Importance As transcatheter aortic valve replacement (TAVR) is considered for younger and lower-risk populations, the durability of bioprosthetic valves is increasingly important. Limited data exist on long-term (7 years and beyond) valve durability. Objective To report 7-year valve durability outcomes for low-risk patients with symptomatic severe aortic stenosis treated with TAVR vs surgery. Design, Setting, and Participants Between March 2016 and October 2017, a total of 1000 patients were enrolled at 71 centers in the US and Canada and randomized to undergo TAVR vs surgery. The patient population for the present analysis consisted of all patients who underwent valve implantation (495 with TAVR and 453 with surgery). The last 7-year follow-up occurred in March 2025. Interventions Patients were randomized to balloon-expandable TAVR with the SAPIEN 3 valve or surgery with any commercially available valve. Main Outcomes and Measures The main outcomes of this analysis were stage 2 or 3 bioprosthetic valve dysfunction (BVD) related to structural valve deterioration (SVD), thrombosis, or endocarditis; all-cause bioprosthetic valve failure (BVF); BVF related to SVD; and aortic valve reintervention at 7 years. Analyses are presented as cumulative incidence rates with death as a competing risk. Results The mean (SD) age of the study population was 73.5 (6.0) years, and 657 participants (69.3%) were male. Of 671 patients who were still alive and enrolled in the study at 7-year follow-up, 537 (80.0%) were available for echocardiographic analysis. Cumulative incidence rates of stage 2 or 3 SVD-related BVD (7.3% vs 7.6%; hazard ratio [HR], 0.96; 95% CI, 0.59-1.57; P = .88), all-cause BVF (6.9% vs 7.5%; HR, 0.91; 95% CI, 0.55-1.49; P = .69), SVD-related BVF (3.9% vs 5.3%; HR, 0.72; 95% CI, 0.39-1.36; P = .31), and valve reintervention (6.0% vs 5.5%; HR, 1.09; 95% CI, 0.62-1.90; P = .77) were low and similar for TAVR and surgery, respectively. Stage 2 or 3 thrombosis-related BVD (subclinical and clinical) occurred more frequently with TAVR (5.2% vs 0.9%; HR, 5.52; 95% CI, 1.92-15.85; P < .001), although most events occurred within 3 years and few progressed to BVF. Rates of stage 2 or 3 endocarditis-related BVD were also low and similar (0.4% in the TAVR group vs 0.5% in the surgery group; HR, 0.85; 95% CI, 0.12-6.07; P = .87). The proportion of patients alive and free of all-cause BVF was 73.4% (331/451) with TAVR vs 74.8% (288/385) with surgery ( P = .69). Conclusions and Relevance In this ad hoc analysis of a randomized clinical trial among low-risk patients with symptomatic severe aortic stenosis randomized to TAVR or surgery, both TAVR and surgery demonstrated comparable and sustained valve durability, with low and similar rates of SVD, all-cause BVF, and reintervention through 7 years. These findings may inform discussions of valve replacement strategies. Trial Registration ClinicalTrials.gov Identifier: NCT02675114

BACKGROUND:Patients with non-ST elevation acute coronary syndrome (NSTE-ACS) who have significant left main and/or three-vessel disease (LM/3VD) are at particularly high risk for poor outcomes. Timely identification and revascularization of these patients is essential. However, growing healthcare resource limitations necessitate patient triage and prioritization to avoid delays in care. AIMS:To identify clinical predictors of LM/3VD available at initial NSTE-ACS presentation and validate a prediction model in independent cohorts. METHODS:Retrospective data of NSTE-ACS patients from National Cardiovascular Data Registries of three institutional cohorts were analyzed. Logistic regression identified predictors of LM/3VD in an index cohort to develop a predictive model. The model's performance was subsequently evaluated in the remaining two cohorts. RESULTS:Among 1706 NSTE-ACS patients, 24 % had LM/3VD. Seven clinical predictors-age ≥ 65, male sex, diabetes, ECG abnormalities, heart rate > 90 bpm, history of stroke/TIA, and signs of heart failure-were used to derive the MADISON score. The model demonstrated an AUC-ROC of 0.67 across cohorts. At the prespecified clinical threshold (score ≥ 4), the MADISON score showed high specificity (83.5-95 %) but low-to-moderate sensitivity (3.5-34.4 %) for LM/3VD detection. CONCLUSIONS:A high MADISON score (≥4) reliably identifies patients at increased risk of LM/3VD with high specificity, supporting its potential use for triage and prioritization of patient care in resource-limited settings.

Introduction: In patients with non-ST elevation acute coronary syndrome (NSTE-ACS), identifying those with a high probability of having high-risk disease such as left main (LM) or three-vessel disease (3VD) could influence decisions to preload with P2Y12 inhibitors and timing of coronary angiography. The MADISON score was developed to predict LM/3VD on coronary angiography in patients with NSTE-ACS. In this study, we validated the MADISON score using data from an external cohort. Methods: The MADISON score was first developed using a retrospective cohort of 1700 patients presenting with NSTE-ACS at the University of Wisconsin-Madison (UW) (2011-2018). Those with prior CABG, cardiac arrest/shock, and bleeding on initial presentation were excluded from the analysis. Multivariable estimates were employed and model performance was assessed using receiver operating characteristic curve analysis. The score was then validated using a retrospective Houston Methodist Hospital (HMH) cohort of 622 patients (2019-2022). Results: The MADISON score variables and their adjusted odds ratios (95% CI) are presented in Figure 1A. Risk categories and corresponding LM/3VD probabilities are presented in Figure 1B. In the UW cohort, the area under the curve (AUC) was 0.68 (0.65-0.71) (Figure 2A). Interestingly, the AUC was also 0.68 (0.64-0.72) in the HMH validation cohort (Figure 2B). Conclusions: The MADISON score performed well and similarly between 2 large, independent cohorts in predicting patients most likely to have LM/3VD. The MADISON score is a simple and practical tool to guide decisions. Prospective validation of the score is planned to evaluate its impact on clinical outcomes.

Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion. Here, we describe 2 patients with overlapping de novo 2q24.2q24.3 deletions, characterized by array-CGH. This is the smallest 2q24.2q24.3 region of overlap described in the literature encompassing only 9 genes (SLC4A10, DPP4, GCG, FAP, IFIH1, GCA, KCNH7, FIGN, GRB14). We focused our attention on SLC4A10, DPP4, and KCNH7, genes associated with neurological features. Our patients presented similar features: intellectual disability, developmental and language delay, hypotonia, joint laxity, and dysmorphic features. Only patient 2 showed profound deafness and also carried a heterozygous mutation of the GJB2 gene responsible for autosomal recessive deafness 1A (DFNB1A: OMIM 220290). Could the disruption of a gene present in the 2q24.2q24.3 deleted region be responsible for her profound hearing loss?

This case series presents patients who presented to the hospital with an outside hospital cardiac arrest and were initially resuscitated successfully. All patients suffered fatal traumatic injuries during the resuscitation process with the common variable being the use of mechanical cardiopulmonary resuscitation (CPR) device. The goal of this case series is to describe the limitations and potential fatal side effects of CPR. We also present a review of literature with our impressions of the appropriate indications for the use of mechanical CPR.Learning objectives:1) Recognize appropriate indications for the use of mechanical vs manual cardiopulmonary resuscitation (CPR). 2) Identify signs and symptoms of mechanical CPR-related complications.

Cardiac amyloidosis can occasionally demonstrate an atypical pattern of infiltration, causing asymmetric septal thickening and a left ventricular outflow tract (LVOT) gradient with systolic anterior motion (SAM) of the mitral valve resembling obstructive hypertrophic cardiomyopathy. We present a case of a 70-year-old man with cardiac light-chain amyloidosis and LVOT obstruction successfully treated with alcohol septal ablation (ASA). Following the procedure, he reported significant improvement in his heart failure symptoms as well as improvement in LVOT gradient and SAM of the mitral valve. This case demonstrates that ASA is a technically feasible and effective procedure for relieving LVOT obstruction in cardiac amyloidosis and can be considered as a treatment option in patients whose symptoms are refractory to medical therapy.

Interstitial 6p25.1p24.3 microdeletions are rare events and a clear karyotype/phenotype correlation has not yet been determined. In this study, we present the clinical and molecular description of a child with a de novo 6p25.1p24.3 microdeletion, characterized by array-CGH, associated with mild intellectual disability, facial dysmorphisms, hypopigmentation of the skin of the abdomen, heart defects, mild pontine hypoplasia and hypotonia. This deleted region contains 14 OMIM genes ( NRN1 , F13A1 , RREB1 , SSR1 , RIOK1 , DSP , BMP6 , TXNDC5 , BLOC1S5 , EEF1E1 , SLC35B3 and HULC) . To the best of our knowledge until now only six cases have been reported presenting an interstitial microdeletion, but a unique case carries a deleted region containing the same genes of our patient. We compared clinical features and genetic data with that of the previously reported patient. We also analysed the gene content of the deleted region to investigate the possible role of specific genes in the clinical phenotype of our patient.

AIMS:In paradoxical low-flow low-gradient severe aortic stenosis (PLFLG AS) patients, stroke volume index (SVI) is reduced despite preserved left ventricular ejection fraction (LVEF). Although reduced SVI is already known as a poor prognostic predictor, the outcomes of PLFLG AS patients after transcatheter aortic valve replacement (TAVR) have not been clearly defined. We retrospectively investigated the post-TAVR outcomes of PLFLG AS patients in comparison with normal-flow high-gradient aortic stenosis (NFHG AS) patients. METHODS:The current observational study included 245 patients with NFHG AS (mean transaortic pressure gradient ≥40 mmHg and LVEF ≥ 50%) and 48 patients with PLFLG AS (mean transaortic pressure gradient <40 mmHg, LVEF ≥ 50% and SVI < 35 ml/m2). The endpoints were all-cause mortality, hospitalization for valve-related symptoms or worsening congestive heart failure and New York Heart Association functional class III or IV. RESULTS:PLFLG AS patients had a significantly higher proportion with a history of atrial fibrillation/flutter as compared with NFHG AS patients. All-cause mortality of PLFLG AS patients was worse than that of NFHG AS patients (P = 0.047). Hospitalization for valve-related symptoms or worsening congestive heart failure was more frequent in PLFLG AS patients than in NFHG AS patients (P = 0.041). New York Heart Association functional class III-IV after TAVR was more frequently observed in PLFLG AS patients (P = 0.019). CONCLUSION:The outcomes of PLFLG AS patients were worse than those of NFHG AS patients in this study. Preexisting atrial fibrillation/flutter was frequent in PLFLG AS patients, and may affect their post-TAVR outcomes. Therefore, closer post-TAVR follow-up should be considered for these patients.

Objective Aortic stenosis (AS) is common among elderly patients. Since transcatheter aortic valve replacement (TAVR) is a less invasive procedure than surgical aortic valve replacement for symptomatic severe AS, super-elderly patients have tended to undergo TAVR. We retrospectively investigated the post-TAVR outcome in super-elderly patients with severe AS. Methods This analysis included 433 patients who underwent TAVR in the University of Wisconsin Hospital and Clinics from 2012 to 2017. Post-TAVR mortality, complications in-hospital, rehospitalization, the New York Heart Association (NYHA) functional class and echocardiographic parameters were compared between patients <85 years old (n = 290) and ≥85 years old (n = 143). Results The patients ≥85 years old less frequently had a history of coronary artery disease (73.1% vs. 62.2%, p=0.026) and hypertension (87.2% vs. 77.6%, p=0.012) than younger patients. Furthermore, the patients ≥85 years old had moderate-severe mitral regurgitation more frequently (19.3% vs. 28.7%, p=0.037) at baseline than younger patients. There was no significant difference in in-hospital outcomes between the age groups. The 30-day mortality was worse in patients ≥85 years old than in younger ones (0.7% vs. 3.5%, p=0.042). While there was no significant difference in the long-term mortality between the 2 groups, the estimated 1-year mortality from Kaplan-Meier curves were 9.6% in patients <85 years old and 14.9% in patients ≥85 years old. The rate of in-hospital complications, rehospitalization rate, improvement in the NYHA functional class and echocardiographic parameters were comparable between the two groups. Conclusion The outcomes of super-elderly patients after TAVR were acceptable, suggesting that these patients could benefit from TAVR.

Objective To evaluate the impact of increased pulmonary artery systolic pressure (PASP) on outcomes after transcatheter aortic valve replacement (TAVR). Methods A total of 242 patients who underwent TAVR were retrospectively reviewed. Transthoracic echocardiography estimated PASP. The cohorts were divided into three groups according to the numerical change of PASP; Increased (post-TAVR PASP at 1 month minus pre-TAVR PASP, >= + 5 mmHg; n = 52), No change (-5 to +5 mmHg; n = 86) and Decreased (<= -5 mmHg; n = 104). Patient demographics and clinical outcomes until 1 year were evaluated. Logistic regression model was used for multivariate risk analysis. Results At 1 year, the Increased group showed higher mortality (21 +/- 6%) than the No change group (5 +/- 2%) (hazard ratio [HR]: 4.8, 95% confidence interval [CI]: 1.7-13.5; p < .01) and the Decreased group (8 +/- 3%) (HR: 2.8, 95% CI: 1.1-6.7; p = .02). Rehospitalization rate for valve-related or heart failure was also higher in the Increased group (21 +/- 6%) than the No change group (10 +/- 3%) (HR: 2.4, 95% CI: 1.1-6.0; p = .04). Predictors of PASP deterioration were hypertension (odds ratio [OR]: 3.9, 95% CI: 1.1-13.8; p = .04) and left ventricular end-diastolic diameter >50 mm (OR: 2.2, 95% CI: 1.1-4.6; p = .04), and the increased PASP remained an independent predictor of 1-year all-cause mortality (HR; 2.7, 95% CI: 1.0-6.8; p = .04). Conclusions Regardless of the baseline PASP, patients with increased PASP at 1 month after successful TAVR were at higher risk of mortality and rehospitalization within 1 year. Strict medical management should be considered for patients who showed dilated left ventricle preoperatively.

Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been involved in neuronal growth and connectivity. Genetic variants, in or near the NEGR1 locus, have been associated with obesity and, more recently, with learning difficulties, intellectual disability, and psychiatric disorders. Here, we described the only second report of NEGR1 gene disruption in 1p31.1 microdeletion in two patients. Patient 1 is a 14-year-old female with neurological and psychiatric features present also in her family. Patient 2 is a 5-month-old infant showing global hypotonia as unique neurological features till now. This patient also carries 7p22.1 duplication, of paternal origin, that could be responsible for some malformations present in the child. We hypothesize a role of NEGR1 in producing the phenotype of our patients and compare them with other cases previously reported in the literature and DECIPHER database to better identify a possible genotype-phenotype correlation.

The 16p12.2 chromosome band contains three large segmental duplications: BP1, BP2 and BP3, providing a substrate for recombination and recurrent chromosomal rearrangements. The '16p12.2 microdeletion' is a recurrent deletion comprised between BP2 and BP3, associated with variable clinical findings. We identified a heterozygous 16p12.2 microdeletion spanning between BP1 and BP2 in a child evaluated for short stature and mild dyslexia. Unexpectedly, the mother carried the same deletion in the homozygous state and suffered from severe hearing loss. Detailed family history revealed consanguinity of the maternal grandparents. The 16p12.2 microdeletion is a rare condition and contains only three genes: METTL9, IGSF6 and OTOA of which the OTOA is considered responsible for DFNB22 hearing loss (MIM: 607039) under its homozygous condition. A number of OTOA mutations have been described, whereas very few cases of a 16p12.2 microdeletion similar to that observed in our family have been reported. In conclusion, we describe a rare 'distal 16p12.2microdeletion' widening the phenotypic spectrum associated with the recurrent 16p12.2 microdeletion and support the causative role of OTOA microdeletion in hearing impairment.

ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system. We report on 2 brothers, aged 7.6 and 20 years, presenting with cognitive impairment, epilepsy, autistic features, hearing loss, and obesity. Array-CGH analysis demonstrated 2 rare CNVs in both siblings: a paternally inherited microdeletion of ∼145 kb at 3p22.1, disrupting the ULK4 gene, and a maternally inherited microduplication of ∼117 kb at Xq21.1 including only the BRWD3 gene. As already described for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counseling because of an evident variable penetrance. We discuss the possible correlations between the clinical phenotype of our patients and the function of the genes involved in these microrearrangements.

Heterogeneous clinical and neuropsychological features, such as intellectual disability, developmental and language delay, hypotonia, and, to a lesser extent, microcephaly that is present in about the half of the reported patients, characterize the 3q29 microduplication syndrome with usually a milder phenotype compared with the corresponding 3q29 microdeletion syndrome. The duplications described so far range from 2.3 Mb to 1.6 Mb, spanning from TFRC to BDH1 genes. Here we report on two patients with overlapping interstitial duplications of the 3q29 region differing in size. Patient 1 harboured a common-seized 3q29 microduplication spanning ∼1.6 Mb, while patient 2 carried a very small 3q29 microduplication of 448.8 Kb encompassing only two genes, DLG1 and BDH1. Both patients presented clinical characteristics similar to those reported in the literature in 3q29 microduplication syndrome. Interestingly, heterotopic gray matter nodules were found along the right lateral ventricle on brain MRI in patient 1, thus expanding the neuroradiological phenotype in 3q29 microduplication syndrome, while patient 2 allowed us to define with more precision the smallest region of overlap (SRO). Gene content analysis of the duplicated region suggests that gain-of-dosage of DLG1 and BDH1 may be a good candidate for the main clinical features of this syndrome.

Submicroscopic chromosomal alterations usually involve different protein-coding genes and regulatory elements that are responsible for rare contiguous gene disorders, which complicate the understanding of genotype-phenotype correlations. Chromosome band 3p26.3 contains 3 genes encoding neuronal cell adhesion molecules: CHL1, CNTN6, and CNTN4. We describe 2 boys aged 8 years and 11 years mainly affected by intellectual disability and autism spectrum disorder, who harbor a paternally inherited 3p26.3 microdeletion and a 3p26.3 microduplication, respectively. Both anomalies involved only the CNTN6 gene, which encodes contactin 6, a member of the contactin family (MIM 607220). Contactins show pronounced brain expression and function. Interestingly, phenotypes in reciprocal microdeletions and microduplications of CNTN6 are very similar. In conclusion, our data, added to those reported in the literature, are particularly significant for understanding the pathogenic effect of single gene dosage alterations. As for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.

17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases. Seventeen patients have been reported so far. Here, we present another patient with 17q11.2 duplication and no signs of neurofibromatosis type 1, identified by array-CGH. We compared clinical features and genetic data with those of previously reported patients with 17q11.2 microduplications. We also analyzed the gene content of the duplicated region in order to investigate the possible role of specific genes in the clinical phenotype of our patient.