Daily Cardiology Research Analysis
Three impactful cardiology studies stood out: a mechanistic discovery links the KIF13B/ITCH/CBL/MERTK axis to impaired macrophage efferocytosis and accelerated atherosclerosis, with pharmacologic rescue in mice; a randomized CEASE-AF trial shows durable 24‑month superiority of hybrid epicardial–endocardial ablation over catheter ablation for persistent/long-standing AF; and a multicenter cohort reveals that noncardiac referral pathways in severe aortic stenosis are associated with less timely fo
Summary
Three impactful cardiology studies stood out: a mechanistic discovery links the KIF13B/ITCH/CBL/MERTK axis to impaired macrophage efferocytosis and accelerated atherosclerosis, with pharmacologic rescue in mice; a randomized CEASE-AF trial shows durable 24‑month superiority of hybrid epicardial–endocardial ablation over catheter ablation for persistent/long-standing AF; and a multicenter cohort reveals that noncardiac referral pathways in severe aortic stenosis are associated with less timely follow-up/AVR and higher mortality.
Research Themes
- Macrophage efferocytosis mechanisms in atherosclerosis
- Durability of hybrid ablation for persistent/long-standing atrial fibrillation
- Health system pathways and outcomes in severe aortic stenosis
Selected Articles
1. The macrophage-derived motor protein KIF13B enhances MERTK-mediated efferocytosis and prevents atherosclerosis in mice.
Across human plaques and multiple mouse models, loss of KIF13B impairs macrophage efferocytosis by reducing ITCH and permitting CBL-mediated ubiquitination/degradation of MERTK, thereby worsening atherosclerosis. Pharmacologic CBL antagonism (NX-1607) restored MERTK, rescued efferocytosis, and reduced plaque burden, identifying a druggable KIF13B/ITCH/CBL/MERTK axis.
Impact: This study uncovers a previously unrecognized mechanism controlling macrophage efferocytosis and plaque progression and demonstrates in vivo pharmacologic rescue, paving a translational path to modulate residual inflammatory risk in atherosclerosis.
Clinical Implications: While preclinical, targeting the KIF13B/ITCH/CBL/MERTK axis may enhance efferocytosis and plaque stability beyond lipid lowering. It supports development of agents (e.g., CBL antagonists) for patients with persistent inflammatory risk.
Key Findings
- KIF13B expression is reduced in human atherosclerosis and inversely associates with plaque progression in mice.
- Myeloid Kif13b deletion enlarges plaques and increases macrophage apoptosis without altering plasma lipids.
- Mechanistically, KIF13B loss lowers ITCH, enabling CBL-mediated ubiquitination/degradation of MERTK and impairing efferocytosis.
- Oral CBL antagonist NX-1607 restores MERTK, rescues efferocytosis, and mitigates atherosclerosis in Kif13b-deficient mice.
Methodological Strengths
- Multi-system approach: human plaque analyses, global/myeloid knockouts, bone marrow chimeras, and in vitro macrophage studies.
- Mechanistic validation with pharmacologic intervention (CBL antagonist) demonstrating in vivo reversibility.
Limitations
- Predominantly preclinical findings; human data are correlative.
- Safety, specificity, and clinical translatability of CBL antagonism require rigorous evaluation.
Future Directions: Validate the KIF13B/ITCH/CBL/MERTK axis in diverse human cohorts, assess plaque biology endpoints in large animals, and initiate early-phase trials of targeted modulators (e.g., CBL antagonists) focused on efferocytosis enhancement.
BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disorder with high morbidity and mortality rates worldwide. Emerging evidence has reported that kinesin family member 13B (KIF13B), a crucial motor protein, integrates hepatic lipid metabolism and inflammatory response to protect liver disease. However, the relationship between KIF13B and atherosclerosis remains unknown. The present study aimed to elucidate the specific role of KIF13B in atherosclerosis and its potential therapeutic significance. METHODS: The investigation first assessed the relationship between the expression levels of KIF13B and the progression of atherosclerosis in human cohort data and carotid plaques from patients. Subsequently, the authors generated Kif13b knockout (Kif13b-/-) mice on low-density lipoprotein receptor (Ldlr)-deficient background (Ldlr-/-) to obtain double knockouts (Kif13b-/-;Ldlr-/-) and myeloid-specific Kif13b knockout mice (Lyz2 Cre;Kif13bf/f) with adeno-associated virus 8 (AAV8)-mediated overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). Moreover, Ldlr-/- mice received bone marrow transplants from either Kif13b-/-;Ldlr-/- or Ldlr-/- mice and were fed a Western diet (WD) for 12 weeks. RESULTS: KIF13B expression was significantly reduced in patients with atherosclerosis and negatively associated with the severity of atherosclerotic progress in WD-fed Ldlr-/- mice. In contrast to Kif13b-/-;Ldlr-/- mice showing a significant increase in plasma total cholesterol and more atherosclerosis lesions compared with the corresponding control mice, depletion of myeloid-derived Kif13b and bone marrow transplantation with macrophages lacking Kif13b both did not alter plasma lipid levels but elicited the larger atherosclerotic plaques with increased macrophage infiltration and more apoptotic cells. In vitro studies showed that upon oxidized low-density lipoprotein treatment, macrophages with Kif13b deficiency also display significantly increased cholesterol accumulation and impaired efferocytosis with reduced MER proto-oncogene, tyrosine kinase (MERTK) expression. Mechanistic study revealed that loss of Kif13b decreased the expression of Itchy E3 ubiquitin protein ligase (ITCH), leading to accelerated ubiquitination and degradation of MERTK mediated by Casitas B-lineage lymphoma (CBL) in macrophages. Moreover, oral administration of NX-1607, a CBL antagonist, significantly reversed the reduction of MERTK protein level and defective efferocytosis, ultimately protecting against atherosclerotic development caused by Kif13b deficiency in vivo. CONCLUSIONS: The study results revealed that KIF13B is a crucial modulator responsible for maintaining proper macrophage efferocytosis to prevent atherosclerotic development through KIF13B/ITCH/CBL/MERTK axis, suggesting that KIF13B will be a potential therapeutic target for the treatment of atherosclerosis in future clinical trials.
2. Durable effectiveness and safety of hybrid ablation versus catheter ablation: 2-year results from the randomized CEASE-AF trial†.
In persistent/long-standing AF, hybrid epicardial–endocardial ablation achieved 66.3% drug-free arrhythmia freedom at 24 months versus 33.3% with catheter ablation, with similar major complication rates and markedly fewer reinterventions. The durability of the 12‑month absolute benefit (≈33%) was maintained at 24 months.
Impact: Provides rare 24‑month randomized evidence supporting a procedural strategy that halves recurrence and reduces reinterventions in difficult non-paroxysmal AF, informing care pathways and patient counseling.
Clinical Implications: For symptomatic, drug-refractory persistent AF (and LSPAF), hybrid ablation should be considered where expertise exists, given superior durability without excess major complications and fewer redo procedures.
Key Findings
- At 24 months, arrhythmia freedom off class I/III AADs: 66.3% (HA) vs 33.3% (CA); absolute difference 33.0% (95% CI 14.3–48.3; P<0.001).
- Major complications were similar: 10.8% (HA) vs 9.6% (CA); P=1.0.
- Reinterventions were significantly fewer after HA: 18.9% vs 52.9% (P<0.001).
Methodological Strengths
- Prospective, multicentre randomized design with registered protocol (NCT02695277).
- Intention-to-treat analysis with 24‑month follow-up and clinically meaningful endpoints.
Limitations
- Modest sample size and 2:1 randomization; potential performance bias inherent to complex hybrid procedures.
- Industry funding; generalizability depends on surgical–electrophysiology team expertise.
Future Directions: Larger pragmatic RCTs comparing hybrid strategies across operator experience, cost-effectiveness analyses, and structured pathways to scale hybrid programs where appropriate.
OBJECTIVES: The CEASE-AF trial demonstrated that epicardial-endocardial hybrid ablation (HA) had superior effectiveness compared to endocardial catheter ablation (CA) for non-paroxysmal atrial fibrillation (AF), without significantly increasing major complications during a 12-month period. Most contemporary AF ablation trials have not evaluated durability beyond 12 months. Therefore, 24-month effectiveness and safety of HA and CA are compared. METHODS: CEASE-AF is a prospective, multicentre, randomized trial. Patients 18-75 years of age with symptomatic, drug refractory persistent AF and left atrial diameter >4.0 cm or long-standing persistent AF were randomized 2:1 to HA (posterior wall and pulmonary vein isolation with left atrial appendage exclusion) or CA (pulmonary vein isolation). Secondary effectiveness was freedom from AF/atrial flutter/atrial tachycardia off class I/III anti-arrhythmic drugs except for those who previously failed at doses not exceeding those previously failed through a 24-month follow-up period. Major complications and reinterventions were evaluated. RESULTS: The intention-to-treat population was 102 patients with HA and 52 patients with CA. Seventy-five percent were male, 80.5% had persistent AF and 19.5% had long-standing persistent AF, with a mean age of 60.7 ± 7.9 years. Effectiveness for 24 months was 66.3% (63/95) with HA and 33.3% (17/51) with CA [absolute difference 33.0% (95% confidence interval 14.3%, 48.3%; P < 0.001)]. Major complication rates were 10.8% (11/102) with HA and 9.6% (5/52) with CA (P = 1.0), and fewer patients had reinterventions after HA than CA [18.9% (18/95) vs 52.9% (27/51), P < 0.001]. CONCLUSIONS: CEASE-AF demonstrated that the 32.4% absolute benefit of HA over CA for 12 months was durable for 24 months at 33% with continued similar safety rates and fewer reinterventions after HA (funded by AtriCure, Inc.; NCT02695277). CLINICALTRIALS.GOV REGISTRATION: NCT02695277.
3. Referral patterns and clinical outcomes in patients with severe aortic stenosis: A multicenter cohort study.
In 4,249 patients with newly diagnosed severe AS, 42% never underwent AVR (32% despite symptoms). When the index echocardiogram was ordered by noncardiac providers, patients had markedly lower odds of early cardiology follow-up/AVR, fewer AVRs, and higher mortality—especially in low-flow, low-gradient AS.
Impact: Highlights system-level gaps in referral pathways that directly affect life-saving therapy uptake and survival in severe AS, providing actionable targets for quality improvement.
Clinical Implications: Implement standardized alerts and direct cardiology referral protocols for severe AS diagnosed outside cardiology; prioritize expedited evaluation of low-flow, low-gradient AS; monitor pathway metrics (90‑day follow-up/AVR) across service lines.
Key Findings
- Overall, 42% did not undergo AVR during follow-up; 32% of symptomatic patients remained without AVR.
- Noncardiac ordering of the index echo was associated with lower early follow-up/AVR (aOR 0.33), fewer AVRs (aHR 0.59), and higher mortality (aHR 1.65).
- Disparities were more pronounced in low-flow, low-gradient severe AS.
Methodological Strengths
- Large, multicenter real-world cohort across three health systems with robust multivariable modeling.
- Clinically relevant process and outcome endpoints (early follow-up/AVR, AVR rates, mortality).
Limitations
- Observational design with potential residual confounding and misclassification of provider specialty.
- Generalizability depends on health system structures; symptom burden and patient preferences not fully captured.
Future Directions: Test system-level interventions (EHR alerts, auto-referral pathways) in pragmatic trials; investigate barriers in low-flow, low-gradient AS; evaluate equity impacts of redesigned referral processes.
BACKGROUND: Patients with severe aortic stenosis (AS) require timely follow-up by cardiac specialists and aortic valve replacement (AVR). This multicenter study evaluates how the specialty of the provider who ordered the initial echocardiogram influences these endpoints. METHODS: Patients from 3 health systems with a first echocardiogram (index echo) diagnosing severe AS from Jan 1, 2019 to Dec 31, 2022, were categorized based on the specialty of the provider ordering the echo. Endpoints included a composite outcome of early cardiac follow-up or AVR (within 90 days), AVR during follow-up, and mortality. Logistic regression and Cox proportional hazard models were used to identify factors associated with the endpoints. RESULTS: 4,249 patients (77 years; 58% male; 88% white; 72% symptomatic AS) were followed for a median of 552 days. Eighty-nine percent of patients achieved the composite outcome, yet 1,801 patients (42%) did not receive an AVR during the follow-up period, including 32% of symptomatic patients. Patients referred for the index echo by noncardiac specialty providers had lower rates of early cardiac follow-up or AVR (adjusted OR: 0.33, 95% CI, 0.25-0.43), lower AVR rates (adjusted HR: 0.59, 95% CI, 0.53-0.66), and higher mortality (adjusted HR: 1.65; 95% CI, 1.44-1.90) compared to the patients referred by a cardiology provider; the discrepancy was more pronounced in patients with low-flow, low-gradient AS. CONCLUSION: In this large multicenter study of patients with severe AS, patients with a noncardiac specialty provider were less likely to receive timely cardiac follow-up and AVR, and had higher mortality. Initiatives to address disparities in care and improve outcomes for this high-risk population are needed.