Background The diagnosis of carotid sinus syndrome requires the reproduction of spontaneous symptoms during carotid sinus massage (CSM) alongside clinical features indicative of a reflex mechanism. In contrast, the significance of asymptomatic asystolic carotid sinus hypersensitivity (CSH) remains uncertain, as it is frequently observed in older adults without syncope. Objectives This study aimed to evaluate the correlation between asymptomatic asystolic CSH and spontaneous events documented via implantable loop recorder (ILR). Methods In this study, 92 reflex syncope patients with an asymptomatic pause >3 seconds during CSM (average 4.9 ± 1.7 seconds) received an ILR and were followed for a median of 23.1 months. The control group consisted of reflex syncope patients with negative CSM drawn from a historical ILR population and matched with the propensity score method to the CSH group based on clinical variables. Results During the observation period, 38 (41.3%) CSH patients had recurrence of syncope, which was associated with asystole of 8.0 seconds (95% CI: 5.3-13.5 seconds) in 29 (76.3%) cases. Although the actuarial rate of total syncope recurrence in CSH group was similar to that in the control group (HR: 1.22; P = 0.40), CSH patients showed a higher rate of asystolic syncope (HR: 2.13; P = 0.011) and asystolic pauses (HR: 2.06; P = 0.009). Conclusions Patients with asymptomatic asystolic CSH were more likely to experience spontaneous asystolic syncope than those without CSH. Among CSH patients who experienced a recurrence of syncope documented by an ILR, the positive predictive value of an asystolic pause detected during CSM was 76.3%.

BACKGROUND:Cardioneuroablation (CNA) should focus on the vagal ganglia located in the right atrium close to the sinoatrial and the atrioventricular nodes. OBJECTIVE:The study aimed to evaluate the efficacy and safety of right atrial CNA. METHODS:Patients with severe, asystolic reflex syncope identified by implantable loop recorder (ILR) or tilt testing underwent right atrial CNA and were subsequently monitored using ILR. RESULTS:The population included 28 patients with a mean age of 40.5 ± 13.4 years, of whom 71% were men. Over a median follow-up period of 12.5 months, 8 patients experienced 44 episodes of asystole lasting longer than 3 seconds, as recorded by an ILR. The burden of asystolic episodes significantly reduced from 0.89 episodes per month before CNA (145 over 163 patient-months) to 0.11 episodes per month after CNA (44 over 397 patient-months), with a relative risk reduction of 0.12, P = .0001. Similarly, the burden of syncopal episodes decreased from 0.23 episodes per month before CNA to 0.06 episodes per month after CNA, resulting in an relative risk reduction of 0.24, P = .0001. Median heart rate increased from 75 bpm (interquartile range: 72-79) before ablation to 83 bpm (interquartile range: 78-85) after ablation, lasting up to 9 months post-procedure. No patients experienced complications during the procedure. During follow-up, 2 patients received pacemakers, 1 underwent a redo procedure, and 4 experienced mild transient symptoms: 3 had palpitations and 1 had dyspnea, none requiring therapy. CONCLUSION:Right atrial CNA reduced asystolic episodes by 88% and syncopal episodes by 76% during the mid-term follow-up. Adverse events were infrequent and mild.

The study aimed to assess the haemodynamic effects of fludrocortisone and midodrine, alone or combined, in patients with recurrent syncope and/or symptoms due to hypotension and ≥ 1 daytime systolic blood pressure (SBP) drop < 90 mmHg or ≥ 2 daytime SBP drops < 100 mmHg recorded by 24-h ambulatory blood pressure monitoring (ABPM1). A total of 53 patients (mean age, 40.9 ± 18.5 years, 37 female) were treated with fludrocortisone (0.05–0.2 mg per day) and/or midodrine (2.5–10 mg two or three times per day). A second ABPM (ABPM2) was performed within 6 months and the results of ABPM1 AND ABPM2 were compared to assess the effects of BP-rising drugs. In 32 patients assigned to fludrocortisone, 24-h SBP increased from 107.1 ± 9.9 mmHg to 116.3 ± 14.9 (p = 0.0001), the number of daily SBP drops < 90 mmHg decreased by 73

Background and Aims Identifying the haemodynamic mechanism of autonomic syncope is the essential pre-requisite for effective and personalized therapy aimed at preventing recurrences. The present study assessed the diagnostic efficacy of a two-step assessment. Methods Multicentre prospective, cross-sectional, observational study. Patients affected by severe autonomic syncope underwent a two-step assessment including 24-h ambulatory blood pressure monitoring and short cardiovascular autonomic function assessment (SCAFA). SCAFA consisted of carotid sinus massage (CSM), performed in patients >= 40 years old, a passive standing test, and a 'fast' head-up tilt test scheduled sequentially during one session on a tilt table. Results The study population consisted of 333 patients, 102 <= 40 years old and 231 > 40 years old. Any positive response was observed in 298 (89%) patients (92 [92%] in younger and 134 [89%] in older), with hypotensive phenotype accounting for 226 (68%), bradycardic phenotype for 21 (6%) and mixed phenotype for 51 (15%) of cases. The mean duration of the SCAFA procedure was 25 (IQR 20-32) min. Ambulatory blood pressure monitoring, CSM, passive standing, and head-up tilt test were positive in 60%, 15%, 3%, and 71% of patients, respectively. More than one test was positive in 51% and 49% of patients <= 40 and >40 years, respectively. Large inter-centre variability of CSM positivity rate, which remained significant after adjustment for demographic and clinical variables, was observed (P = .003). Conclusions The standardized 2STEPS protocol offers an easy-to-perform and time-saving diagnostic work-up allowing identification of the haemodynamic mechanism of loss of consciousness in most patients with autonomic syncope. This protocol provides the necessary background for a personalized mechanism-specific therapy.

BACKGROUND:We aimed to identify the target of deprescribing, i.e. the 24-hour SBP increase needed to achieve the greatest reduction of SBP drops. METHOD:Forty hypertensive patients (mean age 73.6 ± 9.3 years, 26 females) with reflex syncope and SBP drops on a screening ABPM were advised to withdraw or to reduce their therapy. The study objective was the reduction of SBP drops <90 mmHg and <100 mmHg on a second ABPM performed within 3 months. RESULTS:Out of a total of 98 drugs taken during ABPM 1, 44 were withdrawn, 16 had a dose reduction and 38 remained unchanged at the time of ABPM 2. 24-hour SBP increased from 119.7 ± 10.1 mmHg to 129.4 ± 13.2 mmHg during ABPM2. Total disappearance of daytime SBP drops <100 mmHg was achieved in 20 (50 %) patients who had 24-hour SBP of 134±13 mmHg and an increase from ABPM 1 of 12 (IQR 5-20) mmHg. Compared with the 20 patients who had persistence of drops, these patients had a greater reduction of the number of hypotensive drugs (67 % versus 19 %, p = 0.002) and a greater rate of withdrawals (62 % versus 29 %, p = 0.003). CONCLUSION:In hypertensive patients with reflex syncope, an increase of 12 mmHg and an absolute value of 24-hour SBP of 134 mmHg appear to represent the optimal goals aimed to prevent SBP drops. Drugs withdrawal, rather than simply dose reduction, is mostly required to achieve the above target.

AIMS:Systolic blood pressure (SBP) drops recorded by 24-h ambulatory blood pressure (BP) monitoring (ABPM) identify patients with susceptibility to reflex syncope and orthostatic intolerance. We tested the hypothesis that treatments aimed to increase BP (reassurance, education, and lifestyle measures plus pharmacological strategies) can reduce SBP drops. METHODS AND RESULTS:This was a multicentre, observational proof-of-concept study performed in patients with reflex syncope and/or orthostatic intolerance and with SBP drops on a screening ABPM. Among 144 eligible patients, 111 underwent a second ABPM on average 2.5 months after start of treatment. Overall, mean 24-h SBP increased from 114.1 ± 12.1 to 121.4 ± 14.5 mmHg (P < 0.0001). The number of SBP drops <90 and <100 mmHg decreased by 61%, 46% during daytime, and by 48% and 37% during 24-h period, respectively (P < 0.0001 for all). The dose-response relationship between difference in 24-h average SBP increase and reduction in number of SBP drops reached a plateau around ∼15 mmHg increase of 24-h SBP. The reduction in SBP drop rate was consistent and significant in patients who underwent deprescription of hypotensive medications (n = 44) and in patients who received BP-rising drugs (n = 67). CONCLUSION:In patients with reflex syncope and/or orthostatic intolerance, an increase in average 24-h SBP, regardless of the implemented strategy, significantly reduced the number of SBP drops and symptom burden. A 13 mmHg increase in 24-h SBP appears to represent the optimal goal for aborting the maximal number of SBP drops, representing a possible target for future interventions. ClincalTrials.gov identifier: NCT05729724.

An Implantable Cardioverter-Defibrillator was implanted in an asymptomatic 56-year-old man, with type 2 Brugada pattern on ECG, inducible ventricular fibrillation at elective electrophysiological study, and a family history of sudden cardiac death. Seventeen years later, the patient was admitted to the hospital due to palpitations related to a typical atrial flutter. A transthoracic echocardiogram unexpectedly revealed a clinically manifest hypertrophic cardiomyopathy.

Gonadotropin-Releasing Hormone (GnRH) is a decapeptide responsible for the control of the reproductive functions. It shows C- and N-terminal aminoacid modifications and two other distinct isoforms have been so far identified. The biological effects of GnRH are mediated by binding to high-affinity G-protein couple receptors (GnRHR), showing characteristic very short C tail. In mammals, including humans, GnRH-producing neurons originate in the embryonic nasal compartment and during early embryogenesis they undergo rapid migration towards the hypothalamus; the increasing knowledge of such mechanisms improved diagnostic and therapeutic approaches to infertility. The pharmacological use of GnRH, or its synthetic peptide and non-peptide agonists or antagonists, provides a valid tool for reproductive disorders and assisted reproduction technology (ART).The presence of GnRHR in several organs and tissues indicates additional functions of the peptide. The identification of a GnRH/GnRHR system in the human endometrium, ovary, and prostate has extended the functions of the peptide to the physiology and tumor transformation of such tissues. Likely, the activity of a GnRH/GnRHR system at the level of the hippocampus, as well as its decreased expression in mice brain aging, raised interest in its possible involvement in neurogenesis and neuronal functions. In conclusion, GnRH/GnRHR appears to be a fascinating biological system that exerts several possibly integrated pleiotropic actions in the complex control of reproductive functions, tumor growth, neurogenesis, and neuroprotection.This review aims to provide an overview of the physiology of GnRH and the pharmacological applications of its synthetic analogs in the management of reproductive and non-reproductive diseases.

BACKGROUND:Conduction system pacing (CSP) using His bundle pacing (HBP) or left bundle branch area pacing (LBBAP) has emerged as an alternative to right ventricular pacing (RVP). Comparative data on the risk of complications between CSP and RVP are lacking. OBJECTIVE:This prospective, multicenter, observational study aimed to compare the long-term risk of device-related complications between CSP and RVP. METHODS:A total of 1029 consecutive patients undergoing pacemaker implantation with CSP (including HBP and LBBAP) or RVP were enrolled. Propensity score matching for baseline characteristics yielded 201 matched pairs. The rate and nature of device-related complications occurring during follow-up were prospectively collected and compared between the 2 groups. RESULTS:During a mean follow-up duration of 18 months, device-related complications were observed in 19 patients: 7 in RVP (3.5%) and 12 in CSP (6.0%) (P = .240). On dividing the matched cohort into 3 groups with similar baseline characteristics according to pacing modality (RVP, n = 201; HBP, n = 128; LBBAP, n = 73), patients with HBP showed a significantly higher rate of device-related complications than did patients with RVP (8.6% vs 3.5%; P = .047) and patients with LBBAP (8.6% vs 1.3%; P = .034). Patients with LBBAP showed a rate of device-related complications similar to that of patients with RVP (1.3% vs 3.5%; P = .358). Most of the complications observed in patients with HBP (63.6%) were lead related. CONCLUSION:Globally, CSP was associated with a risk of complications similar to that of RVP. Considering HBP and LBBAP separately, HBP showed a significantly higher risk of complications than did both RVP and LBBAP whereas LBBAP showed a risk of complications similar to that of RVP.

The impairment of development/migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons is the main cause of Kallmann's syndrome (KS), an inherited disorder characterized by hypogonadism, anosmia, and other developmental defects. Olfactorin is an extracellular matrix protein encoded by the UMODL1 (uromodulin-like 1) gene expressed in the mouse olfactory region along the migratory route of GnRH neurons. It shares a combination of WAP and FNIII repeats, expressed in complementary domains, with anosmin-1, the product of the ANOS1 gene, identified as the causative of KS. In the present study, we have investigated the effects of olfactorin in vitro and in vivo models. The results show that olfactorin exerts an anosmin-1-like strong chemoattractant effect on mouse-immortalized GnRH neurons (GN11 cells) through the activation of the FGFR and MAPK pathways. In silico analysis of olfactorin and anosmin-1 reveals a satisfactory similarity at the N-terminal region for the overall arrangement of corresponding WAP and FNIII domains and marked similarities between WAP domains' binding modes of interaction with the resolved FGFR1-FGF2 complex. Finally, in vivo experiments show that the down-modulation of the zebrafish z-umodl1 gene (orthologous of UMODL1) in both GnRH3:GFP and omp(2k):gap-CFPrw034 transgenic zebrafish strains leads to a clear disorganization and altered fasciculation of the neurites of GnRH3:GFP neurons crossing at the anterior commissure and a significant increase in olfactory CFP + fibers with altered trajectory. Thus, our study shows olfactorin as an additional factor involved in the development of olfactory and GnRH systems and proposes UMODL1 as a gene worthy of diagnostic investigation in KS.

Abstract Introduction Vasovagal syncope is traditionally considered a benign condition due to parasympathetic nervous system activation. Here is a case of reflex syncopal episodes that triggered recurrent Takotsubo Syndrome (TS) with life–threatening presentation. Report of a Case A 71-year-old female presented to the Emergency Department (ED) complaining with dyspnoea and chest pain developed half an hour after a vasovagal syncope. Her past medical history was consistent with arterial hypertension, dyslipidaemia, and well-tolerated reflex syncopal episodes since she was a child. At hospital admission, a 12-leads ECG showed T-wave inversion in anterior leads while transthoracic echocardiogram (TTE) showed hypokinesia of the mid-apical segments, reduced left ventricular ejection fraction (LVEF) [40%], and severe mitral regurgitation (MR). Blood tests revealed increased hs-troponin I values [peak value: 1500 ng/L]. A coronary angiography (CA) was thus performed in the suspect of NSTEMI, showing non obstructive coronary disease. A diagnosis of TS was eventually made with ECG normalisation and resolution of echocardiographic abnormalities at 6 month follow-up. Five years later, the patients presented to the ED because of a new syncopal episode followed by severe pulmonary oedema. Since the presence of electrocardiographic T-wave inversion, apical segments akinesia and elevated hs-troponin I were consistent with NSTEMI, a CA was performed revealing (again!) normal coronary vessels. A suspect of TS relapse was thus made. Three months after discharge, ECG and echocardiogram were normal and a syncope diagnostic work–up was suggested. A 24/h ambulatory blood pressure monitoring demonstrated normal pressure values and a tilt test confirmed the well-established history of reflex syncope showing a remarkable cardioinhibitory response. A pacemaker implant was thus indicated. Discussion TS is a heart syndrome characterized by transient contractile dysfunction historically related to catecholamine activation of alpha and beta receptors. While sympathetic system involvement in the development of TS is clearly established, new evidence is emerging about the vagal role in the etiopathogenesis of the disease. Although syncopal episodes could be related to TS, because of LVOT obstruction or major arrhythmias, according to our experience, TS may be triggered by vagal hypertonus [i.e., after vasovagal syncopal episodes]. In similar situation, the implantation of a pace-maker could be considered to prevent future dangerous complications related to recurrent reflex syncope even if well tolerated by the patients. Conclusion In our experience, recurrent episodes of TS appeared triggered by reflex syncope. A condition traditionally considered benign may instead have life-threatening consequences. Moreover, the role of parasympathetic and vagal tone in the development of TS needs further investigation that may lead to the design of new strategies of clinical diagnosis and management.

LGMDR3, LGMDR4, LGMDR5 are recessive autosomal diseases, there are no specific treatments, except for some physical therapies that prevent worsening of muscle contractures and therapies associated with cardiac and respiratory problems. In 2013 the volunteer organization named Family Group of Beta-sarcoglycanopathy (GFB ODV; www.lgmd2e.org) was established to stimulate and support basic and clinical research on these diseases. Since 2012, families of the GFB ODV funded a research project of gene therapy for LGMDR4, under the supervision of Prof. J. Mendell, at the Ohio State University (Columbus, Ohio, USA). The first clinical trial, conducted by Sarepta Therapeutics, is currently underway. In 2018 GFB Odv promoted a natural history study on Italian patients "Clinical Determinants of disease progression in patients with beta-sarcoglycan gene mutations", led by Prof. Yvan Torrente, of the University of Milan, Ospedale Maggiore Policlinico in Milan, Italy. Since 2021 GFB Odv has started an ongoing observational study on the quality of life in patients with beta-sarcoglycan, alpha-sarcoglycan, and gamma-sarcoglycan gene mutation, again in collaboration with Prof. Yvan Torrente. The study is aimed at international GFB patients. At this time 139 patients from 45 countries have joined the Project: in particular, 68 with LGMDR4, 32 with LGMDR5, 39 with LGMDR3. 201 questionnaires have already been filled out. The ACTIVLIM, ABILHAND, EK, PEDSQL and PROMIS scales are used in the study, both in paper and electronic format. The study will run for 3 years and the scales will be given to patients every 6 months.

Abstract Introduction Brugada Syndrome (BrS) is a genetically inherited condition associated with the risk of fatal arrhythmias and sudden cardiac death (SCD) occurring in a structurally normal heart. This disorder was historically related to mutations in the SCN5A gene, but recent observations suggest a more complex genetic inter-play, highlighting the possible overlap with structural cardiomyopathies, including hypertrophic cardiomyopathy (HCM). Case Presentation In May 2005, an asymptomatic 56-year-old man with a family history of unexplained SCD was referred to our outpatient clinic. A 12-lead ECG showed a type 2 Brugada pattern whilst transthoracic echocardiogram (TTE) was normal. Ventricular fibrillation (VF) was induced during an elective electrophysiological study and a transvenous implantable cardioverter-defibrillator (ICD) was implanted for primary prevention. More than 10 years later, in March 2022, our patient was admitted to the hospital because of palpitations. The ECG revealed a typical atrial flutter with a high ventricular rate, successfully treated with catheter ablation. Post-procedural ECG showed the persistence of type 2 Brugada pattern in association with new-onset T wave inversion in inferolateral leads and signs of ventricular hypertrophy. TTE revealed asymmetric left ventricular hypertrophy, with left ventricular outflow tract (LVOT) obstruction determined by mitral systolic anterior motion and preserved LV systolic function. The patient was treated with optimal medical therapy with symptom improvement and reduction of LVOT obstruction at a 3-month follow-up TTE. Discussion The distinction between Brugada phenocopy and BrS electrocardiogram patterns is not obvious, and according to our experience a Brugada type 2 pattern could be an early ECG marker of a concealed HCM which became manifest over an extended follow-up. Brugada ECG phenocopies are clinical entities characterized by type 1 or type 2 Brugada patterns elicited by an underlying condition, the disappearance of the pattern with the resolution of the condition and the absence of classical symptoms. Several pathogenic variants involving other and different genes have been recently reported suggesting a possible overlap with structural cardiomyopathies. Recently, two other cases of incidental findings of a Brugada ECG pattern in the context of HCM were described. Both patients had a common pathogenetic splicing mutation in the MYBPC3 sarcomeric gene (encoding for the cardiac myosin-binding protein C) responsible for HCM with no genetic mutations associated with Brugada syndrome. This fact suggests that patients are not simultaneously affected by BrS and HCM but a clinically manifest HCM with a specific genetic background can lead to an early BrS electrical manifestation. Conclusion Our experience confirms that a Brugada type 2 ECG pattern could be a very early sign of a concealed HCM manifested over 10 years later. The importance of proper risk stratification and regular follow-up has thus crucial implications in patient clinical management. However, whether Brugada pattern associated with structural heart disease is linked to an increased risk of sudden cardiac death is still unknown and needs further investigations.

Read the full review for this Faculty Opinions recommended article: GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing.

Context: Despite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it.Objective: To assess changes in and factors associated with testicular position during childhood.Design: Testicular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, and 7 years and reproductive hormones at 3 months were measured.Setting: Prenatally recruited, prospective longitudinal birth cohort.Participants: A total of 2545 boys were recruited prenatally in a Danish-Finnish birth cohort and had a testicular position examination available. A subset of 680 Danish and 362 Finnish boys had serum reproductive hormone concentrations and insulin-like growth factor I (IGF-I) determined at 3 months.Main Outcome Measures: Testicular distance to pubic bone (TDP), serum reproductive hormone, and IGF-I concentrations.Results: TDP increased from birth to 3 months and decreased thereafter. Length, gestational age, weight for gestational age, and penile length were positively associated with larger TDP and thus lower testicular position in a linear mixed-effect model. Furthermore, IGF-I concentration, inhibin B/follicle-stimulating hormone ratio, and testosterone/luteinizing hormone ratio were all independently and positively associated with longer TDP.Conclusions: We provide longitudinal data on postnatal changes in TDP. TDP is dynamic and associated with Leydig and Sertoli cell function as well as with IGF-I levels during the first months of life at mini-puberty of infancy. TDP may thus be a useful biomarker of postnatal testicular function. PMID: 29408984

Background: Isolated hypogonadotropic hypogonadism (IHH) is a rare, clinically heterogeneous condition, caused by the deficient secretion or action of gonadotropin releasing hormone (GnRH). It can manifest with absent or incomplete sexual maturation, or as infertility at adult-age; in a half of cases, IHH is associated with hypo/anosmia (Kallmann syndrome). Although a growing number of genes are being related to this disease, genetic mutations are currently found only in 40% of IHH patients. Case description: Severe congenital hyposmia was diagnosed in a 25-year-old Caucasian man referred to the Ear-Nose-Throat department of our clinic. The patient had no cryptorchidism or micropenis and experienced a physiological puberty; past medical history and physical examination were unremarkable. Olfactory structures appeared hypoplasic, while hypothalamus, pituitary gland, and stalk were normal on MRI (neuroradiological imaging); testosterone levels, as well as pulsatile gonadotropin secretion and other pituitary hormones were unaffected at the time of first referral. At the age of 48, the patient returned to our clinic for sexual complaints, and the finding of low testosterone levels (6.8 and 5.8 nmol/L on two consecutive assessments) with inappropriately normal gonadotropin levels led to the diagnosis of hypogonadotropic hypogonadism. GnRH test was consistent with hypothalamic origin of the defect. Next generation sequencing was then performed revealing a rare heterozygous allelic variant in SPRY4 gene (c.158G>A, p.R53Q). The biological and clinical effects of this gene variant had never been reported before. A diagnosis of Kallmann syndrome was finally established, and the patient was started on testosterone replacement therapy. Conclusion: This case describes the clinical phenotype associated with a rare SPRY4 gene allelic variant, consisting in congenital severe smell defect and adult-onset IHH; in patients with apparently isolated congenital anosmia genetic analysis can be valuable to guide follow up, since IHH can manifest later in adulthood. Characterization of other modifying genes and acquired environmental factors is needed for a better understanding of the physiopathology and clinical manifestations of this disease.Copyright © 2019 Indirli, Cangiano, Profka, Mantovani, Persani, Arosio, Bonomi and Ferrante. PMID: 31781046