[New Treatment Strategies in Patients with Heart Failure with Reduced Ejection Fraction: Beyond Neurohormonal Inhibition].

Patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Although guideline-directed medical therapy is well established, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF with consequent higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as cornerstones to reduce residual risk of both cardiovascular mortality and readmission for heart failure. The following review will debate about emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the new therapeutic strategies in cardiorenal patients.

Fabry disease: a rare disorder calling for personalized medicine.

Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon.

QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

INTRODUCTION: QTc interval prolongation is increasingly frequent as CKD advances and predicts death in dialysis. However, predictors and mortality-risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH, and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD. METHODS: Participants underwent protocolized baseline and semi-annual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over three years. RESULTS: 2,254 participants (34.1% female; mean age 68.7 years; mean glomerular filtration rate 41.4 ml/min/m2) enrolled. Baseline LVH (left ventricular mass index >131 g/m2 (>100 g/m2 if female)) was present in 10.8% and prolonged QTc intervals (>=500 ms) in 1.5%. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p=0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p<0.001) and adjusted (hazard ratio 3.15 (1.38, 7.16, p=0.006)) mortality rates than those with QTc intervals <500 ms. CONCLUSIONS: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH, and with a tripling of mortality-risk in patients with predialysis CKD.

New Challenges in Heart Failure with Reduced Ejection Fraction: Managing Worsening Events.

Patients with an established diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Despite guideline-directed medical therapy, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF, and patients experiencing WHF carry a substantially higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as arrows in the quiver for clinicians to address the residual risk of HF hospitalization and cardiovascular deaths in patients with WHF. This question-and-answer-based review will discuss the emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC), the new therapeutic approaches to treat WHF and then move on to their timing and safety concerns (i.e., renal profile).

Peritoneal dialysis discontinuation: to the root of the problem.

As the global burden of chronic kidney disease continues to increase, the use of peritoneal dialysis is often advocated as the preferred initial dialysis modality. Observational studies suggest a survival advantage for peritoneal dialysis over hemodialysis for the initial 2-3 years of dialysis. Peritoneal dialysis has been associated with better graft survival after kidney transplantation and has a reduced cost burden compared to hemodialysis. However, several medical and non-medical reasons may limit access to peritoneal dialysis, and less than 20% of patients with end-stage kidney disease are treated with peritoneal dialysis worldwide. In this narrative review, we sought to summarize the recent medical literature on risk factors for peritoneal dialysis discontinuation, distinguishing the early and the late phase after peritoneal dialysis initiation. Although the definition of clinically relevant outcomes varies among studies, we observed that center size, older age, and the presence of many comorbidities are risk factors associated with peritoneal dialysis discontinuation, regardless of the phase after peritoneal dialysis initiation. On the contrary, poor technique training and late referral to nephrology care, as opposed to the need for a caregiver, patient burnout and frequent hospitalizations, are related to early and late peritoneal dialysis drop-out, respectively. The aim of the review is to provide an overview of the most relevant parameters to be considered when advising patients in the selection of the most appropriate dialysis modality and in the clinical management of peritoneal dialysis patients. In addition, we wish to provide the readers with a critical appraisal of current literature and a call for a consensus on the definition of clinically relevant outcomes in peritoneal dialysis to better address patients' needs.

Finerenone: Questions and Answers-The Four Fundamental Arguments on the New-Born Promising Non-Steroidal Mineralocorticoid Receptor Antagonist.

Chronic kidney disease (CKD) is one of the most common complications of diabetes mellitus and an independent risk factor for cardiovascular disease. Despite guideline-directed therapy of CKD in patients with type 2 diabetes, the risk of renal failure and cardiovascular events still remains high, and diabetes remains the leading cause of end-stage kidney disease in affected patients. To date, current medications for CKD and type 2 diabetes mellitus have not reset residual risk in patients due to a high grade of inflammation and fibrosis contributing to kidney and heart disease. This question-and-answer-based review will discuss the pharmacological and clinical differences between finerenone and other mineralocorticoid receptor antagonists and then move on to the main evidence in the cardiovascular and renal fields, closing, finally, on the potential role of therapeutic combination with sodium-glucose cotransporter 2 inhibitors (SGLT2is).

The Impact of Cholecaciferol Supplementation on Bone Mineral Density in Long-Term Kidney Transplant Recipients.

Although reduced bone mineral density (BMD) is associated with a higher risk of fractures, morbidity, and mortality in kidney transplant patients (KTRs), there is no consensus on optimal treatment for the alterations of BMD in this population. This study aims at assessing the effect of cholecalciferol supplementation on BMD over a follow-up period of 2 years in a cohort of long-term KTRs. Patients with age ≥ 18 years were included and divided into two subgroups based on treatment with bisphosphonate and/or calcimimetics and/or active vitamin D sterols (KTRs-treated) or never treated with the above medications (KTRs-free). BMD was evaluated at lumbar vertebral bodies (LV) and right femoral neck (FN) with standard DEXA at the beginning and end of the study. According to World Health Organization (WHO) criteria, results were expressed as T-score and Z-score. Osteoporosis and osteopenia were defined as T score ≤ -2.5 SD and T score < -1 and >-2.5 SD, respectively. Cholecalciferol was supplemented at a dose of 25,000 IU/week over 12 weeks followed by 1500 IU/day. KTRs-free (n. 69) and KTRs-treated (n. 49) consecutive outpatients entered the study. KTRs-free were younger (p < 0.05), with a lower prevalence of diabetes (p < 0.05) and of osteopenia at FN (46.3 % vs. 61.2 %) compared to KTRs-treated. At the entry none of the study subjects had a sufficient level of cholecalciferol; Z-score and T-score at LV and FN were not different between groups. At the end of the study period, serum cholecalciferol concentration was significantly increased in both groups (p < 0.001); the KTRs-free group presented an improvement in both T-score and Z-score at LV (p < 0.05) as well as a lower prevalence of osteoporotic cases (21.7% vs. 15.9%); in contrast, no changes were recorded in KTR-treated individuals. In conclusion, supplementation with cholecalciferol ameliorated Z-score and T-score at LV in long-term KTRs who had been never treated with active or inactive vitamin D sterols, bisphosphonates, and calcimimetics. Future endeavours are needed to confirm these preliminary findings.

The "FIFTY SHADOWS" of the RALES Trial: Lessons about the Potential Risk of Dietary Potassium Supplementation in Patients with Chronic Kidney Disease.

Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin-angiotensin-aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of "occult" CKD, HF, and in patients taking RAASis and/or MRAs.

Atrial Fibrillation and Anticoagulant Treatment in End-Stage Renal Disease Patients: Where Do We Stand?

The frequent coexistence in daily clinical practice of chronic kidney disease (CKD) and atrial fibrillation (AF), especially in the elderly, represents a conundrum for physicians, mainly related to the management of anticoagulant therapy. The reduction of estimated glomerular filtration rate (eGFR) impairs anticoagulant clearance, increasing bleeding propensity. Moreover, dysfunctional responses of endothelial cells and inflammatory systems both trigger thromboembolic status. Those mechanisms pose an increased risk of adverse events for AF patients with CKD. While several data suggested the use of direct oral anticoagulants (DOACs) over warfarin as preferred anticoagulant strategy in patients with Stage 3A to Stage 4 CKD (eGFR range of 15-49 mL/min/1.73 m2), less is known about the optimal anticoagulation management in patients with end-stage renal disease (ESRD) or on renal replacement therapy (RRT). Furthermore, a pivotal feature to be considered when choosing the anticoagulant drug in CKD patients is represented by nephroprotective capability. Indeed, anticoagulant therapy with warfarin showed detrimental effects on kidney function, whereas DOACs demonstrated a beneficial effect on renal function preservation. Mounting data showed that, when pharmacological treatment cannot be pursued due to contraindication to anticoagulation, left atrial appendage occlusion (LAAO) may represent a valid alternative. This brief review outlines the current knowledge regarding anticoagulation therapy in ESRD/RRT patients, reporting new lines of evidence on the nephroprotective effect of oral anticoagulants and on the use of LAAO as a non-pharmacological alternative to oral anticoagulation.

Machine learning for prediction of in-hospital mortality in coronavirus disease 2019 patients: results from an Italian multicenter study.

BACKGROUND: Several risk factors have been identified to predict worse outcomes in patients affected by SARS-CoV-2 infection. Machine learning algorithms represent a novel approach to identifying a prediction model with a good discriminatory capacity to be easily used in clinical practice. The aim of this study was to obtain a risk score for in-hospital mortality in patients with coronavirus disease infection (COVID-19) based on a limited number of features collected at hospital admission. METHODS AND RESULTS: We studied an Italian cohort of consecutive adult Caucasian patients with laboratory-confirmed COVID-19 who were hospitalized in 13 cardiology units during Spring 2020. The Lasso procedure was used to select the most relevant covariates. The dataset was randomly divided into a training set containing 80% of the data, used for estimating the model, and a test set with the remaining 20%. A Random Forest modeled in-hospital mortality with the selected set of covariates: its accuracy was measured by means of the ROC curve, obtaining AUC, sensitivity, specificity and related 95% confidence interval (CI). This model was then compared with the one obtained by the Gradient Boosting Machine (GBM) and with logistic regression. Finally, to understand if each model has the same performance in the training and test set, the two AUCs were compared using the DeLong's test. Among 701 patients enrolled (mean age 67.2 ±â€Š13.2 years, 69.5% male individuals), 165 (23.5%) died during a median hospitalization of 15 (IQR, 9-24) days. Variables selected by the Lasso procedure were: age, oxygen saturation, PaO2/FiO2, creatinine clearance and elevated troponin. Compared with those who survived, deceased patients were older, had a lower blood oxygenation, lower creatinine clearance levels and higher prevalence of elevated troponin (all P < 0.001). The best performance out of the samples was provided by Random Forest with an AUC of 0.78 (95% CI: 0.68-0.88) and a sensitivity of 0.88 (95% CI: 0.58-1.00). Moreover, Random Forest was the unique model that provided similar performance in sample and out of sample (DeLong test P = 0.78). CONCLUSION: In a large COVID-19 population, we showed that a customizable machine learning-based score derived from clinical variables is feasible and effective for the prediction of in-hospital mortality.

[Atrial fibrillation, oral anticoagulation and nephroprotection: caution or bravery?]

Atrial fibrillation (AF) and chronic kidney disease (CKD) are strictly related and share several risk factors (i.e. hypertension, diabetes mellitus, congestive heart failure). As consequence, AF is very common among CKD patients, especially in those with end stage renal disease (ESRD). Moreover, patients with AF and advanced kidney disease have a higher mortality rate than patients with preserved renal function due to an increased incidence of stroke and an unpredicted elevated hemorrhagic risk. The adequate long-term oral anticoagulation in this subgroup of patients represents a major challenging issue faced by physicians in clinical practice. Direct oral anticoagulants (DOACs) are currently contraindicated in patients with ESRD while vitamin K antagonists (VKAs) are characterized by a narrow therapeutic window, increased tissue calcification and an unfavorable risk/benefit ratio with low stroke prevention effect and augmented risk of major bleeding. The purpose of this review is to shed light on the applications of DOAC therapy in CKD patients, especially in ESRD patients.

Sex-related differences in patients with coronavirus disease 2019: results of the Cardio-COVID-Italy multicentre study.

INTRODUCTION: The role of sex compared to comorbidities and other prognostic variables in patients with coronavirus disease (COVID-19) is unclear. METHODS: This is a retrospective observational study on patients with COVID-19 infection, referred to 13 cardiology units. The primary objective was to assess the difference in risk of death between the sexes. The secondary objective was to explore sex-based heterogeneity in the association between demographic, clinical and laboratory variables, and patients' risk of death. RESULTS: Seven hundred and one patients were included: 214 (30.5%) women and 487 (69.5%) men. During a median follow-up of 15 days, deaths occurred in 39 (18.2%) women and 126 (25.9%) men. In a multivariable Cox regression model, men had a nonsignificantly higher risk of death vs. women (P = 0.07).The risk of death was more than double in men with a low lymphocytes count as compared with men with a high lymphocytes count [overall survival hazard ratio (OS-HR) 2.56, 95% confidence interval (CI) 1.72-3.81]. In contrast, lymphocytes count was not related to death in women (P = 0.03).Platelets count was associated with better outcome in men (OS-HR for increase of 50 × 103 units: 0.88 95% CI 0.78-1.00) but not in women. The strength of association between higher PaO2/FiO2 ratio and lower risk of death was larger in women (OS-HR for increase of 50 mmHg/%: 0.72, 95% CI 0.59-0.89) vs. men (OS-HR: 0.88, 95% CI 0.80-0.98; P = 0.05). CONCLUSIONS: Patients' sex is a relevant variable that should be taken into account when evaluating risk of death from COVID-19. There is a sex-based heterogeneity in the association between baseline variables and patients' risk of death.

The connubium among diabetes, chronic kidney disease and atrial fibrillation.

The burden of cardiovascular comorbid conditions was significantly higher in patients with atrial fibrillation (AF); most of them are affected by hypertension, chronic kidney disease (CKD) and/or diabetes mellitus (DM). DM represents a well-known risk factor for the development and maintenance of AF; the coexistence of DM and AF is also associated with an increased risk of mortality and stroke. Moreover, DM is currently the main cause of renal impairment and the leading cause of dialysis in the world. The hyperglycemia is responsible for inducing redox imbalance and both systemic and intrarenal inflammation, playing a critical role in the pathogenesis of diabetic kidney disease. Long-term thromboembolic preventive therapy in AF patients with DM and CKD may be more challenging because both DM and CKD have been independently associated with an increased thromboembolic and bleeding risk, which results from the prothrombotic and proinflammatory status. Vitamin K antagonists (VKAs) are characterized by numerous critical issues such as a narrow therapeutic window, increased tissue calcification and an unfavorable risk/benefit ratio with low stroke prevention effect and augmented risk of major bleeding. On the other hand, Direct Oral Anticoagulants (DOACs) are currently contraindicated in dialysis patients even if mounting evidence suggests that they may have a nephroprotective role in AF patients with DM and CKD. Consequently, the choice of anticoagulant therapy in this setting of patient seems to be very challenging. The aim of this review is to investigate the role of DOACs in diabetic patients and its nephroprotective role by reviewing the current literature.

Bone Mineral Density Changes in Long-Term Kidney Transplant Recipients: A Real-Life Cohort Study of Native Vitamin D Supplementation.

Vitamin D insufficiency has been associated with reduced bone mineral density (BMD) in kidney transplant patients (KTRs). However, the efficacy of vitamin D supplementation on BMD remains poorly defined, especially for long-term KTRs. We aimed to investigate the effect of native vitamin D supplementation on the BMD of KTRs during a 2-year follow-up. Demographic, clinical, and laboratory data were collected. BMD was evaluated with standard DEXA that was performed at baseline (before vitamin D supplementation) and at the end of study period. BMD was assessed at lumbar vertebral bodies (LV) and right femoral neck (FN) by a single operator. According to WHO criteria, results were expressed as the T-score (standard deviation (SD) relative to young healthy adults) and Z-score (SD relative to age-matched controls). Osteoporosis and osteopenia were defined as a T-score ≤ -2.5 SD and a T-score < -1 and a > -2.5 SD, respectively. Based on plasma levels, 25-OH-vitamin D (25-OH-D) was supplemented as recommended for the general population. Data from 100 KTRs were analyzed. The mean study period was 27.7 ± 3.4 months. At study inception, 25-OH-D insufficiency and deficiency were recorded in 65 and 35 patients. At the basal DEXA, the percentage of osteopenia and osteoporosis was 43.3% and 18.6% at LV and 54.1% and 12.2% at FN, respectively. At the end of the study, no differences in the Z-score and T-score gains were observed. During linear mixed model analysis, native vitamin D supplementation was found to have a negative nitration with Z-score changes at the right femoral neck in KTRs (p < 0.05). The mean dose of administered cholecalciferol was 13.396 ± 7.537 UI per week; increased 25-OH-D levels were found (p < 0.0001). Either low BMD or 25-OH-vitamin D concentration was observed in long-term KTRs. Prolonged supplementation with 25-OH-D did not modify BMD, Z-score, or T-score.

Combined Role of Troponin and Natriuretic Peptides Measurements in Patients With Covid-19 (from the Cardio-COVID-Italy Multicenter Study).

Data concerning the combined prognostic role of natriuretic peptide (NP) and troponin in patients with COVID-19 are lacking. The aim of the study is to evaluate the combined prognostic value of NPs and troponin in hospitalized COVID-19 patients. From March 1, 2020 to April 9, 2020, consecutive patients with COVID-19 and available data on cardiac biomarkers at admission were recruited. Patients admitted for acute coronary syndrome were excluded. Troponin levels were defined as elevated when greater than the 99th percentile of normal values. NPs were considered elevated if above the limit for ruling in acute heart failure (HF). A total of 341 patients were included in this study, mean age 68 ± 13 years, 72% were men. During a median follow-up period of 14 days, 81 patients (24%) died. In the Cox regression analysis, patients with elevated both NPs and troponin levels had higher risk of death compared with those with normal levels of both (hazard ratio 2.94; 95% confidence interval 1.31 to 6.64; p = 0.009), and this remained significant after adjustment for age, gender, oxygen saturation, HF history, and chronic kidney disease. Interestingly, NPs provided risk stratification also in patients with normal troponin values (hazard ratio 2.86; 95% confidence interval 1.21 to 6.72; p = 0.016 with high NPs levels). These data show the combined prognostic role of troponin and NPs in COVID-19 patients. NPs value may be helpful in identifying patients with a worse prognosis among those with normal troponin values. Further, NPs' cut-point used for diagnosis of acute HF has a predictive role in patients with COVID-19.

Early Neurological ASsessment with pupillometrY during Cardiac Arrest REsuscitation (EASY-CARE): protocol for an observational multicentre prospective study.

INTRODUCTION: Out-of-hospital cardiac arrest is burdened with a high rate of ineffective resuscitation and poor neurological outcome among survivors. To date, there are few perfusion assessment tools during cardiopulmonary resuscitation and none of them provide reliable data. Despite the lack of information, physicians must decide whether to extend or terminate resuscitation efforts. METHOD AND ANALYSIS: This is a multicentre prospective, observational cohort study, involving adult patients, victims of unexpected out-of-hospital cardiac arrest. Early Neurological ASsessment with pupillometrY during Cardiac Arrest Resuscitation aims to primarily describe the reliability of quantitative pupillometry through use of the Neurological Pupillary Index (NPi) during the manoeuvre of cardiopulmonary resuscitation, as a predictor of the return of spontaneous circulation. The second objective is to seek and describe the association between the NPi and neurological outcome in the surviving cohort. Patients will be excluded if they are less than 18 years of age, have sustained traumatic brain injury, cerebrovascular emergencies, direct injury to the eyes or have pupil anomalies. Neurological outcome will be collected at intensive care unit discharge, at 30 days, 6 months and at 1 year. The Glasgow Coma Scale (GCS) will be used in the emergency department; modified Rankin Score will be adopted for neurological assessment; biomarkers and neurophysiology exams will be collected as well. ETHICS AND DISSEMINATION: The study has been approved by Ethics Committee of Milano. Local committee acceptance is required for each of the centres involved in the clinical and follow-up data collection. Data will be disseminated to the scientific community through original articles submitted to peer-reviewed journals and abstracts to conferences. TRIAL REGISTRATION NUMBER: NCT05192772.