Daily Cardiology Research Analysis
Analyzed 151 papers and selected 3 impactful papers.
Summary
An individual-participant meta-analysis established a clinically actionable threshold (AASI ≥0.50) for ambulatory arterial stiffness that improves cardiovascular risk stratification. Basic–translational work identified a first-in-class small molecule (VU0494372) that corrects KCNQ1 trafficking and augments IKs, suggesting a new therapeutic avenue for congenital long-QT syndrome. A large contemporary US registry confirmed persistent operator volume–outcome relationships for TAVR and MTEER, informing credentialing and quality policies.
Research Themes
- Cardiovascular risk stratification using ambulatory metrics
- Ion-channel trafficking therapeutics for inherited arrhythmia
- Operator experience and outcomes in structural heart interventions
Selected Articles
1. End Point-Based Threshold for the Ambulatory Arterial Stiffness Index.
This individual-participant meta-analysis (12,558 participants, 14 cohorts) identified AASI ≥0.50 as a reproducible risk-carrying threshold associated with higher all-cause and cardiovascular events over a median 10.7 years. AASI improved model performance beyond traditional risk factors and findings were replicated in an independent sample.
Impact: Defines an actionable AASI threshold to operationalize ambulatory blood pressure-derived arterial stiffness in risk stratification, supporting integration into preventive cardiology.
Clinical Implications: Clinicians can use AASI ≥0.50 to flag patients for intensified risk factor control and closer follow-up, complementing standard office and ambulatory blood pressure metrics.
Key Findings
- Across 12,558 individuals, each 1-SD increase in AASI was associated with higher risk of all-cause death (HR 1.08) and cardiovascular events (HR 1.13).
- A reproducible risk-carrying threshold for AASI converged to 0.50, with HRs ≈1.13–1.19 across derivation and replication subsets.
- Adding AASI (continuous or thresholded) significantly improved model performance beyond traditional risk factors and subgroup analyses were confirmatory.
Methodological Strengths
- Individual-participant data meta-analysis across 14 population cohorts
- Prespecified derivation and replication with multivariable Cox modeling
Limitations
- Observational nature limits causal inference
- Potential heterogeneity in AASI derivation and ambulatory monitoring protocols across cohorts
Future Directions: Prospective implementation studies to test AASI-guided management strategies and integration into cardiovascular risk calculators.
BACKGROUND: The ambulatory arterial stiffness index (AASI) is increasingly used in clinical research and practice. This individual-participant meta-analysis aims to consolidate the prognostic accuracy of AASI in the general population and to derive an end point-based AASI risk threshold. METHODS: In 12 558 individuals enrolled in 14 population studies (48.8% women; mean age, 59.3 years), AASI was derived by regressing 24-hour diastolic on systolic blood pressure (mm Hg/mm Hg). Using Cox regression, the risk-carrying AASI threshold was established by examining stepwise increasing AASI levels and by determining the AASI level, yielding a 10-year risk similar to an office systolic pressure of 140 mm Hg. RESULTS: Over 10.7 years (median), 3027 all-cause deaths and 2183 cardiovascular end points occurred. In all participants, multivariable-adjusted hazard ratios expressing the all-cause deaths and cardiovascular end point risk per 1-SD AASI increment were 1.08 (95% CI, 1.04-1.13) and 1.13 (95% CI, 1.07-1.18). In a randomly defined subset of 8189 individuals, the risk-carrying AASI thresholds converged to 0.50 with hazard ratios (≥0.50 versus <0.50) of 1.14 (95% CI, 1.04-1.26) for all-cause deaths and 1.13 (95% CI, 1.01-1.26) for cardiovascular end point. In the replication sample (n=4369), these hazard ratios were 1.13 (95% CI, 1.01-1.26) and 1.19 (95% CI, 1.04-1.35). AASI continuous or per threshold significantly improved model performance. Analyses of secondary end points and subgroups stratified by sex, age, hypertension status and treatment, history of cardiovascular disease, and nocturnal dipping were confirmatory. CONCLUSIONS: Over and beyond traditional risk factors, AASI improves risk stratification. Exceeding the risk-carrying 0.50 AASI threshold necessitates increased vigilance in managing risk factors before irreversible cardiovascular complications occur.
2. High throughput screening identifies a trafficking corrector for long-QT syndrome associated KCNQ1 variants.
A small molecule (VU0494372) was identified that increases total and surface KCNQ1 and enhances IKs in WT and a pathogenic variant (V207M), correcting trafficking without altering transcription or degradation. A putative interaction site near ML277 binding was suggested, providing a druggable approach to address the root molecular defect in KCNQ1-related LQTS.
Impact: Demonstrates feasibility of trafficking-corrector pharmacology for ion-channelopathies, potentially transforming treatment of KCNQ1-driven LQTS beyond beta-blockade and device therapy.
Clinical Implications: If validated in vivo, trafficking correctors could complement or replace current therapies for select LQTS genotypes by restoring IKs through improved KCNQ1 surface expression.
Key Findings
- VU0494372 increased total and cell-surface KCNQ1 and trafficking efficiency for WT and multiple LQTS-associated variants.
- A 16-hour treatment enhanced IKs in cells co-expressing KCNQ1/KCNE1 (WT and V207M).
- Mechanism favored accelerated trafficking without affecting transcription, degradation, or thermal stability; a potential binding site near ML277 was suggested.
Methodological Strengths
- High-throughput screening coupled with electrophysiology for functional validation
- Multiple orthogonal assays to parse trafficking vs. expression mechanisms
Limitations
- Preclinical in vitro work without in vivo efficacy or safety data
- Limited number of KCNQ1 variants tested; generalizability across genotypes uncertain
Future Directions: Evaluate in vivo pharmacodynamics, safety, and efficacy across broader KCNQ1 variants and explore structure-activity relationships for optimization.
Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss-of-function secondary to impaired trafficking of the channel to the plasma membrane. There are currently no therapeutic approaches that address this underlying molecular defect. Using a high-throughput screening paradigm, we identified VU0494372, a small molecule that increases total and cell surface levels and trafficking efficiency of WT KCNQ1 as well as three LQTS-associated variants. Additionally, 16-hour treatment of cells with VU0494372 increased IKs (KCNQ1-KCNE1 current) for WT KCNQ1 and the LQTS-associated variant V207M in cells co-expressing KCNE1. VU0494372 had no impact on KCNQ1 transcription, degradation, or thermal stability, and increased the rate of KCNQ1 reaching the cell surface. We identified a potential direct interaction site with KCNQ1 at or near the binding site of the KCNQ1 potentiator ML277. Together, these findings demonstrate that small molecules can increase the expression levels and cell surface trafficking efficiency of KCNQ1 and introduce a potential new pharmacological approach for treating LQTS.
3. Contemporary Operator Procedural Volumes and Outcomes for TAVR and MTEER in the US.
In 410,350 procedures from the US TVT Registry (2020–2023), low-volume operators had higher adjusted 30-day mortality and in-hospital complications for TAVR and higher complications for MTEER, independent of hospital volume. Operator outcomes for TAVR and MTEER were not correlated, underscoring procedure-specific learning curves.
Impact: Provides definitive, contemporary, operator-level evidence supporting minimum volume standards and targeted proctoring in structural heart interventions.
Clinical Implications: Programs should consider operator-specific volume thresholds for credentialing and ongoing quality review, and tailor mentorship pathways separately for TAVR and MTEER.
Key Findings
- Low-volume TAVR operators (<15/year) had higher adjusted 30-day mortality (OR 1.13) and in-hospital complications (OR 1.09) vs high-volume (>37/year).
- Low-volume MTEER operators (<8/year) had higher in-hospital complications (OR 1.31); 30-day mortality differences were not significant.
- Associations persisted across hospital volume strata; operator-level outcomes for TAVR and MTEER were not correlated.
Methodological Strengths
- National all-comers registry with very large sample size and contemporary practice
- Two-level random-effects modeling adjusting for patient and site factors
Limitations
- Observational design with residual confounding possible despite adjustment
- Short-term (30-day) endpoints; long-term durability not assessed
Future Directions: Define evidence-based operator volume thresholds, assess longitudinal learning curves, and evaluate targeted training/proctoring interventions.
IMPORTANCE: Recent evidence suggests that hospital-level associations between procedural volume and outcomes for transcatheter aortic valve replacement (TAVR) and mitral transcatheter edge-to-edge repair (MTEER) may be plateauing. Less is known about the operator volumes-outcomes association in the contemporary era. OBJECTIVE: To determine whether an operator-level volume-outcomes association exists for TAVR and MTEER in the contemporary era. DESIGN, SETTING, AND PARTICIPANTS: This cohort study examined data from patients undergoing TAVR or MTEER between January 2020 and December 2023 included in the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) Registry, a national all-comers real-world registry. Consecutive patients undergoing TAVR for aortic stenosis or MTEER for mitral regurgitation were included. Data analysis was performed from October 2024 to December 2025. EXPOSURE: TAVR or MTEER. MAIN OUTCOMES AND MEASURES: The primary outcome measures were (1) 30-day all-cause mortality, (2) a 30-day composite outcome, and (3) in-hospital procedural complications following TAVR or MTEER. Data from the STS/ACC TVT Registry were analyzed for patients undergoing TAVR or MTEER between 2020 and 2023. The primary analysis assessed the association between operator volume and 30-day outcomes using a 2-level random-effects logistic regression model. The interaction between operator and hospital volumes and the association between TAVR and MTEER outcomes were also evaluated. RESULTS: A total of 358 943 patients underwent TAVR at 827 hospitals (7524 operators; median [IQR] annual volume, 24 [11-47]), and 51 407 patients underwent MTEER at 493 hospitals (2483 operators; median [IQR] annual volume, 12 [7-19]). For TAVR, median (IQR) patient age was 79.0 (73.0-85.0) years, and 152 186 patients (42.4%) were female; for MTEER, median (IQR) patient age was 79.0 (71.0-84.0) years, and 23 402 patients (45.5%) were female. Low-volume operators demonstrated inferior process of care measures compared with high-volume operators. In adjusted analyses, a higher risk of 30-day mortality (odds ratio [OR], 1.13; 95% CI, 1.02-1.26; P = .02) and in-hospital complications (OR, 1.09; 95% CI, 1.03-1.16; P = .005) was observed for low-volume TAVR operators (<15/y) compared with high-volume operators (>37/y). For MTEER, in-hospital complications (OR, 1.31; 95% CI, 1.11-1.56; P = .002) were higher for low-volume operators (<8/y) compared with high-volume operators (>16/y), while 30-day mortality was not different (OR, 1.16; 95% CI, 0.96-1.41; P = .12). Associations were consistent across hospital volume strata. Operator-level outcomes for TAVR and MTEER were not correlated. CONCLUSIONS AND RELEVANCE: In this cohort study, results from a large, contemporary US registry demonstrate a persistent inverse association between operator volume and patient outcomes for both TAVR and MTEER. These findings may help inform future policies aimed at ensuring optimal outcomes.