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Objective An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data reports suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. Design Retrospective analysis of longitudinal data from a multicentric registry. Methods Auxological, biochemical and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age>10.9 years, Tanner stage≤2) treated with transdermal 17β-oestradiol patches for at least one year. Induction was started at a median dose of 0.14 mcg/kg/day with a six-monthly increase and was considered completed for 49/95 patients who started progesterone with concomitant oestrogen adult dose. Results At the end of induction, the achievement of the complete breast maturation was associated with 17β-oestradiol dose at progesterone introduction. ULD showed a significant correlation with 17β-oestradiol dosage. Final ULD was>65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17β-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. Conclusions Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17β-oestradiol dose and an appropriate clinical response.

We assessed the capability of an integrated multisensory patch-type monitor (RootiRx®) in detecting episodes of reflex (pre)syncope induced by tilt table test (TTT). Firstly, we performed an intrapatient comparison of cuffless systolic blood pressure (SBP), R–R interval (RRI) and variability (power spectrum analysis) obtained by means of the RootiRx® with those obtained with conventional methods (CONV) with validated finger pressure devices at baseline in supine position and repeatedly during TTT in 32 patients affected by likely reflex syncope. Secondly, the LF/HF values obtained with RootiRx® during TTT were analyzed in 50 syncope patients. Compared with baseline supine recordings, during TTT a decrement of median SBP was observed with CONV (−53.5 mmHg) but not with RootiRx® ®(−1 mmHg). Conversely, RRI reduction (CONV: 102 ms; RootiRx®: 127 ms) and RRI Low Frequency/High Frequency powers ratio (LF/HF) increase (CONV: 1.6; RootiRx®: 2.5) were similar. The concordance was good for RRI (0.97 [95% CI 0.96–0.98]) and fair for LF/HF ratio (0.69 [95% CI 0.46-0.83]). During the first 5 min of TTT the LF/HF ratio was higher in patients who later developed syncope than in no-syncope patients. This ratio was significantly different among patients with syncope, presyncope or without symptoms at the time of syncope (p value = 0.02). In conclusion, cuffless RootiRx® was unable to detect rapid drops of SBP occurring during impending reflex syncope and thus cannot be used as a diagnostic tool for hypotensive syncope. On the other hand, RRI mean values and LF/HF power ratios obtained with RootiRx® were consistent with those simultaneously obtained using conventional methods.

Aims: To describe the proportion of patients with syncope among those affected by hypertrophic cardiomyopathy (HCM) and the relevance of syncope as risk factor for sudden cardiac death and life-threatening arrhythmic events. Method and results: Systematic review of original articles that assessed syncope in HCM patients. Literature search of PubMed including all English publications from 1973 to 2021.We found 57 articles for a total of 21.791 patients; of these, 14 studies reported on arrhythmic events in the follow-up. Syncope was reported in 15.8% (3.452 of 21.791) patients. It was considered unexplained in 91% of cases. Life-threatening arrhythmic events occurred in 3.6% of non-syncopal patients and in 7.7% of syncopal patients during a mean follow-up of 5.6 years. A relative risk of 1.99 (95%CI 1.39 to 2.86) was estimated for syncope patients by the random effect model using Haldane continuity correction for 0 events. Conclusions: In the current practice, the cause of syncope remained unexplained in most patients affected by HCM. The management of patients seems mainly driven by risk stratification rather than identification of the aetiology of syncope. There is a need of precise instructions how to apply the recommendations of current guidelines to this disease, which tests are indicated and how to interpret their findings. The protocol was registered in Prospero (ID: 275963).

Purpose:To propose an algorithm of the major and minor diagnostic criteria for macular myopic choroidal neovascularization (mCNV). Methods:This single-center, retrospective, cross-sectional study was based in Istituto Auxologico Italiano, Milan, Italy. Two authors evaluated the clinical and imaging parameters of eyes with high myopia (spherical equivalent of -6D or less) and suspected to have naïve, recurrent, or inactive mCNV. Recordings of the eyes that met the inclusion criteria were then independently evaluated by two other senior retinal specialists. Fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), and OCT angiography were used for multimodal imaging. Results:One-hundred and twenty-two eyes (n = 107; 39 men, 68 women) were included in the study. The mean patient age was 66 years (range, 22-89 years). There were 83 and 39 eyes in the active mCNV and control groups, respectively. The best diagnostic algorithm had positive- and negative-predictive values of 89% and 85%, respectively, and was based on four criteria: leakage/staining on FA, retinal thickening, fuzzy area on SD-OCT, and recent metamorphopsia. When excluding FA-derived findings, retinal pigment epithelium (RPE) features played a diagnostic role in 33 eyes (27%). Twenty-seven eyes with active mCNV (32%) did not have the fuzzy area. Taken singularly, no clinical or imaging parameter had both sensitivity and specificity greater than 78%. Matching of 2 or 3 biomarkers did not yield a sensitivity or specificity greater than 79%. Sensitivities and specificities ≥ 90% were found in ten criteria combinations that included four to five biomarkers. The most frequent were metamorphopsia, fuzzy area, retinal thickening, and leakage. Less frequently, they included hemorrhage, staining, and RPE features such as elevation, flattening, and focal interruption. For all the parameters, the agreement between the investigators was good (Cohen k ≥ 0.66), being the lowest when detecting the ELM interruption within the lesion. Conclusions:A combination of at least four clinical and biological markers yielded the highest positive- and negative-predictive values. More ("major") and less ("minor") frequent diagnostic criteria are proposed.

Background and objective: Obstructive sleep apnea (OSA) is associated with heart derangements detected at echocardiography as higher left ventricular mass index (LVMI), higher left ventricular end-diastolic diameter, lower left ventricular ejection fraction (LVEF), and impaired diastolic function. However, the currently used parameter to define OSA diagnosis and severity, the apnea/hypopnea index (AHI), poorly predicts cardiovascular damage, cardiovascular events, and mortality. Our study aimed to assess if other polygraphic indices of OSA presence and severity, in addition to AHI, might better predict echocardiographic cardiac remodeling. Methods and results: We enrolled two cohorts of individuals referred for suspected OSA to the outpatient facilities of the IRCCS Istituto Auxologico Italiano, Milano, and of the Clinica Medica 3, Padova. All patients underwent home sleep apnea testing and echocardiography. Based on the AHI the cohort was divided into no-OSA (AHI

Background Among patients with heart failure and a preserved left ventricular ejection fraction (HFpEF), a distinct hemodynamic phenotype has been recently described, with potential clinical implication, i.e. latent pulmonary vascular disease (PVD). HFpEF patients with latent PVD have been shown to have worse outcome after creation of an interatrial septal shunt. However, the pathophysiological significance of latent PVD in HFpEF has not been thoroughly investigated. Methods We retrospectively analyzed our cohort of consecutive patients with HFpEF who have undergone a right heart catheterization at rest and during exercise between 2016 and 2020. HFpEF was defined based on a resting and/or exercise hemodynamics: pulmonary artery wedge pressure (PAWP) > 15 mmHg at rest; PAWP during exercise >= 25 mmHg; PAWP/cardiac output (CO) slope > 2 mmHg/L/min. Latent PVD was defined based on exercise pulmonary vascular resistance (PVR) > 1.74 WU. Results Out of 199 exercise right heart catheterization, 86 patients had a hemodynamic diagnosis of HFpEF. Of these, 68 (79%) qualified as HFpEF without PVD (HFpEF-PVR-) and 16 (21%) qualified as latent PVD (HFpEF-PVR+). HFpEF-PVR+ were older, presented more frequently with diabetes mellitus or glucose intolerance, had higher H2FPEF and HFA-PEFF scores, slightly lower LVEF, had more frequently a history of atrial fibrillation and had more frequently at tricuspid regurgitation ≥ moderate (p 2 WU) also at rest (72% vs 10%, p Conclusions HFpEF-PVR+ is associated with peculiar clinical and hemodynamic characteristics, reflecting a more advanced and polycomorbid HFpEF profile, characterized by heightened pulmonary vascular reactivity and overt cardiac limitation to exercise.

Background Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problem 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. Aim To explore the impact of severe STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. Methods We 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 matched HFpEF patients with mild or no STR (HFpEF-controls). Results 13 HFpEF-STR (mean age 72 years, 85% females, BMI 28 Kg/m2) and 13 age-, sex-, and BMI-matched HFpEF-controls patients were included. HFpEF-STR had higher (p Conclusions Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, mining the typical HFpEF pathophysiology. Exercise pathophysiology of secondary tricuspid regurgitation (STR) in heart failure with preserved ejection fraction (HFpEF).

Phase angle (PhA) is a recently proposed marker of nutritional status in many clinical conditions. Its use in patients with obesity presents different critical concerns due to the higher variability of the two measured parameters (resistance, R, and reactance, Xc) that contribute to the determination of PhA. Controversial is the relation between PhA and BMI that might vary with graded levels of obesity due to the variation in fat and free fat mass. Obesity is frequently associated with metabolic, hepatic, cardiovascular and kidney diseases that introduce variations in PhA values, in relation to multimorbidity and severity degree of these diseases. It is reported that the improvement of clinical condition is associated with a positive change in PhA. Also, the treatment of obesity with weight loss might confirm this effect, but with different responses in relation to the type and duration of the intervention applied. In fact, the effect appears not only related to the percentage of weight loss but also the possible loss of free fat mass and the nutritional, metabolic and structural modifications that might follow each therapeutic approach to decrease body weight. We can conclude that the PhA could be used as marker of health status in patients with obesity supporting an appropriate weight loss intervention to monitor efficacy and fat free mass preservation.

Aims Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. The study hypothesis was that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM. Methods and results ABPM data from reflex syncope patients and controls, matched by average 24 h SBP, age, sex, and hypertension were compared. Patients with constitutional hypotension, orthostatic hypotension, and predominant cardioinhibition during carotid sinus massage or prolonged electrocardiogram monitoring or competing causes of syncope were excluded. Daytime and nighttime SBP drops ( Conclusion SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

Objective: Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. We hypothesized that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM. Design and method: We conducted a retrospective analysis comparing ABPM data from reflex syncope patients and controls, matched by average 24-hour SBP, age, sex and hypertension. Patients with constitutional hypotension, orthostatic hypotension, predominant cardioinhibition or competing causes of syncope were excluded. Daytime and night-time SBP drops ( 90% and 80–90%, respectively. Findings were validated in an independent sample. Results: In the Derivation cohort, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drop < 90 mmHg provided the best diagnostic yield (91% specificity, 32% sensitivity, Odds Ratio [OR] = 4.6, p = 0.001). Two or more-daytime drops < 100 mmHg achieved 84% specificity and 40% sensitivity (OR = 3.5, p = 0.001). Results were confirmed in the Validation cohort: one or more daytime SBP drop < 90 mmHg provided 94% specificity and 29% sensitivity (OR = 6.2, p < 0.001), while two or more daytime SBP drops < 100 mmHg achieved 83% specificity and 35% sensitivity (OR = 3.5, p < 0.001) Conclusions: SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

Aims In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. Methods and results In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10–0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22–0.73; P = 0.002]. Conclusions Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. Study registration ClinicalTrials.gov Identifier: NCT02137187.

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), and the PAWP/cardiac output (CO) slope during exercise was extrapolated. Twenty-eight studies were identified, providing data for 2230 HFpEF patients and 706 controls. At peak exercise, patients with HFpEF achieved higher PAWP [30 (29–31) vs. 16 (15–17) mmHg, P Conclusions The haemodynamic profile of HFpEF patients is consistent across studies and characterized by a higher left and right filling pressure at rest, magnified by physical exercise. Our analysis strongly suggests that PAWP/CO slope might allow for a more consistent identification of HFpEF, irrespective of body position. This variable likely overcomes the shortcomings of an isolated peak PAWP measurement, allowing for a more univocal identification of HFpEF in patients with unexplained dyspnoea.

Aims Long scanning times impede cardiac magnetic resonance (CMR) clinical uptake. A ‘one-size-fits-all’ shortened, focused protocol [e.g. only function and late-gadolinium enhancement (LGE)] reduces scanning time and costs, but provide less information. We developed two 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 ischaemic heart disease underwent the tailored CMR. Each scan consisted of standard cines, LGE imaging, native T1-mapping, and extracellular volume. Fat/oedema modules, right ventricle cine, and in-line quantitative perfusion mapping were performed as clinically required. Workflow was optimized to avoid gaps. See Figure 1 for protocol details. Time target was 30% (CMR: from 42 ± 8 to 28 ± 6min; stress-CMR: from 50 ± 10 to 34 ± 6min, both P 45% of cases. Quality grading was similar between the two 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 ischaemic heart disease.

Phase angle (PhA) is a recently proposed marker of nutritional status in many clinical conditions. Its use in patients with obesity presents different critical concerns due to the higher variability of the two measured parameters (resistance, R, and reactance, Xc) that contribute to the determination of PhA. Controversial is the relation between PhA and BMI that might vary with graded levels of obesity due to the variation in fat and free fat mass. Obesity is frequently associated with metabolic, hepatic, cardiovascular and kidney diseases that introduce variations in PhA values, in relation to multimorbidity and severity degree of these diseases. It is reported that the improvement of clinical condition is associated with a positive change in PhA. Also, the treatment of obesity with weight loss might confirm this effect, but with different responses in relation to the type and duration of the intervention applied. In fact, the effect appears not only related to the percentage of weight loss but also the possible loss of free fat mass and the nutritional, metabolic and structural modifications that might follow each therapeutic approach to decrease body weight. We can conclude that the PhA could be used as marker of health status in patients with obesity supporting an appropriate weight loss intervention to monitor efficacy and fat free mass preservation.