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. 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). 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

Sodium-Glucose Cotransporter inhibitors (SGLTi) are established therapies for heart failure (HF), chronic kidney disease, and type 2 diabetes. Their role in hypertrophic cardiomyopathy (HCM) remains undefined. This systematic review synthesizes available evidence on SGLTi efficacy and safety in HCM. We systematically searched PubMed, Embase, and Cochrane to 2 June 2025 for studies reporting cardiovascular outcomes or safety adverse events in HCM patients treated with SGLTi. Three studies were included, comprising 5046 HCM patients, of whom 2523 (50%) received SGLTi. The population was predominantly male (68.9%), mean age 63.4 (±12.7), with high diabetes prevalence (90.6%). Cohorts were heterogeneous: one included 41.6% obstructive HCM, one only non-obstructive HCM, and one unspecified obstruction. Follow-up ranged 6–37.2 months. The high prevalence of diabetes and hypertension, along with limited genetic data, suggest some patients may have metabolic-mixed phenotypes rather than classic sarcomeric HCM. Two studies, (n = 4998, 90.5% diabetics) reported an association between SGLTi and reduced all-cause mortality. HF hospitalizations results were inconsistent: one study (n = 4126, 100% diabetics) showed reduction, while two other (respectively n = 48, 100% diabetics, and n = 872, 45.5% diabetics) resulted neutral. Two studies (n = 920) reported comparable adverse events. Evidence on SGLTi in HCM is limited, largely observational, and confined to diabetic-metabolic patients. Observed reduction in all-cause mortality likely reflects these metabolic or mixed phenotypes rather than classical sarcomeric HCM. Effects on HF hospitalizations remain uncertain. No safety concerns emerged. These findings are hypothesis-generating and highlight need for randomized controlled trials of SGLTi in HCM with or without diabetes.

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications.