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The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis, promoting critical structural changes in every component of the cardiovascular system, including the heart and blood vessels. Consequently, the RAAS is a crucial therapeutic target for several chronic diseases of the cardiovascular system, spanning from arterial hypertension (AH) to heart failure (HF). AH represents a leading risk factor for the development of symptomatic HF, particularly with left ventricle (LV) preserved ejection fraction (HFpEF). LV diastolic dysfunction and cardiac remodelling are the first discernible manifestations of heart disease in patients with AH. Typically, AH develops many years before the diagnosis of overt HF, providing a therapeutic target for preventive strategies. Treatment of AH is based on different classes of antihypertensive drugs, which show differences in their capacity to prevent the evolution towards HF. The blockers of the RAAS are effective drugs to treat AH and prevent HF with reduced ejection fraction (HFrEF), but the evidence of the potential benefits in patients with HFpEF remains limited. In this review, the authors summarise data from several clinical trials of HFpEF and HFrEF, focusing on the mechanisms leading the transition from AH to HF and late complications.

Detailed data on clinical presentations and outcomes of children with COVID-19 in Europe are still lacking. In this descriptive study, we report on 130 children with confirmed COVID-19 diagnosed by 28 centers (mostly hospitals), in 10 regions in Italy, during the first months of the pandemic. Among these, 67 (51.5%) had a relative with COVID-19 while 34 (26.2%) had comorbidities, with the most frequent being respiratory, cardiac, or neuromuscular chronic diseases. Overall, 98 (75.4%) had an asymptomatic or mild disease, 11 (8.5%) had moderate disease, 11 (8.5%) had a severe disease, and 9 (6.9%) had a critical presentation with infants below 6 months having significantly increased risk of critical disease severity (OR 5.6, 95% CI 1.3 to 29.1). Seventy-five (57.7%) children were hospitalized, 15 (11.5%) needed some respiratory support, and nine (6.9%) were treated in an intensive care unit. All recovered.Conclusion:This descriptive case series of children with COVID-19, mostly encompassing of cases enrolled at hospital level, suggest that COVID-19 may have a non-negligible rate of severe presentations in selected pediatric populations with a relatively high rates of comorbidities. More studies are needed to further understand the presentation and outcomes of children with COVID-19 in children with special needs.What is Known:• There is limited evidence on the clinical presentation and outcomes of children with COVID-19 in Europe, and almost no evidence on characteristics and risk factors of severe cases.What is New:• Among a case series of 130 children, mostly diagnosed at hospital level, and with a relatively high rate (26.2%) of comorbidities, about three-quarter had an asymptomatic or mild disease.• However, 57.7% were hospitalized, 11.5% needed some respiratory support, and 6.9% were treated in an intensive care unit.

Background Mitochondrial dysfunction is a hallmark of cardiometabolic diseases. Circulating mitochondrial DNA (mtDNA) profiles could refine risk stratification, but current methods do not account for different fractions of circulating mtDNA. We investigated whether patients with type 2 diabetes and/or heart failure (HF) have a specific signature of the total circulating mtDNA profile, including intracellular and cell-free fractions. Methods We performed a complete clinical assessment, including blood tests, 12-lead ECG and ultrasound at rest and during cardiopulmonary exercise. Ultrasound congestion was defined at rest as inferior vena cava of ≥ 21 mm, lung B-lines ≥ 4, or discontinuous renal venous flow. In fasting whole blood and plasma samples collected at rest, we simultaneously measured the copy number of the cellular and cell-free components of mtDNA by real-time quantitative polymerase chain reaction (qPCR) using custom standards. We calculated the ratio of cell mtDNA to cell-free mtDNA as an index of mitochondrial efficiency. Results We enrolled 120 consecutive patients: 50 (42%) with HF and preserved ejection fraction (HFpEF), 40 (33%) with HF and reduced ejection fraction (HFrEF) and 30 (25%) at risk of developing HF; 42/120 (35%) had diabetes. Cell-free mtDNA was increased in patients with HF (with higher levels in HFrEF than HFpEF) and those with diabetes. Cell-free mtDNA was also higher in patients with systemic inflammation (expressed by high-sensitivity C-reactive protein [hs-CRP] ≥ 0.2 mg/dL with neutrophil-lymphocyte ratio [NLR] > 3) and more ultrasound signs of congestion. The cell/cell-free mtDNA ratio showed opposite trends (all p  < 0.05), but there were no significant differences in cell mtDNA. Cell-free mtDNA and mtDNA ratio independently predicted the presence of ≥ 2 ultrasound signs of congestion and effort intolerance (peak oxygen consumption < 16 mL/kg/min) at ROC analysis and using multivariable regressions after adjustment for age, sex, hs-CRP, NLR, high-sensitivity Troponin T and NT-proBNP. Conclusions Patients with HF and diabetes have an altered circulating mtDNA signature characterised by higher cell-free mtDNA and lower mtDNA ratio, whereas cellular mtDNA remains unaffected. Cell-free mtDNA and mtDNA ratio are associated with impaired response to exercise, higher systemic inflammation and increased congestion. Circulating mitochondrial profile could be a new biomarker of mitochondrial status in cardiometabolic diseases. Graphical abstract

Overweight and obesity are major risk factors for heart failure (HF), contributing to its development through metabolic, neurohormonal, haemodynamic, and inflammatory alterations. While overweight/obesity increases the risk of developing HF, its impact on patient outcomes remains complex. The “obesity paradox” suggests that a higher BMI may be associated with improved survival in patients with established HF. However, recent GLP-1 receptor agonist (GLP-1 RA) trials suggest that intentional weight loss positively influences outcomes in overweight/obese patients with HF. This seemingly contradictory evidence highlights the need for a deeper understanding of the mechanisms linking adiposity to HF outcomes. A more precise characterization of adiposity phenotypes using alternative and accurate measures of pathological fat accumulation is crucial in identifying individuals who may benefit most from anti-obesity treatments. In this context, recent research underscores the role of epicardial adipose tissue (EAT) in HF pathophysiology, as it directly influences cardiac function and structure through inflammatory, metabolic, and mechanical effects. This narrative review summarises current evidence on the impact of weight loss on HF outcomes, focusing on recent GLP-1 RA trial results. Additionally, it highlights epidemiological and molecular data supporting EAT as a novel adiposity measure that might allow refining patient selection for pharmacological weight-loss treatments. Finally, it emphasizes the need for future research to identify causal pathways linking alternative measures of visceral fat accumulation to HF outcomes. These efforts will be essential in optimizing the benefits of novel weight-loss treatments, ensuring effective and individualized therapeutic strategies for overweight or obese patients with HF. Graphical abstract

Background Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. Methods db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/  + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. Results rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36 , Acox3 , Pparg , Ncoa3 , and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. Conclusions In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development. Graphical Abstract

Background: The nurse-initiated administration of medications, such as paracetamol and ibuprofen, at the time of triage may provide the opportunity to treat pediatric patients more quickly. We aimed to create practical flowcharts that can be used by all EDs with a specific focus on the nurse-initiated administration of medications to optimize the assessment and management of pain and fever in pediatric patients. Methods: Three regional expert meetings were held with a restricted working group composed of three chairmen and a wider working group composed of Directors of Pediatric EDs and Directors of Pediatric Departments, along with the main regional key experts for child healthcare management. Existing protocols were collected in the main centers belonging to the three regions and a unique recommendation was elaborated by the restricted group. This was then discussed and revised during discussion in a wider group. Results: Two protocols were developed for the triage nurse, one for pain and one for fever present. Both are initiated with assessment of the child’s pain or fever, followed by a caregiver interview to determine eligibility for the administration of an analgesic/antipyretic. In the case of pediatric pain, an analgesic is administered by the nurse only when the pain is rated as 4–6 and in the absence of specific contraindications. For pediatric fever, an antipyretic should only be administered if the child’s temperature is ≥37.5 °C and in the presence of at least 1 sign of discomfort. If an analgesic/antipyretic is administered, patients should be re-assessed after 1 h, and pediatrician evaluation requested as appropriate. Conclusions: The proposed flowcharts for pediatric pain and fever combine stratification by risk and severity and incorporate the possibility for the prompt administration of an antipyretic/analgesic when indicated.

Background Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance (i.e. impaired peak oxygen consumption, or VO 2peak ). In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations. Methods Eighty-eight adults with well-controlled and uncomplicated T2D and no criteria for HF underwent a maximal iCPET with speckle tracking echocardiography, vascular and endothelial function assessment, as well as a comprehensive biohumoral characterization. Effort intolerance was defined by a VO 2peak below 80% of maximal predicted oxygen uptake. Results Forty-eight patients (55%) had effort intolerance reaching a lower VO 2peak than T2D controls (16.5 ± 3.2 mL/min/kg, vs 21.7 ± 5.4 mL/min/kg, p < 0.0001). Despite a comparable cardiac output, patients with effort intolerance showed reduced peak peripheral oxygen extraction (11.3 ± 3.1 vs 12.7 ± 3.3 mL/dL, p = 0.002), lower VO 2 /work slope (9.9 ± 1.2 vs 11.2 ± 1.4, p < 0.0001), impaired left ventricle systolic reserve (peak S’ 13.5 ± 2.8 vs 15.2 ± 3.0, p = 0.009) and global longitudinal strain (peak-rest ΔGLS 1.7 ± 1.5 vs 2.5 ± 1.8, p = 0.03) than subjects with VO 2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups. Conclusions Effort intolerance and reduced VO 2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.

High blood pressure is the leading cause of death and disability globally and an important treatable risk factor for cardiovascular, cerebrovascular and chronic kidney diseases. Digital technology, including mobile health solutions and digital therapy, is expanding rapidly in clinical medicine and has the potential to improve the quality of care and effectiveness of drug treatment by making medical interventions timely, tailored to hypertensive patients' needs and by improving treatment adherence. Thus, the systematic application of digital technologies could support diagnosis and awareness of hypertension and its complications, ultimately leading to improved BP control at the population level. The progressive implementation of digital medicine in the national health systems must be accompanied by the supervision and guidance of health authorities and scientific societies to ensure the correct use of these new technologies with consequent maximization of the potential benefits. The role of scientific societies in relation to the rapid adoption of digital technologies, therefore, should encompass the entire spectrum of activities pertaining to their institutional role: information, training, promotion of research, scientific collaboration and advice, evaluation and validation of technological tools, and collaboration with regulatory and health authorities.

Luteolin exerts beneficial effects against obesity-associated comorbidities, although its influence on vascular dysfunction remains undetermined. We examined the effects of luteolin on endothelial dysfunction in a mouse model of diet-induced obesity. Standard diet (SD) or high-fat diet (HFD)-fed mice were treated daily with luteolin intragastrically. After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, glucose, and triglycerides were evaluated. Endothelium-dependent relaxations of resistance mesenteric vessels was assessed by a concentration-response curve to acetylcholine, repeated upon N -nitro-L-arginine methylester (L-NAME) or ascorbic acid infusion to investigate the influence of nitric oxide (NO) availability and reactive oxygen species (ROS) on endothelial function, respectively. Intravascular ROS production and TNF levels were measured by dihydroethidium dye and ELISA, respectively. Endothelial NO synthase (eNOS) and superoxide dismutase 1 (SOD1), as well as microRNA-214-3p expression were examined by Western blot and RT-PCR assays, respectively. HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to L-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of L-NAME, suggesting a ROS-dependent reduction of NO availability in HFD vessels. Moreover, media-lumen ratio, intravascular superoxide anion and TNF levels were increased, while vascular eNOS, SOD1, and microRNA-214-3p expression were decreased. In HFD mice, luteolin counteracted the increase in body and epididymal fat weight, and metabolic alterations. Luteolin restored vascular endothelial NO availability, normalized the media-lumen ratio, decreased ROS and TNF levels, and normalized eNOS, SOD1 and microRNA-214-3p expression. Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.

IntroductionSerum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis.AimWe assessed the prognostic role of SUA in patients with and without MS.MethodsWe used data from the multicentre Uric Acid Right for Heart Health study and considered cardiovascular mortality (CVM) as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure.ResultsA total of 9589 subjects (median age 58.5 years, 45% males) were included in the analysis, and 5100 (53%) patients had a final diagnosis of MS. After a median follow-up of 142 months, we observed 558 events. Using a previously validated cardiovascular SUA cut-off to predict CVM (> 5.1 mg/dL in women and 5.6 mg/dL in men), elevated SUA levels were significantly associated to a worse outcome in patients with and without MS (all p < 0.0001) and provided a significant net reclassification improvement of 7.1% over the diagnosis of MS for CVM (p = 0.004). Cox regression analyses identified an independent association between SUA and CVM (Hazard Ratio: 1.79 [95% CI, 1.15–2.79]; p < 0.0001) after the adjustment for MS, its single components and renal function. Three specific combinations of the MS components were associated with higher CVM when increasing SUA levels were reported, and systemic hypertension was the only individual component ever-present (all p < 0.0001).ConclusionIncreasing SUA levels are associated with a higher CVM risk irrespective of the presence of MS: a cardiovascular SUA threshold may improve risk stratification.Graphic abstract