Abstract Background The specific 3D morphological substrates distinguishing the newly defined “massive” and “torrential” functional tricuspid regurgitation (FTR) phenotypes from standard severe disease remain under-characterized. Objectives This study investigates the 3D geometric changes of the tricuspid valve (TV) apparatus across the spectrum of FTR, specifically focusing on the structural definition of massive and torrential grades. Methods Three-dimensional (3D) transesophageal echocardiography (TEE) was performed in 322 patients with FTR secondary to left-sided heart disease. Patients were stratified into mild-moderate (n=166), severe (n=82), and massive-torrential (n=74) groups. TV geometry, including annular dimensions, leaflet tethering, and subvalvular apparatus, was quantified using 3D modeling software. Results Patients with massive-torrential TR were characterized by advanced age, female predominance, and atrial fibrillation (75%). 3D analysis demonstrated that massive-torrential TR represents a distinct phenotype defined by extreme annular circularization (ellipticity index ≈ 1.0) and planar flattening ( P < 0.001). Furthermore, these patients exhibited a critical “leaflet-annulus uncoupling”, where compensatory leaflet growth (relative length < 80%) failed to match the massive annular dilation. Consequently, the regurgitant orifice in massive-torrential grades appeared highly complex, frequently manifesting as multiple irregular orifices. Conclusions Massive and torrential FTR are characterized by a unique geometric profile involving extreme annular circularization, severe leaflet tethering, and leaflet-annulus uncoupling. These morphological insights suggest that conventional repair strategies may be insufficient for these advanced phenotypes, highlighting the necessity for pre-procedural 3D TEE to guide device selection.

Background: Papillary muscles (PMs) are important for mitral valve competence and left ventricular mechanics, but accurate evaluation is often limited by poor visualization in conventional echocardiographic views. We developed papillary muscle-targeted (PM-targeted) echocardiographic views to improve PM visualization and aimed to validate this approach and establish normative reference values in healthy adults. Methods: In protocol 1, posteromedial papillary muscle (PPM) length and maximum diameter measured using PM-targeted and standard views were compared with anatomic measurements in ten ex vivo porcine hearts. In protocol 2, measurements of the anterolateral papillary muscle (APM) and PPM were compared between PM-targeted and standard views in 100 healthy adults. In protocol 3, PM structural, spatial, and functional parameters were measured using PM-targeted views in 245 healthy adults. In protocol 4, PM measurements obtained from 2D PM-targeted views were compared with 3D echocardiographic measurements in 50 patients with ventricular functional mitral regurgitation (VFMR); PM parameters in VFMR were also compared with those in healthy adults. Results: In protocol 1, PM-targeted views showed stronger correlation with anatomic measurements for PPM length than standard views (0.966 vs. 0.752, p = 0.049), while standard views underestimated PPM length. In protocol 2, PM-targeted views enabled complete visualization of APM and PPM and yielded longer PM lengths and smaller maximum diameters than standard views. In protocol 3, males had larger PM maximum diameters and longer tip-to-annulus distances than females (all p < 0.05). With aging, interpapillary distance reduction (ΔIPMD), IPMD fractional shortening (IPMD-FS), and APM length decreased, whereas end-systolic IPMD increased (all p < 0.05). PM parameters correlated positively with body surface area (all p < 0.05). In protocol 4, PM measurements obtained from 2D PM-targeted views showed no differences from 3D echocardiographic measurements and demonstrated good correlation and agreement across assessed PM parameters against 3D echocardiographic measurement as a standard reference. Compared with healthy adults, patients with VFMR showed altered PM geometry/remodeling patterns. Conclusions: PM-targeted echocardiographic views improve visualization and measurement of papillary muscles and provide normative reference values, facilitating more accurate evaluation of PM-related abnormalities in clinical practice.

Abstract Background Echocardiographic Myocardial work (MW) has potential value in hypertrophic obstructive cardiomyopathy (HOCM). This study aimed to utilize corrected MW indices to characterize left ventricular (LV) myocardial mechanical remodeling and evaluate the extent of myocardial fibrosis (MF) in patients with HOCM. Methods We prospectively studied 41 patients with HOCM undergoing septal myectomy (SM). 21 patients underwent intraoperative invasive pressure measurement to validate the noninvasive left ventricular systolic pressure (LVSP) estimation and corrected MW analysis methods. Transthoracic echocardiography was performed in all patients at baseline and 3–6 months after SM. Preoperative and postoperative parameters such as global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were analyzed to investigate the characteristics of LV myocardial mechanical remodeling. The degree of histological MF was evaluated to determine the correlation between corrected MW parameters and MF. Results Noninvasive LVSP estimated by adding systolic blood pressure to the peak LV outflow tract gradient was well consistent with invasively measured LVSP (r = 0.98, P < 0.001; ICC = 0.96, P < 0.001). After SM, GWI, GCW, and GWE were significantly decreased (all P < 0.001), and GWW was significantly increased in HOCM patients (P = 0.002). Postoperatively, all patients exhibited new-onset complete left bundle branch block. Corrected GWI (R²=0.22, P = 0.002) and GCW (R²=0.25, P < 0.001) were independently associated with the extent of MF. Conclusion We validated a corrected method for analyzing MW in HOCM patients. HOCM patients may experience reduced metabolism and compromised contraction coordination after SM. GWI and GCW are associated with the level of MF.

Transplant rejection remains a significant barrier to the long-term success of organ transplantation. Biopsy, although considered the gold standard, is invasive, costly, and unsuitable for routine monitoring. Traditional biomarkers, such as creatinine and troponin, offer limited predictive value owing to their low specificity, and conventional imaging techniques often fail to detect early organ damage, increasing the risk of undiagnosed rejection episodes. Considering these limitations, emerging noninvasive biomarkers and molecular imaging techniques hold promise for the early and accurate detection of transplant rejection, enabling personalized management strategies. This review highlights noninvasive biomarkers that predict, diagnose, and assess transplant prognosis by reflecting graft injury, inflammation, and immune responses. For example, donor-derived cell-free DNA (dd-cfDNA) is highly sensitive in detecting early graft injury, whereas gene expression profiling effectively excludes moderate-to-severe acute rejection (AR). Additionally, microRNA (miRNA) profiling enhances the diagnostic specificity for precise AR detection. Advanced molecular imaging techniques further augment the monitoring of rejection. Fluorescence imaging provides a high spatiotemporal resolution for AR grading, ultrasound offers real-time and portable monitoring, and magnetic resonance delivers high tissue contrast for anatomical assessments. Nuclear imaging modalities such as single photon emission computed tomography and positron emission tomography, enable dynamic visualization of immune responses within transplanted organs. Notably, dd-cfDNA and nuclear medicine imaging have already been integrated into clinical practice, thereby demonstrating the translational potential of these techniques. Unlike previous reviews, this work uniquely synthesizes advancements in both noninvasive biomarkers and molecular imaging, emphasizing their complementary strengths. Biomarkers deliver molecular-level insights, whereas imaging provides spatial and temporal resolution. Together, they create a synergistic framework for comprehensive and precise transplant monitoring. By bridging these domains, this review underscores their individual contributions and collective potential to enhance diagnostic accuracy, improve patient outcomes, and guide future research and clinical applications in transplant medicine.

Background Accurate and early identification of impaired left ventricular (LV) function is essential to the optimal timing of intervention for primary mitral regurgitation. Myocardial work derived from noninvasive pressure‐strain loop is a novel and promising afterload‐independent approach to evaluate LV performance. We hypothesized that it may provide diagnostic and prognostic utility in these patients. This study aimed to evaluate myocardial work parameters in patients with significant primary mitral regurgitation, and explore their association with postinterventional LV ejection fraction and clinical composite events. Methods The study prospectively enrolled 180 patients with severe primary mitral regurgitation at baseline and patients were followed up for postinterventional LV function (>12 months) and clinical events (24.0 [23.3–24.6] months). Logistic regression and Cox proportional hazards regression analyses were performed as appropriate. Results Compared with patients exhibiting postinterventional LV ejection fraction ≥50%, individuals with LV ejection fraction <50% demonstrated lower LV global longitudinal strain, global work index (GWI), global constructive work (GCW), and global work efficiency (P<0.001 for all) and higher global wasted work (P=0.001). Preinterventional LV global longitudinal strain, GWI, GCW, and global work efficiency were independent predictors of postinterventional LV dysfunction (P<0.05 for all). The predictive power of logistic regression models comprising LV global longitudinal strain, GWI, and GCW were similar but stronger than the model comprising LV ejection fraction. Preinterventional LV global longitudinal strain, GWI, GCW, and global work efficiency were independently associated with the risk of composite clinical events during follow‐up (P<0.001 for all). Conclusions Myocardial work parameters, especially GWI, GCW, and global work efficiency, are independent predictors of postinterventional LV dysfunction and are associated with the occurrence of postinterventional clinical composite events.

The intrinsic abilities of macrophages, including innate homing, robust phagocytic capacity, and phenotypic plasticity, make them ideal candidates for targeted drug delivery. By utilizing macrophages as carriers, nanoparticles can be precisely transported to specific physiological sites, enhancing therapeutic efficacy and minimizing off-target effects. This strategy, known as the "macrophages hitchhiking", leverages the natural capabilities of macrophages to traverse biological barriers. The review comprehensively explores the role of macrophages in the pathogenesis of various diseases, highlighting their potential as vehicles for therapeutic interventions. It meticulously categorizes and summarizes the diverse array of nanoparticles that exploit macrophages for targeted delivery. The discussion elaborates on the design of nanoparticles aimed at enhancing macrophage uptake, facilitating the controlled release of therapeutic agents, with a systematic review of the applications. Additionally, the review provides an in-depth analysis of the advantages, limitations, and future directions of this approach. The transformative potential in personalized medicine is underscored, particularly in addressing scalability challenges and advancing the clinical translation of macrophage-targeted nanoparticles. Finally, the potential applications of the macrophage hitchhiking strategy for in situ CAR-Macrophage therapy were proposed. The review aims to catalyze the development of next-generation therapies and pave the way for more precise and effective treatment modalities.

BACKGROUND:Antibody-mediated rejection (AMR) is a critical cause of graft dysfunction after heart transplantation. The diagnostic "gold standard" is invasive endomyocardial biopsy. More precise non-invasive methods are desirable. Ultrasound molecular imaging noninvasively detects molecular changes during disease progression. As CD16a molecules contribute specifically to AMR, we hypothesized that ultrasound molecular imaging with CD16a-targeted probes might be an effective method for AMR detection. METHODS:CD16a-targeted microbubbles (MBCD16a) were prepared as the specific probes. Cardiac AMR models were established via pre-sensitization with donor serum before transplantation. C1 esterase inhibitor (C1-INH) was administered to inhibit complement activation. Ultrasound molecular imaging was performed on day 14 post-transplantation. Histological characterization was confirmed by hematoxylin-eosin staining and immunohistochemistry. RESULTS:In vitro, MBCD16a adhered to CD16a molecules and natural killer cells more strongly than control microbubbles (MBcon). In all allografts, the ultrasound molecular imaging signals of MBCD16a exceeded the signals of MBcon, while there were no differences in the isografts. The signals of MBCD16a were significantly higher in the pre-sensitized allografts than those in the non-sensitized allografts and isografts. In the C1-INH-treated pre-sensitized group, the signals of MBCD16a were still significantly higher than those in the two control groups. Histology showed strong AMR as intense microvascular inflammation in pre-sensitized groups, with sparse complement deposition in the C1-INH-treated allografts. Furthermore, the signals of MBCD16a were strongly correlated with histologically-proven CD16a expression. CONCLUSION:This study demonstrates that ultrasound molecular imaging with CD16a-targeted probes could serve as an effective noninvasive strategy for the monitoring of AMR, including the complement-deficient phenotype.

A 59-year-old male who underwent the Bentall procedure developed a newly identified echogenic mass in the right heart, detected via intraoperative transesophageal echocardiography (TEE). Thrombectomy under TEE guidance successfully removed the thrombus, and the patient recovered well. TEE was crucial for the real-time detection and management of this rare complication.

Abnormal Wnt5a expression, mitochondrial abnormalities and calcium overload have been detected in many metabolic diseases. However, the association of Wnt5a-Ca2+ and mitochondrial dysfunction in diabetic nephropathy (DN) progression remains unknown. We used streptozotocin-induced DBA2/J male mice as a DN model. The mice were treated with losartan (10 mg/kg/d*12 w) or losartan (10 mg/kg/d*12 w) + levamlodipine (5 mg/kg/d*12 w). High glucose (HG) (40 mmol/L)-induced HK-2 cells were used for in vitro experiments. Wnt5a and mitochondrial calcium uniporter (MCU) expression, mitochondrial dynamics, morphological changes and Ca2+ concentration were detected in different groups. Levamlodipine, a kind of calcium channel blocker, in combination with losartan ameliorated tubular injury and reversed mitochondrial fragmentation and dynamic dysfunction more efficiently than losartan alone in diabetic mice. Wnt5a induced Ca2+ uptake and aggravated mitochondrial fusion-fission disorder in HG-stimulated HK-2 cells. In addition, increased MCU formation was found in the mitochondria of tubular cells under HG stimulation and was upregulated by the activation of the Wnt5a-Ca2+ pathway. Our study showed that the Wnt5a-Ca2+ signalling pathway was involved in Ca2+ overload-induced mitochondrial dysfunction possibly through MCU in tubular injury and DN progression. A calcium channel blocker in combination with a renin-angiotensin system inhibitor (RASi) could be a promising therapeutic strategy in DN patients.

BACKGROUND:Identification of significant coronary artery stenosis (CAS) in patients with chronic coronary syndromes (CCS) is crucial for clinical management. Myocardial work (MW) is a new noninvasive method reflecting myocardial metabolism and has been applied in myocardial ischemia. We aimed to explore the value of global MW during vasodilator stress echocardiography in detecting significant CAS. METHODS:Patients with angina or equivalent symptoms underwent coronary angiography and vasodilator stress echocardiography. Significant CAS was defined as ≥70% luminal stenosis in one or more major epicardial vessels or ≥50% in the left main coronary. Global MW was analyzed by speckle-tracking echocardiography with blood pressure. The diagnostic performance of MW parameters in detecting significant CAS was evaluated. RESULTS:One hundred forty-six patients were enrolled into the study, and 67 patients had significant CAS. Coronary flow velocity reserve (CFVR), global longitudinal strain (GLS), global MW index (MWI), and global MW efficiency (MWE) were significantly lower in the significant CAS group than those in the non-significant group both at rest and peak stress (p < 0.001 for CFVR, GLS, MWE; p < 0.01 for MWI). Logistic regression analyses showed that CFVR and peak MWE effectively predicted significant CAS. Peak MWE outperformed other parameters with the highest area under the curve (AUC) of 0.820. Furthermore, the model integrating CFVR and peak MWE (AUC = 0.886) was much better than CFVR or peak MWE alone. CONCLUSIONS:Peak MWE combined with CVFR might be a reliable method of noninvasively screening significant CAS in patients with CCS before invasive angiography.

Genetic mutations are closely linked to various renal diseases, revealing important molecular mechanisms that contribute to kidney dysfunction. Here, we reported a 35-year-old Chinese female diagnosed of glomerulotubular nephropathy with multiple extra-renal manifestations including ptosis, corneal dystrophy, macular degeneration, right foot syndactyly. Whole-exome sequencing identified a homozygous frameshift variant in FAT1 (NM_005245: c.7444_7445delGT, p.Val2482AsnfsTer16). Further analysis revealed that this mutation caused translation repression of FAT1. RNA sequencing showed dysregulation of cell adhesion and Rap1 signaling pathways, while immunofluorescence staining demonstrated disrupted β-catenin junctions and cytoskeletal abnormalities in patient-derived primary urinary epithelial cells. Pull-down assays indicated that the reduction in activated Rap1 levels was correlated with the observed cellular defects. These findings provide compelling evidence that this loss-of-function homozygous FAT1 variant is causally associated with nephropathy and congenital anomalies, likely through degradation of transcribed mRNA and impaired protein expression. The results emphasize the critical role of FAT1 in renal development and provide new insights into the molecular mechanisms underlying these conditions.

Introduction:Patients undergoing maintenance hemodialysis are vulnerable to coronavirus disease 2019 (COVID-19), exhibiting a high risk of hospitalization and mortality. Thus, early identification and intervention are important to prevent disease progression in these patients. Methods:This was a two-center retrospective observational study of patients on hemodialysis diagnosed with COVID-19 at the Lingang and Xuhui campuses of Shanghai Sixth People's Hospital. Patients were randomized into the training (130) and validation cohorts (54), while 59 additional patients served as an independent external validation cohort. Artificial intelligence-based parameters of chest computed tomography (CT) were quantified, and a nomogram for patient outcomes at 14 and 28 days was created by screening quantitative CT measures, clinical data, and laboratory examination items, using univariate and multivariate Cox regression models. Results:The median dialysis duration was 48 (interquartile range, 24-96) months. Age, diabetes mellitus, serum phosphorus level, lymphocyte count, and chest CT score were identified as independent prognostic indicators and included in the nomogram. The concordance index values were 0.865, 0.914, and 0.885 in the training, internal validation, and external validation cohorts, respectively. Calibration plots showed good agreement between the expected and actual outcomes. Conclusion:This is the first study in which a reliable nomogram was developed to predict short-term outcomes and survival probabilities in patients with COVID-19 on hemodialysis. This model may be helpful to clinicians in treating COVID-19, managing serum phosphorus, and adjusting the dialysis strategies for these vulnerable patients to prevent disease progression in the context of COVID-19 and continuous emergence of novel viruses.

Myocardial ischemia/reperfusion injury (MIRI) is the leading cause of irreversible myocardial damage. A pivotal pathogenic factor is ischemia/reperfusion (I/R)-induced cardiomyocyte ferroptosis, marked by iron overload and lipid peroxidation. However, the impact of lipid droplet (LD) changes on I/R-induced cardiomyocyte ferroptosis is unclear. In this study, an aggregation-induced emission probe, TPABTBP is developed that is used for imaging dynamic changes in LD during myocardial I/R-induced ferroptosis. TPABTBP exhibits excellent LD-specificity, superior capability for monitoring lipophagy, and remarkable photostability. Molecular dynamics (MD) simulation and super-resolution fluorescence imaging demonstrate that the TPABTBP is specifically localized to the phospholipid monolayer membrane of LDs. Imaging LDs in cardiomyocytes and myocardial tissue in model mice with MIRI reveals that the LD accumulation level increase in the early reperfusion stage (0-9 h) but decrease in the late reperfusion stage (>24 h) via lipophagy. The inhibition of LD breakdown significantly reduces the lipid peroxidation level in cardiomyocytes. Furthermore, it is demonstrated that chloroquine (CQ), an FDA-approved autophagy modulator, can inhibit ferroptosis, thereby attenuating MIRI in mice. This study describes the dynamic changes in LD during myocardial ischemia injury and suggests a potential therapeutic target for early MIRI intervention.

Mitral regurgitation is the second most prevalent valvular disease, with primary mitral regurgitation (PMR) accounting for 61%–67% of cases. Chronic PMR can result in progressive left ventricular remodeling and dysfunction, ultimately leading to heart failure or other adverse cardiac events. This, in turn, necessitates frequent referrals, hospitalizations, and cardiac surgeries. The optimal timing for PMR surgery has been a subject of ongoing debate and remains a controversial issue. Presently, it is recommended that patients with chronic PMR undergo earlier mitral valve surgery to enhance post-operative outcomes. For example, the recommendation of European and American guidelines about left ventricular end-systolic diameter for surgery has been altered from 45 mm to 40 mm. Echocardiographic parameters are regarded as noteworthy indicators for intervention in patients with PMR. Extensive research has been undertaken in the field of echocardiography to identify more effective indicators that can propose the optimal timing for surgery, encompassing both conventional and novel echocardiography parameters. However, some parameters are not known to clinicians and the cut-off values for these parameters have shown some variations. Furthermore, a comprehensive review of this topic is currently missing. Consequently, this review aims to provide a thorough summary and elucidation of the prognostic significance of various echocardiographic measurements and their corresponding cut-off values, to help the clinical decision-making and further improve the outcomes of patients with PMR.

Background and aimsTranscatheter tricuspid valve replacement (TTVR) has recently emerged as a novel therapeutic approach for managing severe tricuspid regurgitation (TR). However, surgical tricuspid valve replacement (STVR) continues to be the predominant treatment modality. There are limited comparative data on both procedures. This study aimed to compare clinical and echocardiographic outcomes between patients who underwent mini-thoracotomy transatrial LuX-Valve TTVR and those who underwent STVR.MethodsThis study prospectively collected patients with severe TR who underwent TTVR (n = 29) or isolated STVR (n = 59) at Wuhan Union Hospital from 2019 to 2022. All TTVR patients received the LuX-Valve via a mini-thoracotomy and transatrial approach. The clinical and echocardiographic outcomes were compared at 30-day and one-year follow-ups.ResultsAt baseline, patients with LuX-Valve TTVR had higher surgical risk scores and a greater proportion of right ventricular dysfunction compared with STVR. In the early postoperative period, the STVR group had a greater decrease in right ventricular function. Hospital length of stay (LOS), intensive care unit LOS, total procedure time, and tracheal intubation time were shorter in the TTVR than in the STVR group. The incidence of postoperative paravalvular leaks was higher among patients who underwent TTVR. Compared to the STVR group, the pacemaker implantation rate was lower in the TTVR group. During follow-up, the peak tricuspid valve velocity and mean gradient in the TTVR group were consistently lower than those in the STVR group. There was similar mortality between TTVR and STVR at 30-day and one-year follow-ups.ConclusionsThe mini-thoracotomy transatria LuX-Valve TTVR has a higher incidence of paravalvular leaks and a lower rate of pacemaker implantation than STVR, with similar 30-day and one-year mortality rates. In some respects, mini-thoracotomy transatrial LuX-Valve TTVR may be a feasible and safe treatment option for specific populations, or it could potentially serve as an alternative therapy to supplement conventional STVR. Further follow-up is required to assess differences in long-term clinical outcomes and valve durability.