Klinikum der Universität München

BACKGROUND AND AIMS:The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. METHODS:The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan-Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. RESULTS:One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (-11.6, 11.9), massive/torrential -5.8% (-17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (-3.0, 22.7), massive/torrential -15.2% (-28.9, -1.5)]. CONCLUSIONS:Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

BACKGROUND:Diffuse gastric cancer (DGC) is the most common manifestation in germline CTNNA1 variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on CTNNA1-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce. OBJECTIVE:Explore CTNNA1 genotype-phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers. DESIGN:Using molecular, clinical and population data from 1308 individuals from 351 CTNNA1-variant carrier families and 37 428 non-carriers from European and American ancestries, we analysed genotype-phenotype associations with multivariable logistic regression. With CRISPR/Cas9 CTNNA1-knockout gastric cancer (GC) cells and CTNNA1-humanised Drosophila, we assessed CTNNA1-associated loss-of-function mechanisms. RESULTS:CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin. These transcripts are non-functional in Drosophila, in contrast to non-truncating transcripts. DGC risk is eightfold higher in truncating, compared with non-truncating carriers. The risk of GC and lobular breast cancer (LBC) development in CTNNA1-truncating variant carriers is fivefold and eightfold lower than in CDH1 pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers. LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for CTNNA1 genetic testing produced the 'Porto' criteria, which increased CTNNA1-carrier families' pick-up rate by 9%, without performance loss compared with the HDGC 2020 clinical guidelines. Macular dystrophy patterned-2 was positively associated with non-truncating variants, specifically in the αE-catenin M-fragment. CONCLUSION:We provide compelling evidence supporting that CTNNA1-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to CTNNA1 downregulation. We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for CTNNA1-carrier individuals and families.

AIMS:Management of transcatheter aortic valve replacement (TAVR) in aortic stenosis (AS) flow groups-high-gradient (HG-AS), classical low-flow low-gradient (cLFLG-AS), and paradoxical low-flow low-gradient (pLFLG-AS)-is debated. Concomitant mitral regurgitation (MR) worsens outcomes, but the influence of MR aetiology on AS subtypes is unclear. This study aims to evaluate the impact of MR aetiology and severity on outcomes across AS flow groups in TAVR patients. METHODS AND RESULTS:A retrospective analysis was performed on 2658 patients undergoing TAVR (2013-21). MR was categorized as atrial functional (aFMR), ventricular functional (vFMR), or primary MR (PMR). Outcomes included 3-year mortality, MR improvement, and symptomatic benefit. Out of 2658 TAVR patients, 531 (20.0%) showed at least moderate MR (MR ≥ 2+) (50.1% male, median age 83.1 years). The fraction of patients with MR ≥ 2+ was highest among cLFLG-AS patients (34.2%). MR aetiology varied among AS subtypes, with mostly vFMR in cLFLG-AS (83.0%) and highest rates of aFMR (43%) and PMR (45%) in pLFLG-AS patients. Three-year mortality was significantly affected by MR severity [hazard ratio (HR) for MR2+ vs. MR < 2 1.62 (1.38-1.90)]. Differences in 3-year mortality were found in high-gradient (HG)-AS [HR 1.52 (1.16-1.98)] and pLFLG-AS patients [HR 1.73 (1.24-2.40)], but not in cLFLG-AS patients [HR 1.21 (0.93-1.56)]. MR improvement after TAVR was commonly found in HG-AS (67.2%) and least often among pLFLG-AS (48.7%, P = 0.03 compared with HG-AS). While MR improvement was associated with a lower mortality in HG-AS [HR 0.21 (0.10-0.43)] and cLFLG-AS patients [HR 0.48 (0.29-0.79)], this was not the case in pLFLG-AS patients [1.32 (0.67-2.59)]. CONCLUSION:MR aetiology and severity influence outcomes after TAVR depending on AS flow groups.

Delirium is a common yet underrecognized neuropsychiatric syndrome in cardiovascular medicine associated with prolonged hospitalization, increased mortality, and long-term cognitive decline. Patients undergoing interventional or surgical cardiovascular procedures-such as transcatheter aortic valve replacement, surgical aortic valve replacement, coronary artery bypass grafting, or percutaneous coronary interventions-may be particularly vulnerable to its development. Delirium incidence varies widely across cardiovascular procedures, influenced by patient characteristics, procedural invasiveness, and diagnostic methodology. Risk factors include advanced age, baseline cognitive impairment, cerebrovascular disease, extended operative times, perioperative complications, and systemic inflammation. Diagnostic tools such as the Confusion Assessment Method (CAM) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score are established but underutilized in the diagnosis of delirium. While preventive strategies emphasizing non-pharmacological, multicomponent approaches-such as early mobilization, cognitive stimulation, and sleep hygiene-are supported by strong evidence, preventive use of pharmacologic agents remains controversial. Pharmacologic treatment is reserved for select cases; dexmedetomidine shows benefits in intensive care unit settings, while antipsychotics like quetiapine and risperidone may be used cautiously. Overall, delirium poses a significant clinical challenge in cardiovascular medicine and requires a proactive, interdisciplinary approach. Systematic risk assessment and multimodal preventive strategies should be the standard of care, while pharmacologic treatment should be symptom- and context-specific. Further high-quality studies are needed to inform evidence-based guidelines tailored to cardiovascular populations. The present state-of-the-art review summarizes the current literature on the epidemiology, mechanisms, clinical manifestations, diagnosis, prevention, and treatment of delirium in cardiovascular medicine. By integrating findings and interdisciplinary expert discussions from interventional cardiology, cardiac surgery, and psychiatry, it aims to define the unique vulnerability of this patient population, highlight critical knowledge gaps, and lay the foundation for developing targeted, evidence-based management strategies.

BackgroundThere is mounting evidence that conventional replacement strategies with calcium and vitamin D are insufficient to fully prevent complications of chronic hypoparathyroidism (HypoPT) in all patients.MethodsTo investigate the disease burden of chronic HypoPT, we performed a survey in 205 HypoPT patients (159 females; median age 55 years; median disease duration 16 years). Patients received a disease-specific questionnaire asking for subjective health status, comorbidities, disease-related emergencies and interference of HypoPT with daily and work life. Patients were further assessed by the SF-36 questionnaire. Data was compared to sex- and age-matched subjects from the Study of Health in Pomerania SHIP-START, the German Health Interview and Examination Survey for Adults (DEGS1) and to 214 patients with adrenal insufficiency.ResultsClinical symptoms associated with HypoPT during the past 12 months were reported by 92% of patients, requiring medical intervention in 32%. Since primary diagnosis of HypoPT, 36% of patients had presented at least once at an emergency department due to severe hypocalcemia (14.7 events per 100 patient years). Trigger factors for hypocalcemic symptoms were reported by 76% of patients (e.g. physical activity, infections, hot weather). In comparison to population-based controls, patients with HypoPT showed a higher prevalence of renal insufficiency (11% vs. 2%, p<0.001) and more frequently received antihypertensive (44% vs. 34%; p=0.003) and antiepileptic drugs (5% vs. 2%, p=0.01). Lifetime prevalence of both depression (22% vs. 15%, p=0.003) and anxiety (21% vs. 6%, p<0.001) were increased in HypoPT. SF-36 values indicated significantly reduced subjective health status in HypoPT patients compared to controls as well as patients with adrenal insufficiency.ConclusionDespite established treatment, chronic HypoPT is associated with a variety of symptoms with a significant impact on daily life and work life.Trial registrationhttps://ClinicalTrials.gov/NCT03437174.