Stefano Carugo

BACKGROUND: Titin truncating variants ( TTN tv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNt v location also affects clinical phenotype and prognosis. METHODS: We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTN tv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTN tv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS: The study included 467 patients (81% probands, 73% men, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTN tv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P =0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS: TTN tv are differently enriched across the gene in patients with dilated cardiomyopathy/non-dilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

Purpose: Emerging evidence points on an increased mortality risk associated to moderate aortic stenosis (AS), yet this population remains insufficiently characterized. We tested the prognostic value of two echocardiographic coupling indices reflecting right and left-sided cardiac function: the ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio (TAPSE/PASP) and the left atrial volumetric/mechanical coupling index (LACI).Methods: Retrospective, single-center study including 135 patients with moderate AS. TAPSE/PASP was used as a non-invasive surrogate of right ventricular–pulmonary circulation (RV–Pc) coupling, and LACI was defined as ratio of left atrial volume index to mitral a′ velocity. The primary endpoint was all-cause mortality. Cox regression and Kaplan–Meier analyses were used to assess the prognostic value of both indices.Results: During a mean follow-up of 1.61±0.79 years, 33 patients (24%) died. Reduced TAPSE/PASP (< 0.67 mm/mmHg) and elevated LACI (> 5.17) were independently associated with an increased mortality (HR: 3.03 and 3.16, respectively, p < 0.01). These associations remained significant even after adjusting for age. Stratification into three groups - preserved, single, or combined uncoupling -showed progressively lower 1-year survival rates, ranging from 95% to 49% (p < 0.0001). None of the coupling-derived variables was associated with hemodynamic progression or need of aortic valve replacement.Conclusion: TAPSE/PASP and LACI are independently associated with mortality in patients with moderate AS. These parameters may provide incremental prognostic information in this often-overlooked population. These findings may prompt further studies evaluating the potential role of these parameters in helping to refine prognostic phenotyping.

Background:Heterotopic transcatheter caval valve implantation (CAVI) has emerged as a palliative yet promising therapeutic strategy for treating severe tricuspid regurgitation (TR), which aims to reduce systemic venous congestion by implanting bioprosthetic valves in the venae cavae rather than in the native tricuspid annulus. However, despite encouraging procedural success, clinical improvement and survival remain highly variable.Methods:A systematic review of published registries and case series was performed, focusing on the outcomes, procedural success, mortality, and safety of CAVI. Data were extracted from multicenter registries and observational series describing the use of transcatheter stented bioprosthesis or bioprosthesis alone.Results:Across published cohorts and registries, procedural success rates ranged from 90% to 100%, with 30-day mortality ranging from 5% to 25%. The TRICUS EURO study, which included 35 patients across 12 European centers, demonstrated significant improvements in New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at 6 months, with minimal device-related complications and adverse events. The ongoing TRICAV-II pivotal trial (NCT06458907) and EuroTR registry (NCT06307262) are expected to provide larger real-world datasets. Smaller case series and individual reports, typically involving ≤10 patients, confirmed feasibility and symptomatic benefits, particularly reductions in peripheral edema and ascites. However, long-term outcome data remain limited. This study highlights right ventricle (RV) dysfunction, severe pulmonary hypertension, advanced end-organ failure, and clinical frailty as major determinants of unfavorable outcomes.Conclusions:Heterotopic CAVI represents a viable alternative for high-risk patients with severe TR, offering symptomatic improvement and reduced venous congestion when conventional surgery or orthotopic repair is not feasible. However, current evidence is derived primarily from non-randomized studies and limited registries. Ongoing prospective registries and pivotal trials are crucial for defining patient selection, procedural optimization, and long-term survival benefit. Early intervention and multidisciplinary patient selection appear crucial for avoiding futile procedures and identifying patients who may derive true symptomatic and prognostic benefit from CAVI.

Percutaneous epicardial access (PEA), performed on a beating heart under fluoroscopy, enables arrhythmia treatment. However, advancing a needle toward the thin, moving pericardium remains highly challenging and risky. To address this challenge, we present a novel physics-driven sonification method for Extended Reality (XR)-based multisensory navigation to enhance user perception regarding critically sensitive needle landing phase in PEA. Dynamic cardiac anatomy from 4DCTA was reconstructed and registered to a real-world coordinate system. Real-time needle tracking provided data of the needle tip relative to moving cardiac structures, driving the audio-visual feedback module. The visual display presents navigational cues and dynamic cardiac structures, whereas the auditory display encodes physiological cardiac states into a rigorous mapping through a multilayered physical membrane. To prove this novel concept, a phantom study was conducted with twelve cardiologists performing needle insertions under visual-only and multisensory feedback. Results show that the proposed multisensory method improved the navigation safety (χ² = 11.30, p < 0.01), reducing myocardial contact (3.64% vs. 7.27%) and increasing correct access (90.91% vs. 52.73%). Needle placement accuracy improved, with closer membrane proximity (Cliff’s δ = 0.19) and reduced variability (Fligner p < 0.05). Execution time remained comparable, but time–accuracy correlations differed significantly between modalities (Fisher’s p < 0.01). NASA-TLX showed lower cognitive load with multisensory guidance (t = −4.02, p < 0.01). In conclusion, the multisensory system is associated with improved spatiotemporal awareness and suggests potential benefits for surgical navigation, while indicating reduced cognitive load. These findings demonstrate the feasibility of physics-driven sonification for supporting user-centered interaction and motivate further validation in realistic and clinical environments.

Aortic regurgitation (AR) in young adults (aged 18–44 years) is often under‐ or misdiagnosed and is not always benign. As in older populations, prognosis depends on the severity of regurgitation, the underlying cause, early left ventricular dysfunction, and the chosen intervention strategy. Prompt diagnosis and timely treatment improve outcomes, yet the optimal timing for surgery in asymptomatic chronic AR remains uncertain. Recent studies have proposed new thresholds for left ventricular structural and functional assessment to better evaluate the impact of AR on prognosis and guide intervention timing. Echocardiography remains the primary imaging modality, but a multimodality approach is essential to accurately assess AR severity and subtle left ventricular changes. Transesophageal echocardiography with 3‐dimensional imaging is crucial for evaluating valve repair feasibility, particularly when valve‐sparing root repair, reintervention, or transcatheter procedures are considered. Additional tools such as cardiac magnetic resonance, global longitudinal strain, and biomarkers may further enhance disease monitoring. Assessment can be challenging, especially with eccentric jets or complex valve anatomy, and current surgical cut‐offs remain debated. Aortic valve repair is preferred in young patients, including those with concomitant proximal aortic aneurysm, but it remains underutilized. Here, we propose a treatment algorithm for severe AR in young adults, integrating the underlying cause, valve anatomy, and left ventricular function, with a special focus on multimodality imaging to guide monitoring and therapeutic strategies.

Background: Recent advancements in heart failure (HF) therapy have significantly enhanced the management of patients across all phenotypes of left ventricular ejection fraction. However, these multidrug regimens frequently induce alterations in renal function by influencing intrarenal hemodynamics, thereby modifying glomerular capillary pressure. This phenomenon could result in a mild to moderate decline in estimated glomerular filtration rate (eGFR), often classified as “worsening kidney function.” This nomenclature stems from consistent observations of eGFR reductions recorded during HF treatment in clinical trials. This narrative review aims to elucidate why the observed eGFR declines in clinical practice may represent either loss of functioning glomeruli or pharmacologically mediated reductions in intraglomerular pressure that ultimately safeguards long-term renal and cardiovascular outcomes. Methods: By a comprehensive re-examination of data from HF clinical trials conducted with various classes of medications, all affecting eGFR, we sought to provide evidence that the decline in eGFR is associated with the activation of specific mechanisms that collectively contribute to a reduction in glomerular filtration pressure, a prominent factor in maladaptive neurohormonal responses. Results: From the investigation of angiotensin-converting enzyme inhibitors to the more recent non-steroidal mineralocorticoid receptor antagonist, the renal effects of these therapeutic regimens correlate with improvements in patient outcomes. The data consistently indicate that an early decline in eGFR, when coupled with an enhancement in HF outcomes, is associated with a more gradual decline in eGFR during long-term follow-up. Conclusions: Clinicians should recognize early declines in eGFR as indicators of favorable intraglomerular hemodynamic adjustments that mitigate maladaptive neurohormonal responses and contribute to improved long-term outcomes in patients with HF.

Hypertrophic cardiomyopathy (HCM) is a genetically determined heart disease characterized by marked clinical heterogeneity and limited availability of specific circulating biomarkers that reflect underlying disease mechanisms. This study investigated whether plasma-derived extracellular vesicles (EVs) capture disease-related molecular features in patients with HCM. Plasma EVs were characterized for size, cellular origin, and protein cargo using flow cytometry, targeted and untargeted proteomic analyses. While EVs size and concentration were comparable between groups, patients with HCM exhibited an enrichment of platelet-derived EVs (CD41a+) and reductions in neutrophil (CD66b+)- and lymphatic (CD310+)-derived EVs. Proteomic profiling revealed EV-associated proteins linked to platelet activation and thrombo-inflammation. Multivariable protein signatures derived from EVs discriminated patients from controls with performance comparable to plasma-based models and were not influenced by age. These findings indicate that EVs reflect key biological pathways involved in HCM and may support their use in biomarker-oriented studies.