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Abstract The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51–61] years and body mass index 30 [26–36]kg/m2 completed the study. The median nocturnal HR was 65 [60–69] bpm at baseline and increased to 69 [64–77] bpm on reb-oxy vs 66 [59–70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function.

Introduction Chronic mountain sickness (CMS) is a condition characterized by excessive erythrocytosis in response to chronic hypobaric hypoxia. CMS frequently triggers cardiorespiratory diseases such as pulmonary hypertension and right or left heart failure. Ambient hypoxia might be further amplified night-time by intermittent hypoxia related to sleep-disordered breathing (SDB) so that sleep disturbance may be an important feature of CMS. Our aim was to characterize in a cross-sectional study nocturnal hypoxaemia, SDB, blood pressure (BP), arterial stiffness and carotid intima-media thickness (CIMT) in highlanders living at extreme altitude.Methods Men aged 18 to 55 years were prospectively recruited. Home sleep apnoea test, questionnaires (short-form health survey; Montreal cognitive assessment; Pittsburgh Sleep Questionnaire Index and the Insomnia severity index), 24-h ambulatory BP monitoring, CIMT and arterial stiffness were evaluated in 3 groups: i) Andean lowlanders (sea-level); ii) highlanders living at 3,800 m and iii) highlanders living at 5,100 m. Analyses were conducted in sub-groups according to 1) CMS severity 2) healthy subjects living at the three different altitude.Results Ninety-two males were evaluated at their living altitudes. Among the 54 highlanders living at 5,100 m, subjects with CMS showed lower mean nocturnal oxygen saturation (SpO2), SpO2 nadir, lower pulse wave velocity and higher nocturnal BP variability than those with no-CMS. Lower nocturnal SpO2 nadir was associated with higher CMS severity (ß= −0.14, p=.009). Among the 55 healthy subjects, healthy highlanders at 5,100 m were characterized by lower scores on quality of life and sleep quality scales and lower mean SpO2 compared to lowlanders.Conclusions Lower nocturnal SpO2 and higher nocturnal BP variability are associated with CMS severity in individuals living permanently at high altitude. The role of lower SpO2 and higher nocturnal BP variability in the cardiovascular progression of CMS and in the overall prognosis of the disease need to be evaluated in further studies.

Abstract Aims Exercise right heart catheterization (RHC) is considered the gold‐standard test to diagnose heart failure with preserved ejection fraction (HFpEF). However, exercise RHC is an insufficiently standardized technique, and current haemodynamic thresholds to define HFpEF are not universally accepted. We sought to describe the exercise haemodynamics profile of HFpEF cohorts reported in literature, as compared with control subjects. Methods and results We performed a systematic literature review until December 2020. Studies reporting pulmonary artery wedge pressure (PAWP) at rest and peak exercise were extracted. Summary estimates of all haemodynamic variables were evaluated, stratified according to body position (supine/upright exercise). The PAWP/cardiac output (CO) slope during exercise was extrapolated. Twenty‐seven studies were identified, providing data for 2180 HFpEF patients and 682 controls. At peak exercise, patients with HFpEF achieved higher PAWP (30 [29–31] vs. 16 [15–17] mmHg, P

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841.

IntroductionDifferent approaches, involving different areas and figures, are useful for the rehabilitation of obese subjects through a multidisciplinary hospital path. A focal point of rehabilitation is represented by education on healthy eating by increasing the dietary knowledge patients. Few tools investigating food knowledge are available in Italy: therefore, the need has emerged to develop easy-to-use tools for clinical practice that allow to detect food knowledge to set up a more targeted food re-education. The following work aimed at building and validating a questionnaire capable of investigating the dietary knowledge of the population affected by obesity.MethodsA pool of experts carried out a review of the literature, gathering all the information necessary to select and construct the best set of questions and the format of the final project of the questionnaire. During statistical analysis the validity, reproducibility and stability of the questionnaire were investigate in a sample of 450 subjects with obesity.ResultsEarly analysis disclosed that 5 questions of the original questionnaire had no discriminating power. The successive validation phases were successful, confirming good content validity, stability and reproducibility over time.DiscussionThe questionnaire has all the characteristics to be considered a valid tool for investigating dietary knowledge in the obese population. The psychometric tests confirmed a good internal consistency of the structure, a validity of the content, a good reproducibility and stability over time.

IntroductionPrader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS.MethodsIn this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects.ResultsWaist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all).DiscussionOur results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.

BackgroundBoth secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problems in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified.AimTo explore the impact of STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF.MethodsWe analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age-, sex-, and body mass index (BMI)- matched HFpEF patients with mild or no STR (HFpEF-controls).ResultsTwelve HFpEF with atrial-STR (mean age 72 years, 92% females, BMI 28 Kg/m2) and 12 HFpEF-controls patients were analyzed. HFpEF-STR had higher (p < 0.01) right atrial pressure than HFpEF-controls both at rest (10 ± 1 vs. 5 ± 1 mmHg) and during exercise (23 ± 2 vs. 14 ± 2 mmHg). Despite higher pulmonary artery wedge pressure (PAWP) at rest in HFpEF-STR than in HFpEF-controls (17 ± 2 vs. 11 ± 2, p = 0.04), PAWP at peak exercise was no more different (28 ± 2 vs. 29 ± 2). Left ventricular transmural pressure and cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value < 0.05). This latter was due to lower stroke volume (SV) values both at rest (48 ± 9 vs. 77 ± 9 mL, p < 0.05) and at peak exercise (54 ± 10 vs. 93 ± 10 mL, p < 0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p < 0.01). We found an inverse relationship between pulmonary vascular resistance and SV, both at rest and at peak exercise (R2 = 0.12 and 0.19, respectively).ConclusionsSevere STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, undermining the typical HFpEF pathophysiology.

Abstract Pulmonary hypertension (PH) is associated with a poor prognosis in left heart disease (LHD). We sought to provide an updated analysis on the association of hemodynamic variables, such as pulmonary vascular resistance (PVR), pulmonary artery compliance (PAC), and diastolic pressure gradient (DPG), with prognosis in PH‐LHD, through a systematic literature review. Sixteen articles were identified, including 9600 patients with LHD, heterogeneous in terms of age, sex, and etiology of cardiac disease. In this large population, PVR (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.05−1.0), DPG (HR, 1.02; 95% CI: 1.01−1.02) and PAC (HR, 0.76; 95% CI: 0.69−0.84) were associated with an increased risk of adverse outcome, albeit with a less solid performance of DPG. Similar results were found when hemodynamic variables were analyzed according to the thresholds commonly applied in clinical practice, or subdividing cohorts according to the underlying LHD. Furthermore, cumulative metanalysis indicated that these results are consistently stable since 2018. Thus, PVR, DPG and PAC have an established prognostic value in PH‐LHD. These results are consistent through the years and unlikely to change with further studies.

Background We assessed the reliability and feasibility of blood pressure (BP) measurements by means of a new wearable watch‐type BP monitor (HeartGuide) in detecting episodes of hypotensive (pre)syncope induced by tilt table test. Methods and Results An intrapatient comparison between systolic BP (SBP) measured by means of the HeartGuide device and noninvasive finger beat‐to‐beat BP monitoring was undertaken both at baseline in supine position and repeatedly during tilt table test in patients evaluated for reflex syncope. Intrapatient fall of systolic BP from baseline was measured. Eighty‐one patients (mean age, 61±19 years; 46 women) were included. Overall, HeartGuide was able to yield BP values at the time of BP nadir in 58 (72%) patients (average HeartGuide SBP 102±18 mm Hg, versus finger SBP 101±19 mm Hg). Compared with baseline, the maximum SBP decrease was on average −28.5±27.8 and −30.3±33.9 mm Hg respectively (Lin's concordance correlation coefficient=0.78, r=0.79, P=0.001). In the subgroup of 38 patients with tilt table test induced (pre)syncope, the average HeartGuide SBP during symptoms was 97±16 mm Hg, and the finger SBP was 94±18 mm Hg. Compared with baseline, the maximum SBP decrease was on average −35.2±29.3 and −43.3±31.8 mm Hg, respectively (Lin's concordance correlation coefficient=0.83, r=0.87, P=0.001). Conclusions Our data indicate that the HeartGuide BP monitor can detect low BP during presyncope and that its measure of SBP change is consistent with that simultaneously obtained through continuous BP monitoring, despite some intrapatient variability. Thus, this device might be useful in determining the hypotensive nature of spontaneous (pre)syncopal symptoms, a possibility that should be verified by field studies.

Abstract Background Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. Methods We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. Results Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p

Background Long scanning times impede cardiac magnetic resonance (CMR) clinical uptake. A “one‐size‐fits‐all” shortened, focused protocol (eg, only function and late‐gadolinium enhancement) reduces scanning time and costs, but provides less information. We developed 2 question‐driven CMR and stress‐CMR protocols, including tailored advanced tissue characterization, and tested their effectiveness in reducing scanning time while retaining the diagnostic performances of standard protocols. Methods and Results Eighty three consecutive patients with cardiomyopathy or ischemic heart disease underwent the tailored CMR. Each scan consisted of standard cines, late‐gadolinium enhancement imaging, native T1‐mapping, and extracellular volume. Fat/edema modules, right ventricle cine, and in‐line quantitative perfusion mapping were performed as clinically required. Workflow was optimized to avoid gaps. Time target was 30% (CMR: from 42±8 to 28±6 minutes; stress‐CMR: from 50±10 to 34±6 minutes, both P45% of cases. Quality grading was similar between the 2 protocols. Tailored protocols did not require additional staff. Conclusions Tailored CMR and stress‐CMR protocols including advanced tissue characterization are accurate and time‐effective for cardiomyopathies and ischemic heart disease.

Background: Several studies suggest an association between serum 25-hydroxyvitamin D (25OHD) and the outcomes of Severe Acute Respiratory Syndrome Corona-Virus-2 (SARS-CoV-2) infection, in particular Coronavirus Disease-2019 (COVID-19) related severity and mortality. The aim of the present meta-analysis was to investigate whether vitamin D status is associated with the COVID-19 severity, defined as ARDS requiring admission to intensive care unit (ICU) or mortality (primary endpoints) and with the susceptibility to SARS-CoV-2 and COVID-19-related hospitalization (secondary endpoints).Methods: A search in PubMed, ScienceDirect, Web of Science, Google Scholar, Scopus, and preprints repositories was performed until March 31th 2021 to identify all original observational studies reporting association measures, or enough data to calculate them, between Vitamin D status (insufficiency

Background Animal models used to study pathologies requiring rehabilitation therapy, such as cardiovascular and neurologic disorders or oncologic disease, must be as refined and translationally relevant as possible. Sometimes, however, experimental procedures such as those involving restraint may generate undesired effects which may act as a source of bias. However, the extent to which potentially confounding effects derive from such routine procedures is currently unknown. Our study was therefore aimed at exploring possible undesirable effects of acute restraint stress, whereby animals were exposed to a brightly lit enclosed chamber (R&L) similar to those that are commonly used for substance injection. We hypothesised that this would induce a range of unwanted physiological alterations [such as neuroinflammatory response and changes in body weight and in brown adipose tissue (BAT)] and behavioural modification, and that these might be mitigated via the use of non-aversive handling methods: Tunnel Handling (NAH-T) and Mechanoceptive Handling (NAH-M)) as compared to standard Tail Handling (TH). Methods Two indicators of physiological alterations and three potentially stress sensitive behavioural parameters were assessed. Physiological alterations were recorded via body weight changes and assessing the temperature of Brown Adipose Tissue (BAT) using infra-red thermography (IRT), and at the end of the experiment we determined the concentration of cytokines CXCL12 and CCL2 in bone marrow (BM) and activated microglia in the brain. Nest complexity scoring, automated home-cage behaviour analysis (HCS) and Elevated Plus Maze testing (EPM) were used to detect any behavioural alterations. Recordings were made before and after a 15-minute period of R&L in groups of mice handled via TH, NAH-T or NAH-M. Results BAT temperature significantly decreased in all handling groups following R&L regardless of handling method. There was a difference, at the limit of significance (p = 0.06), in CXCL12 BM content among groups. CXCL12 content in BM of NAH-T animals was similar to that found in Sentinels, the less stressed group of animals. After R&L, mice undergoing NAH-T and NAH-M showed improved body-weight maintenance compared to those exposed to TH. Mice handled via NAH-M spent a significantly longer time on the open arms of the EPM. The HCS results showed that in all mice, regardless of handling method, R&L resulted in a significant reduction in walking and rearing, but not in total distance travelled. All mice also groomed more. No difference among the groups was found in Nest Score, in CCL2 BM content or in brain activated microglia. Conclusions Stress induced by a common restraint procedure caused metabolic and behavioural changes that might increase the risk of unexpected bias. In particular, the significant decrease in BAT temperature could affect the important metabolic pathways controlled by this tissue. R&L lowered the normal frequency of walking and rearing, increased grooming and probably carried a risk of low-grade neuro-inflammation. Some of the observed alterations can be mitigated by Non-aversive handlings.

Musculoskeletal and neuromotor fitness (MSMF) is reduced in obesity. Physical exercise (including whole-body vibration exercise [WBVE]) is reported to improve components related to MSMF. The aim of the study is to evaluate the acute effects of WBVE and maximal voluntary contraction (MVC), alone and in combination, on the cardiorespiratory and MSMF in obese adolescents. Eight obese adolescents performed 3 tests (WBVE, MVC, and MVC + WBVE) in different days and randomly. The outcome measures were diastolic blood pressure (DBP), systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO 2 ), handgrip strength (HS), one-leg standing balance (OLSB) test, sit-and-reach (SR) test, stair climbing test (time: T SCT and power: P SCT ), and sit-to-stand test (time: T STS and power: P STS ). No significant changes were observed in SBP, DBP, MAP, and SpO 2 after the 3 tests, only an HR increase being observed after MVC + WBVE ( P < .01) and MVC alone ( P < .05). No significant differences were found in HS, OLSB, T STS , and P STS after the 3 different sessions. An increase in SR was found after MVC + WBVE, MVC, and WBVE ( P < .01, P < .05, and P < .01, respectively), while a decrease in T SCT ( P < .01) and an increase in P SCT were observed only after WBVE ( P < .01). Taking into account the positive WBVE effects on cardiorespiratory and MSMF, WBVE might represent a nonimpact, viable, and safe exercise suitable for obese patients, which need MSMF improvement without overloading joints.

The treatment of obesity requires creating an energy deficit through caloric restriction and physical activity. Energy needs are estimated assessing the resting energy expenditure (REE) that in the clinical practice is estimated using predictive equations. In the present cross sectional study, we compared, in a large cohort of morbidly obese patients, the accuracy of REE predictive equations recommended by current obesity guidelines [Harris-Benedict, WHO/FAO/ONU and Mifflin-St Jeor (MJ)] and/or developed for obese patients (Muller, Muller BC, Lazzer, Lazzer BC), focusing on the effect of comorbidities on the accuracy of the equations. Data on REE measured by indirect calorimetry and body composition were collected in 4,247 obese patients (69% women, mean age 48 ± 19 years, mean BMI 44 ± 7 Kg/m2) admitted to the Istituto Auxologico Italiano from 1999 to 2014. The performance of the equations was assessed in the whole cohort, in 4 groups with 0, 1, 2, or ≥ 3 comorbidities and in a subgroup of 1,598 patients with 1 comorbidity (47.1% hypertension, 16.7% psychiatric disorders, 13.3% binge eating disorders, 6.1% endocrine disorders, 6.4% type 2 diabetes, 3.5% sleep apnoea, 3.1% dyslipidemia, 2.5% coronary disease). In the whole cohort of obese patients, as well as in each stratum of comorbidity number, the MJ equation had the highest performance for agreement measures and bias. The MJ equation had the best performance in obese patients with ≥3 comorbidities (accuracy of 61.1%, bias of −89.87) and in patients with type 2 diabetes and sleep apnoea (accuracy/bias 69%/−19.17 and 66%/−21.67 respectively), who also have the highest levels of measured REE. In conclusion, MJ equation should be preferred to other equations to estimate the energy needs of Caucasian morbidly obese patients when measurement of the REE cannot be performed. As even MJ equation does not precisely predict REE, it should be better to plan the diet intervention by measuring rather than estimating REE. Future studies focusing on the clinical differences that determine the high inter-individual variability of the precision of the REE predictive equations (e.g., on the organ-tissue metabolic rate), could help to develop predictive equations with a better performance.