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Background: Systemic Lupus Erithematosus (SLE) is associated with increased cardiovascular risk and early vascular aging. The aim of the study was to evaluate aortic and carotid stiffness, central blood pressure (BP) and wave reflection in women with SLE, in order to identify whether different vascular districts are similarly influenced by disease duration, activity and organ damage. Methods: Medical and pharmacological history were collected. Disease activity and organ damage were evaluated by ECLAM e SLICC/ACR-DI scores, respectively. Pulse Wave Velocity (PWV) and Augmentation Index (AI) were acquired by applanation tonometry, whereas carotid intima-media thickness (IMT) and stiffness were obtained by an automated image analysis system. Results: 46 SLE women were enrolled (age 41±10years, BP 116±16/76±9 mmHg). Mean disease duration was 17±9years, ECLAM 0,9±1, SLICC 0,9±1,5. PWV(7,4±1,5 m/s) was related to age (r=0.52, p

Aims: Uncertainty exists about defining true iron deficiency (ID) in heart failure (HF) patients. We assessed the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in HF outpatients., Methods and Results: Iron deficiency was defined according to guidelines (G-ID: ferritin <100 ng/ml or ferritin 100-299 ng/ml with transferrin saturation [TSAT] <20%). Alternative ID definitions based on TSAT (<20%), iron (≤13 μmol/L), and ferritin (<100 or < 300 ng/ml) were explored. Relationships with rest/exercise measures of cardiac function and congestion using ultrasound, effort intolerance and adverse outcome (HF hospitalizations or all-cause mortality) were assessed. Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G-ID. Patients with TSAT <20% or G-ID had greater left atrial volume but similar LVEF. Lower TSAT, iron and haemoglobin, but not ferritin, were associated with more signs of congestion by ultrasound. After correcting for multiple clinical variables, including haemoglobin, TSAT was directly associated with peak oxygen uptake (standardized coefficient 0.069, p = 0.041), while ferritin was not. There was no interaction with HF phenotype (HF with preserved vs. reduced LVEF). During a median follow-up of 18 months, TSAT <20% and iron ≤13 μmol/L were associated with worse outcomes in models adjusted for clinical variables, including LVEF and N-terminal pro-B-type natriuretic peptide (hazard ratio 2.48, 95% confidence interval 1.88-3.17 and 1.93, 1.48-2.52, respectively), while G-ID or ferritin <100 or <300 ng/ml were not., Conclusion: In HF outpatients, TSAT <20% is more consistently associated with congestion by ultrasound and poorer functional capacity than other ID definitions, irrespective of LVEF. TSAT <20% and iron ≤13 μmol/L, but not G-ID or ferritin-based ID, predict a worse prognosis in HF outpatients with preserved and reduced LVEF., (© 2024 European Society of Cardiology.)

Quantitative analysis of peptides in biological fluids offers a high diagnostic and prognostic tool to reflect the pathophysiological condition of the patient. Recently, methods based on liquid chromatography coupled with mass spectrometry (LC-MS) for the quantitative determination of intact peptides have been replacing traditionally used ligand-binding assays, which suffer from cross-reactivity issues. The use of "top-down" analysis of peptides is rapidly increasing since it does not undergo incomplete or non-reproducible digestion like "bottom-up" approaches. However, the low abundance of peptides and their peculiar characteristics, as well as the complexity of biological fluids, make their quantification challenging. Herein, the analytical pitfalls that may be encountered during the development of an LC-MS method for the analysis of intact peptides in biological fluids are discussed. Challenges in the pre-analytical phase, stability after sampling and sample processing, significantly impact the accuracy of peptide quantification. Emerging techniques, such as microextractions, are becoming crucial for improved sample cleanup and enrichment of target analytes. A comparison between the roles of high-resolution and low-resolution mass spectrometry in the quantification of intact peptides, as well as the introduction of supercharging reagents to enhance ionization, will be discussed.

In heart failure (HF), congestion is a key pathophysiologic hallmark and a major contributor to morbidity and mortality. However, the presence of congestion is often overlooked in both acute and chronic settings, particularly when it is not clinically evident, which can have important clinical consequences. Ultrasound (US) is a widely available, non-invasive, sensitive tool that might enable clinicians to detect and quantify the presence of (subclinical) congestion in different organs and tissues and guide therapeutic strategies. In particular, left ventricular filling pressures and pulmonary pressures can be estimated using transthoracic echocardiography; extravascular lung water accumulation can be evaluated by lung US; finally, systemic venous congestion can be assessed at the level of the inferior vena cava or internal jugular vein. The Doppler evaluation of renal, hepatic and portal venous flow can provide additional valuable information. This review aims to describe US techniques allowing multi-organ evaluation of congestion, underlining their role in detecting, monitoring, and treating volume overload more objectively., (© 2024. The Author(s).)

Background: Cardiovascular trials have revealed the positive impact of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes (T2D). However, the specific effects of endogenous GLP-1 on arterial stiffness and renal function remain understudied. This study aimed to explore the influence of endogenous GLP-1 response post-bariatric surgery on arterial stiffness and renal haemodynamic., Methods: Thirty individuals with morbid obesity and without T2D, scheduled for Roux-en-Y Gastric Bypass (RYGB), were included. Clinical parameters, 3-hour oral glucose tolerance test (OGTT) with serial sampling for glycaemia, GLP-1 and insulin, carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient (carotid-DC) and renal resistive index (RRI) measurements were conducted pre-surgery and 1-year post-surgery. Participants were categorized into high-response and low-response groups based on their post-surgery increase in GLP-1 (median increase of 104% and 1%, respectively, pre- vs. post-surgery)., Results: Post-surgery, high-response group demonstrated a greater reduction in cf-PWV (p = .033) and a greater increase (p = .043) in carotid DC compared to low-response group. These enhancements were observed independently of weight loss or blood pressure changes. High-response group exhibited a reduction in RRI (p = .034), although this association was influenced by improvement in pulse pressure. Finally, a multivariate stepwise regression analysis indicated that the percentage increase of GLP1, Δ-GLP1 (AUC) %, was the best predictor of percentage decrease in cf-PWV (p = .014)., Conclusions: Elevated endogenous GLP-1 response following RYGB was associated with improved arterial stiffness and renal resistances, suggesting potential cardio-renal benefits. The findings underscore the potential role of endogenous GLP-1 in influencing vascular and renal haemodynamics independent of traditional weight loss., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

We present an innovative, reliable, and antibody-free analytical method to determine multiple intact natriuretic peptides in human plasma. These biomolecules are routinely used to confirm the diagnosis and monitor the evolution of heart failure, so that their determination is essential to improve diagnosis and monitor the efficacy of treatment. However, common immunoassay kits suffer from main limitations due to high cross-reactivity with structurally similar species. In our method, we pre-treated the sample by combining salting-out with ammonium sulfate with microextraction by packed sorbent technique. Analyses were then carried out by ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. The use of 3-nitrobenzyl alcohol as a supercharger reagent enhanced the ESI ionization and improved the signal-to-noise ratio. The analytical protocol showed good linearity over one order of magnitude, recovery in the range of 94-105 %, and good intra- and inter-day reproducibility (RSD<20 %), and the presence of a matrix effect. Limits of detection were in the range of pg/mL for all peptides (0.2-20 pg/mL). Stability study in plasma samples demonstrated that proper protease inhibitors need to be included in blood collection tubes to avoid peptide degradation. Preliminary analyses on plasma samples from heart failure patients allow the quantification of ANP 1-28 as the most abundant species and the detection of ANP 5-28, BNP 1-32, and BNP 5-32. The method could be used to investigate how cross-reactivity issues among structurally similar species impact determinations by ELISA kits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiometabolic diseases (CMDs) are interrelated and multifactorial conditions, including arterial hypertension, type 2 diabetes, heart failure, coronary artery disease, and stroke. Due to the burden of cardiovascular morbidity and mortality associated with CMDs' increasing prevalence, there is a critical need for novel diagnostic and therapeutic strategies in their management. In clinical practice, innovative methods such as epicardial adipose tissue evaluation, ventricular-arterial coupling, and exercise tolerance studies could help to elucidate the multifaceted mechanisms associated with CMDs. Similarly, epigenetic changes involving noncoding RNAs, chromatin modulation, and cellular senescence could represent both novel biomarkers and targets for CMDs. Despite the promising data available, significant challenges remain in translating basic research findings into clinical practice, highlighting the need for further investigation into the complex pathophysiology underlying CMDs.

Aim: Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case-control and regression analyses., Methods: Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography-cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO 2peak ) normalized for fat-free mass (FFM)., Results: In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m 2 , p = .0003) but comparable FFM. Patients with T2D achieved lower VO 2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p = .0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO 2peakFFM , T2D still displayed reduced VO 2peak by 1.0 (-1.7/-0.3) ml/min/kg FFM , p = .0089, while the effect of BMI [-0.2 (-0.3/0.1) ml/min/kg FFM , p = .06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency., Conclusions: T2D is an independent negative determinant of VO 2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: Obesity is a well-established risk factor for kidney disease, and tubular damage can play a pivotal role in the development of obesity-related kidney damage. This study aimed to investigate the pathophysiological pathways involved in the development of non-albumin proteinuria (NAP), a marker of tubular involvement, in a cohort of subjects with severe obesity and preserved kidney function., Methods: A total of 106 subjects with BMI ≥ 35 kg/m 2 in waiting list for bariatric surgery underwent blood chemistry analysis including metabolic and lipid profile, vascular tests for cardiovascular risk stratification and a comprehensive assessment of kidney function, including renal resistive index (RRI) and NAP measurement., Results: Nineteen patients with ACR ≥ 30 mg/g regardless of NAP values (ALB+), nineteen with NAP≥ 150 mg/g and albuminuria < 30 mg/g (iNAP) and sixty-eight without proteinuria (No-P) were found. Both ALB+ and iNAP groups exhibited a higher prevalence of hypertension and anti-hypertensive treatment compared to No-P, while the prevalence of diabetes was similar between groups. Concerning lipid profile, no differences in total, HDL and LDL cholesterol were found, while ALB+ patients had higher serum triglyceride levels than the other two groups. RRI and carotid-femoral pulse wave velocity (cf-PWV) was significantly higher in ALB+ and iNAP groups compared to No-P. Remarkably, cf-PWV remained still significant after adjustment for age, sex and MBP (p = 0.0004). In overall population, a multiple regression analysis showed that cf-PWV was an independent determinant of NAP in a model including age, sex, glycated hemoglobin, systolic and mean blood pressure (R 2 =0.17, p = 0.031)., Conclusion: iNAP subjects showed increased arterial stiffness comparable to that observed in ALB+ group, suggesting that they may represent a subgroup at higher cardiovascular risk, often unrecognized in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background : We evaluated the bio-humoral and non-invasive haemodynamic correlates of renal congestion evaluated by Doppler renal venous flow (RVF) across the heart failure (HF) spectrum, from asymptomatic subjects with cardiovascular risk factors (Stage A) and structural heart disease (Stage B) to patients with clinically overt HF (Stage C). Methods : Ultrasound evaluation, including echocardiography, lung ultrasound and RVF, along with blood and urine sampling, was performed in 304 patients. Results : Continuous RVF was observed in 230 patients (76%), while discontinuous RVF (dRVF) was observed in 74 (24%): 39 patients had pulsatile RVF, 18 had biphasic RVF and 17 had monophasic RVF. Stage C HF was significantly more common among patients with dRVF. Monophasic RVF was associated with worse renal function and a higher urinary albumin-to-creatinine ratio (uACR). After adjusting for hypertension, diabetes mellitus, the presence of Stage C HF and serum creatinine levels, worsening RVF patterns were associated with higher NT-proBNP levels, worse right ventricular-arterial coupling, larger inferior vena cava and higher echo-derived pulmonary artery wedge pressure. This trend was confirmed when only patients with HF Stage C were analysed after adjusting for the left ventricle ejection fraction (LVEF). Conclusion : Abnormal RVF is common across the HF spectrum. Worsening RVF patterns are independently associated with increased congestion, worse non-invasive haemodynamics and impaired RV-arterial coupling. RVF evaluation could refine prognostic stratification across the HF spectrum, irrespective of LVEF.

Exercise intolerance is a prominent feature of several cardiovascular conditions. However, the physical effort requires the intertwined adaptation of several factors, namely the cardiovascular system, the lungs, and peripheral muscles. Several abnormalities in each domain may be present in a given patient. Cardiopulmonary exercise testing (CPET) has been used to investigate metabolic and ventilatory alterations responsible for exercise intolerance but does not allow for direct evaluation of cardiovascular function. However, this can readily be obtained by concomitant exercise-stress echocardiography (ESE). The combined CPET-ESE approach allows for precise and thorough phenotyping of the pathophysiologic mechanisms underpinning exercise intolerance. Thus, it can be used to refine the diagnostic workup of patients with dyspnoea of unknown origin, as well as improve risk stratification and potentially guide the therapeutic approach in specific conditions, including left and right heart failure or valvular heart disease. However, given its hitherto sporadic use, both the conceptual and technical aspects of CPET-ESE are often poorly known by the clinician. Improving knowledge in this field could significantly aid in anticipating individual disease trajectories and tailoring treatment strategies accordingly. Therefore, we designed this review to revise the pathophysiologic correlates of exercise intolerance, the practical principles of the combined CPET-ESE examination, and its main applications according to current literature., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

This paper describes the AEOLUS pilot study which combines breath analysis with cardiopulmonary exercise testing (CPET) and an echocardiographic examination for monitoring heart failure (HF) patients. Ten consecutive patients with a prior clinical diagnosis of HF with reduced left ventricular ejection fraction were prospectively enrolled together with 15 control patients with cardiovascular risk factors, including hypertension, type II diabetes or chronic ischemic heart disease. Breath samples were collected at rest and during CPET coupled with exercise stress echocardiography (CPET-ESE) protocol by means of needle trap micro-extraction and were analyzed through gas-chromatography coupled with mass spectrometry. The protocol also involved using of a selected ion flow tube mass spectrometer for a breath-by-breath isoprene and acetone analysis during exercise. At rest, HF patients showed increased breath levels of acetone and pentane, which are related to altered oxidation of fatty acids and oxidative stress, respectively. A significant positive correlation was observed between acetone and the gold standard biomarker NT-proBNP in plasma ( r = 0.646, p < 0.001), both measured at rest. During exercise, some exhaled volatiles (e.g., isoprene) mirrored ventilatory and/or hemodynamic adaptation, whereas others (e.g., sulfide compounds and 3-hydroxy-2-butanone) depended on their origin. At peak effort, acetone levels in HF patients differed significantly from those of the control group, suggesting an altered myocardial and systemic metabolic adaptation to exercise for HF patients. These preliminary data suggest that concomitant acquisition of CPET-ESE and breath analysis is feasible and might provide additional clinical information on the metabolic maladaptation of HF patients to exercise. Such information may refine the identification of patients at higher risk of disease worsening., (Creative Commons Attribution license.)

Aims: Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE., Methods and Results: We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A-B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36-0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30-0.63) was similar to controls (0.43, 0.35-0.57) but significantly lower than Stages A-B (0.61, 0.47-0.75) and HFpEF (0.63, 0.42-0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF., Conclusion: A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A-B and HFpEF., (© 2023 European Society of Cardiology.)

Aims: We explored multiple cardiometabolic patterns, including inflammatory and congestive pathways, in patients with heart failure (HF)., Methods and Results: We enrolled 270 HF patients with reduced (<50%, HFrEF; n = 96) and preserved (≥50%, HFpEF; n = 174) ejection fraction. In HFpEF, glycated hemoglobin (Hb1Ac) seemed to be relevant in its relationship with inflammation as Hb1Ac positively correlated with high-sensitivity C-reactive protein (hs-CRP; Spearman's rank correlation coefficient ρ = 0.180, p < 0.05). In HFrEF, we found a correlation between Hb1Ac and norepinephrine (ρ = 0.207, p < 0.05). In HFpEF, we found a positive correlation between Hb1Ac and congestion expressed as pulmonary B lines (ρ = 0.187, p < 0.05); the inverse correlation, although not significant, was found in HFrEF between Hb1Ac and N-terminal pro-B-type natriuretic peptide (ρ = 0.079) and between Hb1Ac and B lines (ρ = -0.051). In HFrEF, we found a positive correlation between E/e' ratio and Hb1Ac (ρ = 0.203, p < 0.05) and a negative correlation between tricuspid annular systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (sPAP) (TAPSE/sPAP ratio) (ρ = -0.205, p < 0.05) and Hb1Ac. In HFpEF, we found a negative correlation between TAPSE/sPAP ratio and uric acid (ρ = -0.216, p < 0.05)., Conclusion: In HF patients, HFpEF and HFrEF phenotypes are characterized by different cardiometabolic indices related to distinct inflammatory and congestive pathways. Patients with HFpEF showed an important relationship between inflammatory and cardiometabolic parameters. Conversely, in HFrEF, there is a significant relationship between congestion and inflammation, while cardiometabolism appears not to influence inflammation, instead affecting sympathetic hyperactivation.

Background and Aims: Although many studies have been published on the effect of obesity on large and small arteries, there are no data in the literature regarding the effect of obesity on medium-sized arteries, and in particular of small conduit arteries. The aim of the present study was to investigate whether patients with severe obesity presented structural or functional alterations in different arterial segments., Methods and Results: 34 patients with severe obesity (BMI≥35 kg/m 2 ) and 34 age-and sex-matched normal weight patients were recruited as controls. Aortic stiffness (carotid-femoral pulse wave velocity) and wave reflection (augmentation index) were recorded. Ultrasound images of common carotid, radial and interdigital arteries were acquired for the assessment of wall-to-lumen ratio, wall cross-sectional area (WCSA), compliance, distensibility coefficient (DC) and Young's elastic modulus (Einc). Insulin sensitivity was calculated by oral glucose sensitivity index (OGIS). No differences between groups in carotid artery remodeling were found, while WCSA of the radial and interdigital arteries were higher in obese group than in controls. As regard the parameters of vascular elasticity, the DC of radial and interdigital arteries were lower (p = 0.025 and p = 0.001, respectively), as well as the Einc of radial arteries was higher (p = 0.021), in subject with obesity compared to controls. All these correlations were consistent after adjustment for the main covariates. Finally, in a multiple regression analysis OGIS was and independent determinant of interdigital artery DC (R 2  = 0.29, p = 0.001)., Conclusions: For the first time, we describe an outward remodeling and increased stiffness in small conduit arteries in severe obesity., Competing Interests: Declaration of competing interest The authors declare no competing interests. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Ventricular-arterial coupling (VAC) can be evaluated as the ratio between arterial stiffness (pulsed wave velocity [PWV]) and myocardial deformation (global longitudinal strain [GLS])., Objectives: This study aimed to evaluate VAC across the spectrum of heart failure (HF)., Methods: The authors introduced a Doppler-derived, single-beat technique to estimate aortic arch PWV (aa-PWV) in addition to tonometry-derived carotid-femoral PWV (cf-PWV). They measured PWVs and GLS in 155 healthy controls, 75 subjects at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 236 patients in stage C heart failure with preserved ejection fraction (HFpEF) (n = 104) or heart failure with reduced ejection fraction (HFrEF) (n = 132). They evaluated peak oxygen consumption and peripheral extraction using combined cardiopulmonary-echocardiography exercise stress., Results: aa-PWV was obtainable in all subjects and significantly lower than cf-PWV in all subgroups (P < 0.01). PWVs were directly related and increased with age (all P < 0.0001). cf-PWV/GLS was similarly compromised in HFrEF (1.09 ± 0.35) and HFpEF (1.05 ± 0.21), whereas aa-PWV/GLS was more impaired in HFpEF (0.70 ± 0.10) than HFrEF (0.61 ± 0.14; P < 0.01). Stage A-B had values of cf-PWV/GLS and aa-PWV/GLS (0.67 ± 0.27 and 0.48 ± 0.14, respectively) higher than controls (0.46 ± 0.11 and 0.39 ± 0.10, respectively) but lower than stage C (all P < 0.01). Peak arteriovenous oxygen difference (AVO 2 diff) was inversely related with cf-PWV/GLS and aa-PWV/GLS (all P < 0.01). Although cf-PWV/GLS and aa-PWV/GLS independently predicted peak VO 2 in the overall population (adjusted R 2  = 0.33 and R 2 = 0.36; all P < 0.0001), only aa-PWV/GLS was independently associated with flow reserve during exercise (R 2  = 0.52; P < 0.0001)., Conclusions: Abnormal VAC is directly correlated with greater severity of HF and worse functional capacity. HFpEF shows a worse VAC than HFrEF when expressed by aa-PWV/GLS., Competing Interests: Funding Support And Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a complex clinical syndrome characterized by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalization is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterization of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and hemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography [ESE]). The purpose of this narrative review was to summarize the potential advantages of using an integrated CPET-ESE evaluation in the characterization of both subjects at risk of developing HF and patients with stable HF.

The COVID-19 pandemic is causing unprecedented damage to our society and economy, globally impacting progress towards the SDGs. The integrated perspective that Agenda 2030 calls for is ever more important for understanding the vulnerability of our eco-socio-economic systems and for designing policies for enhanced resilience. Since the emergence of COVID-19, countries and international institutions have strengthened their monitoring systems to produce timely data on infections, fostering data-driven decision-making often without the support of systemic-based simulation models. Evidence from the initial phases of the pandemic indicates that countries that were able to implement effective policies before the number of cases grew large (e.g. Australia) managed to contain COVID-19 to a much greater extent than others. We argue that prior systemic knowledge of a phenomenon provides the essential information to correctly interpret data, develop a better understanding of the emerging behavioural patterns and potentially develop early qualitative awareness of how to react promptly in the early phases of destructive phenomena, eventually providing the ground for building more effective simulation models capable of better anticipating the effects of policies. This is even more important as, on its path to 2030, humanity will face other challenges of similar dynamic nature. Chief among these is Climate Change. In this paper, we show how a Systems Thinking and System Dynamics modelling approach is useful for developing a better understanding of these and other issues, and how systemic lessons learned from the COVID-19 case can help decision makers anticipate the destructive dynamics of Climate Change by improving perceptions of the potential impacts of reinforcing feedback and delays, ultimately leading to more timely interventions to achieve the SDGs and mitigate Climate Change risks., (© 2022 Elsevier Ltd. All rights reserved.)

Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide. Haemodynamic abnormalities, longstanding neurohormonal and inflammatory activation, which are commonly observed in patients with AH, promote cardiac structural remodeling ultimately leading to heart failure (HF) if blood pressure values remain uncontrolled. While several epidemiological studies have confirmed the strong link between AH and HF, the pathophysiological processes underlying this transition remain largely unclear. The combined cardiopulmonary-echocardiography stress test (CPET-ESE) represents a precious non-invasive aid to detect alterations in patients at the earliest stages of HF. The opportunity to study the response of the cardiovascular system to exercise, and to differentiate central from peripheral cardiovascular maladaptations, makes the CPET-ESE an ideal technique to gain insights into the mechanisms involved in the transition from AH to HF, by recognizing alterations that might be silent at rest but influence the response to exercise. Identifications of these subclinical alterations might allow for a better risk stratification in hypertensive patients, facilitating the recognition of those at higher risk of evolution towards established HF. This may also lead to the development of novel preventive strategies and help tailor medical treatment. The purpose of this review is to summarise the potential advantages of using CPET-ESE in the characterisation of hypertensive patients in the cardiovascular continuum., (© 2022. The Author(s).)

Objective: The objective of this work was to investigate technical validation and usability of an innovative, technically simple, easy-to-use, and portable integrated system to assess carotid function and structure by ultrasound., Methods: The studied system integrated a hardware (the Interson SP-L01 embedded ultrasound probe [Interson, Pleasanton, CA, USA]) and a software measuring the instantaneous diameter of the carotid artery in real-time from B-mode ultrasound image sequences (Carotid Studio, by Quipu Srl [Pisa, Italy]). Technical validation was evaluated by intra-operator reproducibility of two measurements acquired by an expert operator, and agreement with state-of-the-art technique (Mylab25 by Esaote SpA [Genova, Italy], Carotid Studio 4.3 by Quipu Srl) was evaluated in laboratory settings in 12 healthy volunteers; usability of the portable integrated system was investigated by administering questionnaires to users and the results were reported with scores based on a five-point scale., Results: Twelve (12) healthy volunteers (five men, mean age 44.5±13.6 years, free of cardiovascular disease or risk factors), were recruited. Agreement with state-of-the-art technique was satisfactory, with no significant bias. Coefficient of variation (intra-operator reproducibility) was 3.2% (2.5% SD) for intima-media thickness, 0.9% (0.7% SD) for diameter, and 2.5% (2.2% SD) for distension. Usability questionnaires showed an overall positive judgement of the integrated system with respect to the traditional one, obtaining an average score greater than 4 (on a five-point scale)., Conclusions: A portable, innovative prototype to easily assess ultrasound carotid parameters of vascular ageing was successfully designed, developed, and demonstrated to be comparable with state-of-the art technique. Usability was also satisfactory., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Introduction  High-fidelity team-based simulation has been identified as an effective way of teaching and evaluating both technical and nontechnical skills. Several studies have described the benefits of this modality in a variety of acute care settings, but a lack of standardized methodologies has resulted in heterogeneous findings. Few studies have characterized high fidelity simulation across a broad range of acute care settings and integrated the latest evidence on its educational and patient impact. Methods  The MEDLINE, EMBASE, Cochrane Library, and PsycINFO databases were searched for empirical studies from the last 10 years, investigating high fidelity team-based simulation in surgical, trauma, and critical care training curricula. Results  Seventeen studies were included. Interventions and evaluations were comprehensively characterized for each study and were discussed in the context of four overarching acute care settings: the emergency department/trauma bay, the operating room, the intensive care unit, and inpatient ad hoc resuscitation teams. Conclusions  The use of high-fidelity team-based simulation has expanded in acute care and is feasible and effective in a wide variety of specialized acute settings, including the emergency department/trauma bay, the operating room, the intensive care unit, and inpatient ad hoc resuscitation teams. Training programs have evolved to emphasize team-based, multidisciplinary education models and are often conducted in situ to maximize authenticity. In situ simulations have also provided the opportunity for system-level improvement and discussions of complex topics such as social hierarchy. There is limited evidence supporting the impact of simulation on patient outcomes, sustainability of simulation efforts, or cost-effectiveness of training programs. These areas warrant further research now that the scope of utilization across acute care settings has been characterized.

Objective: The objective of the study is to investigate in the hypertensive population the possible differential association between increased aortic and/or carotid stiffness and organ damage in multiple districts, such as the kidney, the vessels, and the heart., Methods: In 314 essential hypertensive patients, carotid-femoral pulse wave velocity (cfPWV, by applanation tonometry) and carotid stiffness (from ultrasound images analysis), together with left ventricular hypertrophy, carotid intima-media thickness, urinary albumin-creatinin ratio, and glomerular filtration rate were measured. Increased cfPWV and carotid stiffness were defined according to either international reference values or the 90th percentile of a local control group (110 age and sex-matched healthy individuals)., Results: When considering the 90th percentile of a local control group, increased cfPWV was associated with reduced glomerular filtration rate, either when carotid stiffness was increased [odds ratio (OR) 13.27 (confidence limits (CL) 95% 3.86-45.58)] or not [OR 7.39 (CL95% 2.25-24.28)], whereas increased carotid stiffness was associated with left ventricular hypertrophy, either when cfPWV was increased [OR 2.86 (CL95% 1.15-7.09)] or not [OR 2.81 (CL95% 1.13-6.97)]. No association between increased cfPWV or carotid stiffness and target organ damage was found when cutoffs obtained by international reference values were used. The concomitance of both increased cfPWV and carotid stiffness did not have an additive effect on organ damage., Conclusion: Aortic and carotid stiffness are differentially associated with target organ damage in hypertensive patients. Regional arterial stiffness as assessed by cfPWV is associated with renal organ damage and local carotid stiffness with cardiac organ damage.

This pilot study evaluated the predictive value of flow-mediated dilation (FMD) for damage accrual in a cohort of SLE patients. Thirty-eight female SLE patients without cardiovascular involvement were enrolled. Clinical history, traditional cardiovascular risk factors, laboratory parameters, disease activity and damage and brachial artery FMD were collected at study entry and after a mean follow-up of 4.5 years. At enrollment, 18 patients (47%) presented active disease; mean FMD was 7.9 ± 3.1%, with no statistically significant differences between women with active and inactive disease. During the follow-up, 3 patients died and 14 accrued organ damage. Baseline FMD did not predict death and damage accrual. FMD showed significant decline over time, which was greater in patients with poor outcome (-3.9% vs -1.9%, p = 0.03). In conclusion, in a cohort of SLE patients, baseline FMD was not predictive of damage accrual. However, the latter was associated with progressive loss of FMD., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Nested stromal-epithelial tumours (NSETs) of the liver have been reported to be extremely unusual primary hepatic neoplasms. To date, few cases have been described in the literature. NSETs have been defined as non-hepatocytic and non-biliary tumours of the liver consisting of nests of epithelial and spindled cells, myofibroblastic stroma and variable intralesional calcification and ossification. Here, we report a case of a young female who underwent liver resection for a large hepatic lesion that proved to be a calcifying NSET on pathological examination. Details about the clinical and histopathological features of the tumour are reported.

Objective: Arterial stiffening has harmful effects; peripheral pulse wave reflections deleteriously increase central pressure, but on the contrary they could also possibly be protective, as the pulse is transmitted to the microcirculation to a lesser extent. The aim of this study was, therefore, to explore the relationship between wave reflection and small vessel damage in the kidney., Methods: In 216 hypertensive patients, data on renal resistive index, obtained by Doppler ultrasound sampling of the interlobar arteries, as well as augmentation index (AIx) and carotid-to-femoral pulse wave velocity (PWV), were retrospectively analyzed. Reflection magnitude was computed through a triangular flow estimate., Results: AIx and reflection magnitude were positively correlated with resistive index; age, BMI, central pulse pressure, and cholesterol, but not AIx or reflection magnitude, were predictors of resistive index in multivariate analyses. Crossing tertiles of PWV and AIx, resistive index did not differ between patients with high AIx and low PWV (n=25; 0.632 (0.064)) and those with low AIx and high PWV (n=17; 0.645 (0.053)), despite a difference in reflection magnitude (74.9 (6.7) vs. 51.2 (7.3)%; P<0.001)., Conclusion: Pressure wave reflection is positively correlated with resistive index in a hypertensive population. No negative relationship was found even adjusting for confounders or when it was examined separately from the influence of arterial stiffness. These findings do not support the hypothesis of peripheral wave reflections having a significant protective role for the microcirculation of a low resistance vascular bed such as the kidney.

Ultrasound assessment of vascular biomarkers has been implemented for screening, prevention and improvement of cardiovascular risk stratification beyond classical risk factors including smoking, diabetes, hypercholesterolemia and hypertension. Thus, the presence of vascular damage at the sub-clinical, asymptomatic stages can identify a "vulnerable" patient, and aid in implementing cardiovascular prevention strategies. Increased intima-media thickness of the common carotid artery is a well-known marker of early atherosclerosis, which significantly correlates with the development of coronary or cerebro-vascular disease. More recently, guidelines for cardiovascular prevention in hypertension also introduced other vascular parameters evaluating both mechanical and functional arterial properties of peripheral arteries. Increased arterial stiffness, which can be detected by ultrasound at the common carotid, has been shown to predict future cardiovascular events and it is already considered a subclinical target organ of hypertensive patients. Even earlier vascular abnormalities such as endothelial dysfunction in the peripheral arteries, detected as reduced flow-mediated dilation of the brachial artery by ultrasound, have also been mentioned for their possible clinical use in the future. This manuscript reviews clinical evidence supporting the use of these different vascular markers for cardiovascular risk stratification, focusing on the need for an accurate, robust and reliable methodology for the assessment of vascular markers, which could improve their predictive value and increase their use in routine clinical practice.

In most patients with an atrial septal defect or patent foramen ovale, a single defect of the interatrial septum may be closed with a single device. However, patients with multiple defects of the interatrial septum may require the use of multiple devices, which involves some technical challenges. We present 5 cases requiring 2 closure devices with clinical and echocardiographic follow up ranging from 3 months to 4 years, demonstrating a high success and low complication rates.