Daily Cardiology Research Analysis
Three impactful cardiology papers emerged today: a mechanistic JCI study identifies asparagine endopeptidase (AEP) as a novel driver of atherosclerosis by cleaving APOA1 and impairing HDL biogenesis; the CONSYST-CRT randomized trial shows conduction system pacing is noninferior to biventricular pacing for CRT clinical response; and the SwissTAVI registry links post-TAVR pacemaker implantation to higher long-term mortality and functional decline.
Summary
Three impactful cardiology papers emerged today: a mechanistic JCI study identifies asparagine endopeptidase (AEP) as a novel driver of atherosclerosis by cleaving APOA1 and impairing HDL biogenesis; the CONSYST-CRT randomized trial shows conduction system pacing is noninferior to biventricular pacing for CRT clinical response; and the SwissTAVI registry links post-TAVR pacemaker implantation to higher long-term mortality and functional decline.
Research Themes
- Atherosclerosis mechanisms and therapeutic targets
- Cardiac resynchronization: conduction system pacing vs biventricular pacing
- Structural heart disease: TAVR outcomes and device-related complications
Selected Articles
1. Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis.
This mechanistic study identifies APOA1 as a direct substrate of AEP, with AEP-mediated cleavage at N208 impairing cholesterol efflux and HDL formation. Genetic AEP deletion or pharmacologic blockade (inhibitor #11a) prevented APOA1 cleavage and markedly reduced atherosclerosis in ApoE−/− and LDLR−/− mice, positioning AEP as a translational therapeutic target.
Impact: It reveals a first-in-kind mechanism linking a lysosomal protease to HDL biogenesis failure and atherosclerosis and demonstrates targetability with a small-molecule inhibitor across two murine models.
Clinical Implications: While preclinical, the AEP–APOA1 axis offers a tractable pathway to enhance cholesterol efflux and HDL functionality; AEP inhibitors could complement LDL-lowering therapy in high-risk atherosclerosis if safety and efficacy translate to humans.
Key Findings
- AEP is upregulated in human atherosclerotic plaques and cleaves APOA1 at residue N208.
- AEP activation impairs cholesterol efflux and HDL formation; AEP deletion attenuates atherosclerosis in ApoE−/− mice.
- Blocking APOA1 cleavage by N208A mutation or with AEP inhibitor #11a markedly reduces atherosclerosis in ApoE−/− and LDLR−/− mice.
Methodological Strengths
- Use of human plaque samples and two independent murine models (ApoE−/− and LDLR−/−)
- Target validation via genetics (AEP knockout, APOA1 N208A) and pharmacology (AEP inhibitor #11a)
Limitations
- Preclinical models may not fully recapitulate human lipoprotein metabolism and plaque biology
- Long-term safety and off-target effects of AEP inhibition were not evaluated in humans
Future Directions: Develop selective, clinically viable AEP inhibitors; validate APOA1 cleavage products as biomarkers; test target engagement and lipid/vascular effects in early-phase human trials.
Atherosclerosis is a slowly progressing inflammatory disease characterized with cholesterol disorder and intimal plaques. Asparagine endopeptidase (AEP) is an endolysosomal protease that is activated under acidic conditions and is elevated substantially in both plasma and plaques of patients with atherosclerosis. However, how AEP accelerates atherosclerosis development remains incompletely understood, especially from the view of cholesterol metabolism. This project aims to reveal the crucial substrate of AEP during atherosclerosis plaque formation and to lay the foundation for developing novel therapeutic agents for Atherosclerosis. Here, we show that AEP is augmented in the atherosclerosis plaques obtained from patients and proteolytically cuts apolipoprotein A1 (APOA1) and impairs cholesterol efflux and high-density lipoprotein (HDL) formation, facilitating atherosclerosis pathologies. AEP is activated in the liver and aorta of apolipoprotein E-null (APOE-null) mice, and deletion of AEP from APOE-/- mice attenuates atherosclerosis. APOA1, an essential lipoprotein in HDL for cholesterol efflux, is cleaved by AEP at N208 residue in the liver and atherosclerotic macrophages of APOE-/- mice. Blockade of APOA1 cleavage by AEP via N208A mutation or its specific inhibitor, #11a, substantially diminishes atherosclerosis in both APOE-/- and LDLR-/- mice. Hence, our findings support that AEP disrupts cholesterol metabolism and accelerates the development of atherosclerosis.
2. Clinical Response to Resynchronization Therapy: Conduction System Pacing vs Biventricular Pacing: The CONSYST-CRT Trial.
In 134 CRT-eligible patients, CSP achieved noninferiority to BiVP for the 12‑month composite clinical endpoint and several secondary endpoints (echocardiographic response, NYHA class, QRS narrowing). LVEF and LVESV changes were similar across arms but did not meet formal NI thresholds, supporting CSP as a viable CRT strategy.
Impact: This is one of the first randomized trials with clinical endpoints directly comparing CSP vs BiVP, informing device strategy selection for CRT.
Clinical Implications: CSP can be considered an alternative to BiVP in CRT candidates, particularly when coronary sinus anatomy is unfavorable or when targeting physiologic activation; programs should develop CSP expertise while awaiting larger confirmatory RCTs.
Key Findings
- Primary composite endpoint noninferiority for CSP vs BiVP at 12 months (23.9% vs 29.8%; P=0.02 for NI).
- Noninferiority for combined hard endpoint (all-cause death, transplant, HF hospitalization), echocardiographic response (66.6% vs 59.7%), NYHA class improvement, and QRS shortening.
- LVEF and LVESV improvements were similar between arms, though NI was not formally met for these specific measures.
Methodological Strengths
- Randomized controlled design with pre-registered protocol (NCT05187611)
- Multiple clinically meaningful endpoints including hard outcomes and echocardiographic response
Limitations
- Modest sample size and open-label design with allowed crossovers may dilute treatment effects
- Not powered for mortality alone; noninferiority not met for some echocardiographic parameters
Future Directions: Large, multicenter RCTs powered for hard outcomes, durability and lead-related complications; cost-effectiveness and patient-reported outcomes comparing CSP vs BiVP.
BACKGROUND: Randomized studies comparing conduction system pacing (CSP) with biventricular pacing (BiVP) are scarce and do not include clinical outcomes. OBJECTIVES: The CONSYST-CRT (Conduction System Pacing vs Biventricular Resynchronization Therapy in Systolic Dysfunction and Wide QRS) trial aimed to test the noninferiority of CSP as compared with BiVP in patients with an indication for cardiac resynchronization therapy, with respect to a combined clinical endpoint at 1-year follow-up. METHODS: A total of 134 patients with cardiac resynchronization therapy indication were randomized to BiVP or CSP and followed up for 12 months. Crossover was allowed when the primary allocation procedure failed. The atrioventricular interval was optimized to obtain fusion with intrinsic conduction. The primary combined endpoint was all-cause mortality, cardiac transplant, heart failure hospitalization, or left ventricular ejection fraction (LVEF) improvement <5 points at 12 months. Secondary endpoints were LVEF increase, LV end-systolic volume (LVESV) decrease, echocardiographic response (≥15% LVESV decrease), QRS shortening, septal flash correction, NYHA functional class improvement, and a combined endpoint of all-cause mortality, cardiac transplantation, and heart failure hospitalization. RESULTS: Sixty-seven patients were allocated to each group. Eighteen patients (26.9%) crossed from CSP to BiVP; 5 (7.5%) crossed over from BiVP to CSP. Noninferiority (NI) was observed for CSP compared with BiVP for the primary endpoint (23.9% vs 29.8%, respectively; mean difference -5.9; 95% CI: -21.1 to 9.2; P = 0.02) and for the combined endpoint of all-cause mortality, cardiac transplantation, and heart failure hospitalization (11.9% vs 17.9%; P < 0.01 NI); echocardiographic response (66.6% vs 59.7%; P = 0.03 NI); NYHA functional class (P < 0.001 NI); and QRS shortening (P < 0.01). LVEF, LVESV, and septal flash endpoint values were similar, but noninferiority was not met (14.1% ± 10% vs 14.4% ± 10%, -27.9% ± 27% vs -27.9% ± 28%, -2.2 ± 2.7 mm vs -2.7 ± 2.4 mm, respectively). CONCLUSIONS: CSP was noninferior to BiVP in achieving clinical and echocardiographic response, suggesting that CSP could be an alternative to BiVP. (Conduction System Pacing vs Biventricular Resynchronization Therapy in Systolic Dysfunction and Wide QRS [CONSYST-CRT]; NCT05187611).
3. Long-Term Outcomes of Patients Requiring Pacemaker Implantation After Transcatheter Aortic Valve Replacement: The SwissTAVI Registry.
In a nationwide prospective cohort of 13,360 TAVR patients, 15% required a pacemaker within 30 days. Pacemaker implantation was independently associated with higher 1‑year overall and cardiovascular mortality (aHR 1.15 and 1.25), increased LVEF decline and worse NYHA class, with excess mortality persisting through 10 years.
Impact: Provides robust, long-term, multicenter evidence linking post-TAVR pacemaker implantation to adverse outcomes, informing procedural strategies to minimize conduction injury.
Clinical Implications: Pre- and intraprocedural strategies to reduce conduction system injury (implantation depth optimization, device selection, cusp overlap, conduction-sparing techniques) should be prioritized; risk–benefit discussions must include potential long-term harms of pacemaker dependency after TAVR.
Key Findings
- Among 13,360 TAVR patients, 15% required pacemaker implantation within 30 days.
- Pacemaker implantation independently associated with higher 1-year all-cause (aHR 1.15) and cardiovascular mortality (aHR 1.25).
- Excess cardiovascular and all-cause mortality persisted through 5 and 10 years; higher rates of LVEF decline ≥10% and NYHA III/IV at 1 year.
Methodological Strengths
- Large, prospective, nationwide registry with long follow-up (up to 10 years)
- Multivariable adjustments and reporting of both mortality and functional/echocardiographic outcomes
Limitations
- Observational design subject to residual confounding and selection bias for pacemaker indication
- Heterogeneity in devices, implantation techniques, and conduction management over a long enrollment period
Future Directions: Randomized or pragmatic strategies to reduce pacemaker rates (implant depth, cusp overlap, device choice, conduction mapping) and to mitigate adverse remodeling in pacemaker-dependent TAVR patients.
BACKGROUND: The impact of pacemaker (PM) implantation on outcomes following transcatheter aortic valve replacement (TAVR) remains controversial, especially as TAVR indications expand to low-risk patients. OBJECTIVES: This study sought to evaluate the all-cause and cardiovascular mortality of patients undergoing PM implantation after TAVR. METHODS: In this prospective, observational, nationwide TAVR cohort study, the outcomes of patients undergoing permanent PM implantation were investigated. Patients were enrolled from 19 centers across Switzerland between February 2011 and June 2022. RESULTS: Among 13,360 patients enrolled (mean age 82 ± 7 years, 47% female, self-expanding valves 48%, median follow-up 889 days [Q1-Q3: 365-1,765 days]), 2,028 (15%) required PM implantation within 30 days post-TAVR. Patients requiring post-TAVR PM implantation were older (82 ± 6 years of age vs 81 ± 7 years of age), were predominantly male (58% vs 50%), and more often had atrial fibrillation (34% vs 29%). At 1-year follow-up, these patients had higher overall mortality (aHR: 1.15; 95% CI: 1.05-1.26; P = 0.002) and cardiovascular mortality (aHR: 1.25; 95% CI: 1.06-1.46; P = 0.006). These trends persisted at 5- and 10-year follow-up. After multivariable adjustments, significantly higher rates of cardiovascular mortality, LVEF decline ≥10%, and NYHA functional class III or IV at 1-year follow-up were observed (aHR: 1.44,; 95% CI: 1.35-1.54; P < 0.001), along with higher all-cause and cardiovascular mortality rates at 5- and 10-year follow-up in patients requiring PM implantation following TAVR compared with those not needing a PM. CONCLUSIONS: In this large nationwide registry, patients receiving PM implantation within 30 days after TAVR had significantly higher rates of overall and cardiovascular mortality up to 10 years. (SwissTAVI Registry; NCT01368250).