Examining the typical hemodynamic performance of nearly 3000 modern surgical aortic bioprostheses.

OBJECTIVES: The objective of this analysis was to assess the normal haemodynamic performance of contemporary surgical aortic valves at 1 year postimplant in patients undergoing surgical aortic valve replacement for significant valvular dysfunction. By pooling data from 4 multicentre studies, this study will contribute to a better understanding of the effectiveness of surgical aortic valve replacement procedures, aiding clinicians and researchers in making informed decisions regarding valve selection and patient management. METHODS: Echocardiograms were assessed by a single core laboratory. Effective orifice area, dimensionless velocity index, mean aortic gradient, peak aortic velocity and stroke volume were evaluated. RESULTS: The cohort included 2958 patients. Baseline age in the studies ranged from 70.1 ± 9.0 to 83.3 ± 6.4 years, and Society of Thoracic Surgeons risk of mortality was 1.9 ± 0.7 to 7.5 ± 3.4%. Twenty patients who had received a valve model implanted in fewer than 10 cases were excluded. Ten valve models (all tissue valves; n = 2938 patients) were analysed. At 1 year, population mean effective orifice area ranged from 1.46 ± 0.34 to 2.12 ± 0.59 cm2, and dimensionless velocity index, from 0.39 ± 0.07 to 0.56 ± 0.15. The mean gradient ranged from 8.6 ± 3.4 to 16.1 ± 6.2 mmHg with peak aortic velocity of 1.96 ± 0.39 to 2.65 ± 0.47 m/s. Stroke volume was 75.3 ± 19.6 to 89.8 ± 24.3 ml. CONCLUSIONS: This pooled cohort is the largest to date of contemporary surgical aortic valves with echocardiograms analysed by a single core lab. Overall haemodynamic performance at 1 year ranged from good to excellent. These data can serve as a benchmark for other studies and may be useful to evaluate the performance of bioprosthetic surgical valves over time. CLINICAL TRIAL REGISTRATION NUMBER: NCT02088554, NCT02701283, NCT01586910 and NCT01531374.

Secondary Pulmonary Alveolar Proteinosis Development during the Treatment for Anti-aminoacyl-tRNA Synthetase Antibody-positive Interstitial Lung Disease.

A 70-year-old woman with anti-aminoacyl-tRNA synthetase (ARS) antibody-positive interstitial lung disease (ARS-ILD) received daily medications and regular cyclophosphamide cycles for recurring exacerbations. Approximately four years after immunosuppression initiation, the patient was admitted for progressive dyspnea on exertion. Chest computed tomography (CT) findings were suggestive of acute exacerbation. Despite intensified immunosuppressive treatment, the radiographic findings worsened, and serum Krebs von den Lungen-6 (KL-6) levels increased. A bronchoalveolar lavage fluid (BALF) examination revealed amorphous globules and alveolar macrophages with eosinophilic granules. Owing to negative anti-GM-CSF antibody tests, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) was established.

3-Year Outcomes After Transcatheter or Surgical Aortic Valve Replacement in Low-Risk Patients With Aortic Stenosis.

BACKGROUND: Randomized data comparing outcomes of transcatheter aortic valve replacement (TAVR) with surgery in low-surgical risk patients at time points beyond 2 years is limited. This presents an unknown for physicians striving to educate patients as part of a shared decision-making process. OBJECTIVES: The authors evaluated 3-year clinical and echocardiographic outcomes from the Evolut Low Risk trial. METHODS: Low-risk patients were randomized to TAVR with a self-expanding, supra-annular valve or surgery. The primary endpoint of all-cause mortality or disabling stroke and several secondary endpoints were assessed at 3 years. RESULTS: There were 1,414 attempted implantations (730 TAVR; 684 surgery). Patients had a mean age of 74 years and 35% were women. At 3 years, the primary endpoint occurred in 7.4% of TAVR patients and 10.4% of surgery patients (HR: 0.70; 95% CI: 0.49-1.00; P = 0.051). The difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: -1.8% at year 1; -2.0% at year 2; and -2.9% at year 3. The incidence of mild paravalvular regurgitation (20.3% TAVR vs 2.5% surgery) and pacemaker placement (23.2% TAVR vs 9.1% surgery; P < 0.001) were lower in the surgery group. Rates of moderate or greater paravalvular regurgitation for both groups were <1% and not significantly different. Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs 12.1 mm Hg surgery; P < 0.001) at 3 years. CONCLUSIONS: Within the Evolut Low Risk study, TAVR at 3 years showed durable benefits compared with surgery with respect to all-cause mortality or disabling stroke. (Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients; NCT02701283).

Structural Valve Deterioration After Self-Expanding Transcatheter or Surgical Aortic Valve Implantation in Patients at Intermediate or High Risk.

Importance: The frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood. Objective: To evaluate the 5-year incidence, clinical outcomes, and predictors of hemodynamic SVD in patients undergoing self-expanding TAVI or surgery. Design, Setting, and Participants: This post hoc analysis pooled data from the CoreValve US High Risk Pivotal (n = 615) and SURTAVI (n = 1484) randomized clinical trials (RCTs); it was supplemented by the CoreValve Extreme Risk Pivotal trial (n = 485) and CoreValve Continued Access Study (n = 2178). Patients with severe aortic valve stenosis deemed to be at intermediate or increased risk of 30-day surgical mortality were included. Data were collected from December 2010 to June 2016, and data were analyzed from December 2021 to October 2022. Interventions: Patients were randomized to self-expanding TAVI or surgery in the RCTs or underwent self-expanding TAVI for clinical indications in the nonrandomized studies. Main Outcomes and Measures: The primary end point was the incidence of SVD through 5 years (from the RCTs). Factors associated with SVD and its association with clinical outcomes were evaluated for the pooled RCT and non-RCT population. SVD was defined as (1) an increase in mean gradient of 10 mm Hg or greater from discharge or at 30 days to last echocardiography with a final mean gradient of 20 mm Hg or greater or (2) new-onset moderate or severe intraprosthetic aortic regurgitation or an increase of 1 grade or more. Results: Of 4762 included patients, 2605 (54.7%) were male, and the mean (SD) age was 82.1 (7.4) years. A total of 2099 RCT patients, including 1128 who received TAVI and 971 who received surgery, and 2663 non-RCT patients who received TAVI were included. The cumulative incidence of SVD treating death as a competing risk was lower in patients undergoing TAVI than surgery (TAVI, 2.20%; surgery, 4.38%; hazard ratio [HR], 0.46; 95% CI, 0.27-0.78; P = .004). This lower risk was most pronounced in patients with smaller annuli (23 mm diameter or smaller; TAVI, 1.32%; surgery, 5.84%; HR, 0.21; 95% CI, 0.06-0.73; P = .02). SVD was associated with increased 5-year all-cause mortality (HR, 2.03; 95% CI, 1.46-2.82; P < .001), cardiovascular mortality (HR, 1.86; 95% CI, 1.20-2.90; P = .006), and valve disease or worsening heart failure hospitalizations (HR, 2.17; 95% CI, 1.23-3.84; P = .008). Predictors of SVD were developed from multivariate analysis. Conclusions and Relevance: This study found a lower rate of SVD in patients undergoing self-expanding TAVI vs surgery at 5 years. Doppler echocardiography was a valuable tool to detect SVD, which was associated with worse clinical outcomes. Trial Registration: ClinicalTrials.gov Identifiers: NCT01240902, NCT01586910, and NCT01531374.

Sex Differences in LV Remodeling and Hemodynamics in Aortic Stenosis: Sex-Specific Criteria for Severe Stenosis?

BACKGROUND: The current criteria for aortic stenosis (AS) severity have not incorporated sex-related differences. OBJECTIVES: The authors investigated sex-related serial changes in left ventricular (LV) structure/function and hemodynamics in AS. METHODS: Serial echocardiograms of patients with severe AS (time 0; aortic valve area [AVA] ≤1 cm2) and ≥1 previous echocardiogram were compared between sexes. RESULTS: Of 927 patients (time 0: AVA 0.87 ± 0.11 cm2, peak velocity 4.03 ± 0.65 m/s, mean Doppler systolic pressure gradient [MG] 40.6 ± 13.1 mm Hg), 393 (42%) were women. Women had smaller body surface area (BSA) (1.77 ± 0.22 m2 vs 2.03 ± 0.20 m2; P < 0.001), lower stroke volume (SV) (81.1 ± 17.2 mL vs 88.3 ± 18.6 mL; P < 0.001), and more frequent low-gradient severe AS (n = 196 [50%] vs n = 181 [34%]; P < 0.001). Women consistently had smaller AVA, indexed AVA (AVAi), peak velocity, and MG than men. The difference in aortic valve gradient lessened when AVAi ≤0.6 cm2/m2 was applied as severe AS (n = 694, women 43%, AVA 0.95 ± 0.17 cm2, AVAi 0.50 ± 0.07 cm2/m2). Peak velocity (3.83 ± 0.66 m/s) and MG (36.5 ± 13.2 mm Hg) were lower based on AVAi severity criteria compared to those based on AVA. Men had a lower left ventricular ejection fraction (LVEF) (55.8% ± 14.8% vs 61.1% ± 11.7%; P < 0.001) and greater reduction in SV (-13.3 ± 19.6 mL vs -7.4 ± 16.4 mL; P < 0.001) as AS progressed from moderate to severe. Concentric LV hypertrophy was more common and E/e' higher in women (21.2 ± 10.9 vs 18.8 ± 9.1; P < 0.001). SV, LVEF, AVA, peak velocity, and MG became precipitously worse when AVA reached 1.2 cm2 in both sexes. CONCLUSIONS: Smaller BSA in women yields lower SV, resulting in lower aortic valve gradient than men. Indexed parameters by BSA are thus important in sex-related differences of aortic valve hemodynamics, but AVAi ≤0.6 cm2/m2 includes individuals with moderate AS. Elevated filling pressure is more common in women. Men experience a larger reduction in SV and LVEF as AS progresses. The definition of AS severity may require different criteria between sexes.

cGAS-STING signaling encourages immune cell overcoming of fibroblast barricades in pancreatic cancer.

Immune checkpoint blockade (ICB) treatment improves the prognosis of several types of solid tumors, however, responsiveness to ICB therapy remains low in pancreatic ductal adenocarcinoma (PDACs), which has a rich tumor microenvironment (TME). The TME is composed of various stromal cells, including cancer-associated fibroblasts (CAFs), which contribute to the establishment of an immunosuppressive microenvironment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate immune pathway that results in the upregulation of immune cell recruiting-cytokines and anti-tumor efficacy. In this study, we aimed to investigate the impact of cGAS-STING expression and the presence of CAFs upon immune cell infiltration in PDACs. cGAS and STING co-expressing PDAC cases showed favorable survival, with many cytotoxic CD8 + T cell infiltrations from the stromal component adjacent to the cancer cells toward cancer cells, but not in cGAS-STING signaling defected PDAC cases. The signatures of tumor-restrain CAFs were expressed in tumors with cGAS-STING signaling. Finally, transwell co-culture experiments demonstrated that immune cell infiltration was impeded by the presence of CAFs, but not by activation of cGAS-STING signaling. In conclusion, pro-infiltration signals, such as cGAS-STING, and characterization of CAFs are crucial in defeating CAF barricades and encouraging immune cell infiltration in PDACs.

Final 3-year clinical outcomes following transcatheter aortic valve implantation with a supra-annular self-expanding repositionable valve in a real-world setting: Results from the multicenter FORWARD study.

OBJECTIVES: The Evolut R FORWARD study confirmed safety and effectivenesss of the Evolut R THV in routine clinical practice out to 1 year. Herein, we report the final 3-year clinical follow up of the FORWARD study. BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a proven alternative to surgery in elderly patients with symptomatic severe aortic stenosis. Long-term clinical outcome data with the Evolut R platform are scarce. METHODS: FORWARD is a prospective multicenter observational study that evaluated the Evolut R system in routine clinical practice at 53 centres. Eligible patients had symptomatic native aortic valve stenosis or failed surgical aortic bioprosthesis and elevated operative risk per Heart-Team assessment. TAVR was attempted in 1039 patients. RESULTS: Mean age was 81.8 ± 6.2 years, 64.9% were women, STS score was 5.5 ± 4.5% and 34.2% were frail. Rates of all-cause mortality and disabling stroke were 24.8% and 4.8% at 3 years. Early need for a new pacemaker implantation after TAVR (all-cause mortality: with new PPI; 21.0% vs. without; 22.8%, p = 0.55) and the presence of > trace paravalvular regurgitation (all-cause mortality: no or trace; 22.0% vs. ≥ mild; 25.5%, p = 0.29) did not affect survival. Between 1 and 3 years incidence rates of valve related intervention, endocarditis and clinically relevant valve thrombosis were low. CONCLUSIONS: The Evolut R valve maintained a favorable safety profile through 3 years in routine clinical practice. Rates of transcatheter heart valve-related adverse events were low.

Electrocardiogram screening for aortic valve stenosis using artificial intelligence.

AIMS: Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS. METHODS AND RESULTS: Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90-2.50). CONCLUSION: An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.

Prognostic Risk Stratification of Patients with Moderate Aortic Stenosis.

BACKGROUND: Currently risk stratification of moderate aortic stenosis (AS) is still incipient. The aim of this study was to identify prognostic factors in patients with moderate AS. METHODS: The prognosis of patients with moderate AS (1 < aortic valve area ≤ 1.5 cm2) stratified by left ventricular ejection fraction (LVEF; 50%), stroke volume index (SVI; 35 mL/m2), and elevated E/e' ratio (average, 14) was compared with that of the age- and sex-matched general population. RESULTS: Of 696 patients (median age, 77 years; aortic valve area 1.3 cm2; 57% men), 279 (40%) died during a median follow-up period of 3.4 years. Mortality was higher in patients with moderate AS than reference (mortality ratio, 2.43; 95% CI, 2.17-2.72). LVEF < 50%, SVI < 35 mL/m2, and elevated E/e' ratio were present in 113 (17%), 54 (8%), and 330 (54%) patients; mortality ratios were 3.89 (95% CI, 3.07-4.85), 6.40 (95% CI, 4.57-8.71), and 2.58 (95% CI, 2.21-3.00), respectively. Even if LVEF or SVI was preserved, the mortality ratio was more than twice than reference (P < .001), but elevated E/e' ratio could discriminate additional patients at higher risk (hazard ratio [HR], 2.71; 95% CI, 1.88-3.91). Two hundred one patients (29%) underwent aortic valve replacement at a median of 2.3 years after the diagnosis of moderate AS. LVEF < 50% (HR, 2.98; 95% CI, 1.39-6.56), SVI < 35 mL/m2 (HR, 3.34; 95% CI, 1.02-10.90) and elevated E/e' ratio (HR, 2.73; 95% CI, 1.26-5.94) were all associated with worse prognosis even if aortic valve replacement was performed. CONCLUSIONS: In patients with moderate AS, those with decreased LVEF and/or SVI are at high risk. Even if these parameters are preserved, patients with elevated E/e' ratios are at intermediate risk. Further investigation is warranted to assess whether earlier intervention could improve outcomes and reduced cardiac-related death among patients at high and intermediate risk.

Total Synthesis of Termicalcicolanone A via Organocatalysis and Regioselective Claisen Rearrangement.

A total synthesis of an anticancer xanthone natural product termicalcicolanone A utilizing multiple nucleophilic aromatic substitutions and pericyclic reactions has been developed. The pyrano[3,2- b]xanthen-6-one scaffold was constructed via NHC-catalyzed aroylation to produce the benzophenone intermediate, Claisen cyclization to form the pyran ring, and intramolecular 1,4-addition to construct the xanthone framework. The prenyl group was introduced in the final stages of the synthesis through regioselective Claisen rearrangement. The synthesis has been achieved in 19 steps.

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas.

BACKGROUND: A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). CASE PRESENTATION: Here, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site. CONCLUSIONS: Although agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.

A case of ascending aortic dissection and rupture caused by giant cell arteritis.

Giant cell arteritis (GCA) is an autoimmune disease characterized by granulomatous inflammation in the wall of medium-sized and large-sized arteries, and it usually occurs in patients over 50 years of age.(1)) Symptoms are nonspecific, and include fatigue, fever, and headache.(2)) It is occasionally combined with aortic complications, and ruptures resulting in death. These complications occur as late events, usually several years after diagnosis and often after other symptoms have subsided.(3)) Physicians should therefore be alert for complications of the large arteries in GCA. Here we present a case of GCA combined with ascending aortic dissection and rupture 3 weeks after diagnosis.

Left atrial remodeling and recurrence of congestive heart failure in patients initially diagnosed with heart failure.

BACKGROUND: Left atrial volumes (LAVs) have been suggested to represent long-term exposure to elevated pressures. This study examined the recurrence of heart failure (HF) based on LAV in patients initially diagnosed with congestive HF (CHF). METHODS: This study comprised 77 patients (age, 75 ± 8 years) with well-documented, clinically defined HF, and complete two-dimensional echocardiographic examinations. The echocardiographic examinations were performed on admission and after medical treatment (90 ± 43 days after initial examination). Patients with atrial fibrillation, flail mitral valve, or mitral valve replacement were excluded from this study. RESULTS: The initial left ventricular ejection fraction (LVEF) was 44 ± 17% and the indexed LAV (LAVI) was 61 ± 22 mL/m(2) . After medical treatment, a decreased LAVI was observed in 38 patients and an increased LAVI (LA remodeling) was observed in 39 patients. With median follow-up periods of 454 days, compared to patients with decreased LAVI, patients with LA remodeling had a significantly higher incidence of CHF recurrence (P = 0.008). Patients with LA remodeling had a CHF-free survival rate of 36 ± 13% vs. 81 ± 9% (those without LA remodeling). A multivariate analysis indicated that, follow-up LV end-systolic volume (P = 0.04), LVEF (P = 0.005) and LAVI (P = 0.04) independently predicted CHF recurrence. CONCLUSIONS: Patients initially diagnosed with CHF follow divergent courses based on their LAV. LA remodeling after medical treatment can be useful for predicting CHF recurrence during follow-up.

A case with myxoma of the left ventricular outflow tract.

Left ventricular (LV) myxomas are rare. We present a case of a LV myxoma arising from the interventricular septum of the LV outflow tract in a 76-year-old woman. General examination of the patient did not reveal any abnormality except for a grade 3/6 systolic murmur in the left parasternal area. Transthoracic echocardiography revealed a round pedunculated mass (size, 23 mm × 11 mm × 10 mm) at the interventricular septum with a broad pedicle. The mass was successfully removed and was pathologically confirmed to be a myxoma. .

Trousseau syndrome with nonbacterial thrombotic endocarditis in a patient with uterine cancer.

This paper aims to describe the usefulness of transthoracic echocardiography in the follow-up of recurrent nonbacterial thrombotic endocarditis (NBTE) associated with neoplastic conditions. A 60-year-old woman with advanced uterine cancer developed recurrent areas of aseptic vegetation on the mitral valve along with cerebral, renal and splenic embolisms. Echocardiographic assessments revealed vegetation and thrombotic events on three occasions. In this case, transthoracic echocardiography was effective in following the decreased frequency of attachment of the NBTE vegetation to the mitral valve and reductions in the size of the area of vegetation following treatment with unfractionated heparin infusion, hysterectomy and chemotherapy.