.44) compared to placebo, maintaining a good safety profile. CONCLUSION: NPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. SYSTEMATIC REVIEW REGISTRATION: CRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811.

Novel Strategies in Diagnosing Heart Failure with Preserved Ejection Fraction: A Comprehensive Literature Review.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent global condition affecting approximately 50% of the HF population. With the aging of the worldwide population, its incidence and prevalence are expected to rise even further. Unfortunately, until recently, no effective medications were available to reduce the high mortality and hospitalization rates associated with HFpEF, making it a significant unmet need in cardiovascular medicine. Although HFpEF is commonly defined as HF with normal ejection fraction and elevated left ventricular filling pressure, performing invasive hemodynamic assessments on every individual suspected of having HFpEF is neither feasible nor practical. Consequently, several clinical criteria and diagnostic tools have been proposed to aid in diagnosing HFpEF. Overall, these criteria and tools are designed to assist healthcare professionals in identifying and evaluating patients who may have HFpEF based on a combination of signs, symptoms, biomarkers, and non-invasive imaging findings. By employing these non-invasive diagnostic approaches, clinicians can make informed decisions regarding the best pharmacological and rehabilitation strategies for individuals with suspected HFpEF. This literature review aims to provide an overview of all currently available methods for diagnosing and monitoring this disabling condition.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry.

AIMS: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. METHODS: The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. RESULTS: We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. CONCLUSIONS: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

This study, from AT-TARGET-IT registry, investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Intensive and early PCSK9i therapy reduce composite major cardiovascular (CV) events in patients in reaching LDL-C target values. A strike early-strike strong strategy is safe and effective.

Normalization of ascending aorta dimension for body size influences pathophysiologic correlation in hypertensive patients: the Campania Salute Network.

AIMS: In the present study, we assessed correlates and their consistency of ascending aorta (AscAo) measurement in treated hypertensive patients. METHODS AND RESULTS: A total of 1634 patients ≥ 18 years old with available AscAo ultrasound were included. Ascending aorta was measured at end-diastole with leading edge to leading edge method, perpendicular to the long axis of the aorta in parasternal long-axis view at its maximal identifiable dimension. Correlations of AscAo and AscAo normalized for height (AscAo/HT) or body surface area (AscAo/BSA) with demographics and metabolic profile were explored. Multi-variable regression was also used to identify potential confounders influencing univariate correlations. Sensitivity analysis was performed using cardiovascular (CV) outcome. Correlations with age, estimated glomerular filtration rate, systolic blood pressure (BP), and heart rate (HR) were similar among the three aortic measures. Women exhibited smaller AscAo but larger AscAo/BSA than men with AscAo/HT offsetting the sex difference. Obesity and diabetes were associated with greater AscAo and AscAo/HT but with smaller AscAo/BSA (all P < 0.001). In multi-variable regression model, all aortic measure confirmed the sign of their relations with sex and metabolic profile independently of age, BP, and HR. In Kaplan-Mayer analysis, only dilated AscAo and AscAo/HT were significantly associated with increased risk of CV events (both P < 0.008). CONCLUSIONS: Among patients with long-standing controlled systemic hypertension, magnitude of aortic remodelling is influenced by the type of the measure adopted, with physiological consistency only for AscAo and AscAo/HT, but not for AscAo/BSA.

Long-standing hypertension leads to the development of aortic remodelling. In particular, the haemodynamic overload due to high blood pressure may contribute to the development of ascending aorta (AscAo) dilatation. With present study we analysed, in treated hypertensive patients, the spectrum of AscAo dilatation using different anthropometric criteria reporting the clinical and echocardiographic correlates: Indexing AscAo for body surface area (BSA) leads to inconsistent negative association with obesity and other metabolic abnormalities while AscAo and AscAo indexed for height present consistent pathophysiologic profile.In sensitivity analysis, AscAo and AscAo indexed for height are significantly associated with incident cardiovascular events while indexation for BSA is not, strongly suggesting the use of AscAo/BSA should be discouraged.

Sacubitril/valsartan reduces cardiac decompensation in heart failure with preserved ejection fraction: a meta-analysis.

BACKGROUND: The impact of sacubitril-valsartan on heart failure (HF) patients with preserved ejection fractions (HFpEF) is uncertain. The purpose of this meta-analysis was to explore the clinical advantages and safety of sacubitril-valsartan in patients with HFpEF. METHODS: PubMed and Web of Science were searched without any restrictions from inception to 8 May 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. RESULTS: Four trials, with a total of 7008 patients were included. Compared with valsartan, sacubitril-valsartan significantly reduced the rate of HF decompensation and of the combined end point of HF decompensation and all-cause mortality. All-cause mortality, New York Heart Association class improvement and rate of hyperkalemia were not significantly different between the two groups. Regarding safety, sacubitril-valsartan was more likely to increase the risk of hypotension. CONCLUSION: This meta-analysis suggests that sacubitril-valsartan may be an effective strategy to reduce HF decompensation events in patients with HFpEF.Systematic Review registration: CRD42022336077.

MicroRNAs: diagnostic, prognostic and therapeutic role in heart failure-a review.

Heart failure is a leading cause of morbidity and mortality, with relevant social and economic burden on global healthcare system. Although the development of novel diagnostic tools and the advance in therapies have deeply influenced the diagnosis and treatment of this disease, improving both prognosis and life expectancy of patients, hospitalization is still high, and mortality remains considerable. MicroRNAs are small endogenous RNA molecules that post-transcriptionally regulate gene expression in both physiological and pathological processes. In recent years, microRNA have arisen as attractive therapeutic targets in the treatment of a wide spectrum of pathologies, including heart failure. In cardiac pathology, deregulation of microRNAs expression and function is associated to adverse outcome and heart failure progression. Circulating levels of specific microRNAs have emerged as useful biomarkers for the diagnosis of heart failure or as prognostic indicators. In the present review, we summarize the state of current research on the role of miRNAs as biomarkers for diagnosis and prognosis in patients with heart failure and their use as potential therapeutic targets for this condition.

Renin-angiotensin system inhibitors reduce cardiovascular mortality in hypertensive patients with severe aortic stenosis undergoing transcatheter aortic valve implantation: insights from the EffecTAVI registry.

Objectives: Arterial hypertension is associated with the triggering of the renin-angiotensin system, leading to left ventricle fibrosis and worse cardiovascular outcomes. In this study, patients with comorbid arterial hypertension and severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) were selected from the EffecTAVI registry to evaluate the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on cardiovascular mortality. Methods: We enrolled 327 patients undergoing TAVI from the EffecTAVI registry. Using Kaplan-Meier event rates and study-stratified multivariable Cox proportional hazards regression models, we evaluated 2-year clinical outcomes according to the ACEI/ARB therapy status at enrollment. Results: Among the included patients, 222 (67.9%) were on ACEIs/ARBs at baseline, whereas 105 (32.1%) were not. Treatment with ACEIs/ARBs was significantly associated with a 2-year decrease in the rate of cardiovascular mortality (HR = 0.44, 95% CI: 0.23-0.81, p = 0.009). This association remained stable after both multivariable adjustment and propensity score matching. Conclusion: In a cohort of hypertensive patients with severe AS who were selected from the EffecTAVI registry, ACEI/ARB treatment at baseline was found to be independently associated with a lower risk of 2-year cardiovascular mortality, suggesting a potential benefit of this treatment. More trials are needed to validate this finding and to understand the full benefit of this treatment.

Efficacy, safety, adherence and persistence of PCSK9 inhibitors in clinical practice: A single country, multicenter, observational study (AT-TARGET-IT).

BACKGROUND AND AIMS: Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i) are recommended in patients at high and very-high cardiovascular (CV) risk, with documented atherosclerotic CV disease (ASCVD), and for very-high risk patients with familial hypercholesterolaemia not achieving LDL-cholesterol (LDL-C) goal while receiving maximally tolerated dose of lipid-lowering therapy (LLT). However, single country real-life data, reporting the use of PCSK9i in clinical practice, are limited. Therefore, we designed AT-TARGET-IT, an Italian, multicenter, observational registry on the use of PCSK9i in clinical practice. METHODS: All data were recorded at the time of the first prescription and at the latest observation preceding inclusion in the study. RESULTS: 798 patients were enrolled. The median reduction in LDL-C levels was 64.9%. After stratification for CV risk, 63.8% achieved LDL-C target; of them, 83.3% took LLTs at PCSK9i initiation and 16.7% did not. 760 patients (95.2%) showed high adherence to therapy, 13 (1.6%) partial adherence, and 25 (3.1%) poor adherence. At 6 months, 99.7% of patients enrolled in the study remained on therapy; there were 519 and 423 patients in the study with a follow-up of at least 12 and 18 months, respectively. Persistence in these groups was 98.1% and 97.5%, respectively. Overall, 3.5% of patients discontinued therapy. No differences in efficacy, adherence, and persistence were found between alirocumab and evolocumab. CONCLUSIONS: PCSK9i are safe and effective in clinical practice, leading to very high adherence and persistence to therapy, and achievement of recommended LDL-C target in most patients, especially when used as combination therapy.

New Evidence About Aortic Valve Stenosis and Cardiovascular Hemodynamics.

Aortic stenosis (AS) is the most common degenerative valvular disease in western word. In patients with severe AS, small changes in aortic valve area can lead to large changes in hemodynamics. The correct understanding of cardiac hemodynamics and its interaction with vascular function is of paramount importance for correct identification of severe AS and to plan effective strategies for its treatment. In the current review with highlight the importance of pressure recovery phenomenon and valvular arterial impedance as novel tools in the evaluation of patients with aortic stenosis.

From Structural to Functional Hypertension Mediated Target Organ Damage-A Long Way to Heart Failure with Preserved Ejection Fraction.

Arterial hypertension (AH) is a major risk factor for the development of heart failure (HF) which represents one of the leading causes of mortality and morbidity worldwide. The chronic hemodynamic overload induced by AH is responsible for different types of functional and morphological adaptation of the cardiovascular system, defined as hypertensive mediated target organ damage (HMOD), whose identification is of fundamental importance for diagnostic and prognostic purposes. Among HMODs, left ventricular hypertrophy (LVH), coronary microvascular dysfunction (CMVD), and subclinical systolic dysfunction have been shown to play a role in the pathogenesis of HF and represent promising therapeutic targets. Furthermore, LVH represents a strong predictor of cardiovascular events in hypertensive patients, influencing per se the development of CMVD and systolic dysfunction. Clinical evidence suggests considering LVH as a diagnostic marker for HF with preserved ejection fraction (HFpEF). Several studies have also shown that microalbuminuria, a parameter of abnormal renal function, is implicated in the development of HFpEF and in predicting the prognosis of patients with HF. The present review highlights recent evidence on the main HMOD, focusing in particular on LVH, CMD, subclinical systolic dysfunction, and microalbuminuria leading to HFpEF.

Lung Ultrasound in Coronary Care Unit, an Important Diagnostic Tool for Concomitant Pneumonia.

Background: In the setting of a coronary care unit (CCU), the early detection of pneumonia is of paramount important to prevent severe complications. This study was designed aiming to evaluate the diagnostic accuracy of lung ultrasound (LUS) in the detection of pneumonia and compared with chest X-ray (CXR). Method: We enrolled 110 consecutive patients admitted to the CCU of Federico II University Hospital. Each patient underwent CXR and bedside LUS on admission. The final diagnosis (pneumonia vs. no pneumonia) was established by another clinician reviewing clinical and laboratory data independent of LUS results and possibly prescribing chest contrast-enhanced CT (n = 34). Results: The mean age was 70 ± 11 years old, and 68% were males. Pneumonia was clinically diagnosed in 26 (23%) patients. LUS was positive for pneumonia in 24 patients (sensitivity 92%, specificity 81%). Chest radiography was positive for pneumonia in nine patients (sensitivity 43%, specificity 95%). Using CT scan as a reference, LUS exhibited 92% sensitivity and a specificity of 96%. In ROC curve analysis, the diagnostic accuracy of CXR and LUS for the diagnosis of pneumonia was 0.86 (95% CI 0.77−0.94), which was higher than CXR 0.68 (95% CI 0.55−0.84), p < 0.05. Conclusion: Based on the findings of the present study, the accuracy of LUS in the detection of pneumonia was significantly higher than chest X-ray with comparable sensibility to CT scan.

Renin-angiotensin-aldosterone system inhibition in patients affected by heart failure: efficacy, mechanistic effects and practical use of sacubitril/valsartan. Position Paper of the Italian Society of Cardiology.

Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community.

Impact of Sacubitril/Valsartan on surfactant binding proteins, central sleep apneas, lung function tests and heart failure biomarkers: Hemodynamic or pleiotropism?

Purpose: Little is known about the mechanism underlying Sacubitril/Valsartan effects in patients with heart failure (HFrEF). Aim of the study is to assess hemodynamic vs. non-hemodynamic Sacubitril/Valsartan effects by analyzing several biological and functional parameters. Methods: Seventy-nine patients (86% males, age 66 ± 10 years) were enrolled. At baseline and 6 months after reaching the maximum Sacubitril/Valsartan tolerated dose, we assessed biomarkers, transthoracic echocardiography, polysomnography, spirometry, and carbon monoxide diffusing capacity of the lung (DLCO). Results: Mean follow-up was 8.7 ± 1.4 months with 83% of patients reaching Sacubitril/Valsartan maximum dose (97/103 mg b.i.d). Significant improvements were observed in cardiac performance and biomarkers: left ventricular ejection fraction increased (31 ± 5 vs. 37 ± 9 %; p < 0.001), end-diastolic and end-systolic volumes decreased; NT-proBNP decreased (1,196 [IQR 648-2891] vs. 958 [IQR 424-1,663] pg/ml; p < 0.001) in parallel with interleukin ST-2 (28.4 [IQR 19.4-36.6] vs. 20.4 [IQR 15.1-29.2] ng/ml; p < 0.001) and circulating surfactant binding proteins (proSP-B: 58.43 [IQR 40.42-84.23] vs. 50.36 [IQR 37.16-69.54] AU; p = 0.014 and SP-D: 102.17 [IQR 62.85-175.34] vs. 77.64 [IQR 53.55-144.70] AU; p < 0.001). Forced expiratory volume in 1 second and forced vital capacity improved. DLCO increased in the patients' subgroup (n = 39) with impaired baseline values (from 65.3 ± 10.8 to 70.3 ± 15.9 %predicted; p = 0.013). We also observed a significant reduction in central sleep apneas (CSA). Conclusion: Sacubitril/Valsartan effects share a double pathway: hemodynamic and systemic. The first is evidenced by NT-proBNP, proSP-B, lung mechanics, and CSA improvement. The latter is confirmed by an amelioration of DLCO, ST-2, SP-D as well as by reverse remodeling echocardiographic parameters.