Daily Cardiology Research Analysis
Analyzed 44 papers and selected 3 impactful papers.
Summary
Today’s top cardiology papers spotlight three practice-informing fronts: oral PCSK9 inhibitors achieving ~60% LDL-C reduction with short-term safety comparable to placebo; contemporary safety signals when performing catheter ablation in patients with cardiac implantable electronic devices, particularly with lattice-tip RF and pulsed-field technologies; and a double-blind RCT showing oral nitrite fails to enhance skeletal muscle mitochondrial respiration or physical function in sedentary older adults, underscoring tissue-specific pharmacokinetics.
Research Themes
- Oral lipid-lowering innovation and translational readiness
- Device–energy interactions and procedural safety in electrophysiology
- Nitric oxide bioavailability, aging, and tissue-specific pharmacology
Selected Articles
1. Safety and efficacy of oral PCSK9 inhibitors in hypercholesterolemia: A systematic review and network meta-analysis.
Across four multicenter RCTs (N=1387), oral PCSK9 inhibitors reduced LDL-C by roughly 60% versus placebo, with a safety profile similar to placebo except for increased diarrhea. Favorable effects extended to non-HDL-C, ApoB, HDL-C, and lipoprotein(a), but follow-up was short and cardiovascular outcomes were not assessed.
Impact: This synthesis suggests oral PCSK9 inhibitors could transform lipid management by delivering monoclonal antibody-like LDL-C lowering without injections. It frames priority gaps for outcomes-focused trials before broad adoption.
Clinical Implications: Pending long-term outcomes and safety data, oral PCSK9 inhibitors may expand options for statin-intolerant patients or those not achieving LDL-C targets, with attention to gastrointestinal tolerability (diarrhea). Integration with ezetimibe and/or low-dose statins could be explored.
Key Findings
- Four low-bias RCTs (N=1387; 8–52 weeks) evaluated oral PCSK9 inhibitors versus placebo.
- LDL-C reductions were largest with enlicitide HiD (MD −62.6%) and NNC0385-0434 HiD (MD −61.8%).
- Safety was similar to placebo except for increased diarrhea (RR 3.25).
- Oral PCSK9 inhibitors improved non-HDL-C, ApoB, HDL-C, and lipoprotein(a); some regimens reduced triglycerides.
- A higher proportion of patients on enlicitide achieved LDL-C targets.
Methodological Strengths
- Comprehensive multi-database search with frequentist random-effects network meta-analysis
- Inclusion limited to randomized, multicenter trials with low risk of bias
Limitations
- Only four RCTs with short follow-up (8–52 weeks) and no cardiovascular outcomes
- Heterogeneity across doses and compounds; long-term safety remains uncertain
Future Directions: Conduct longer, larger head-to-head and add-on trials assessing cardiovascular outcomes, adherence, and safety; compare against PCSK9 mAbs/inclisiran; evaluate combinations with statins/ezetimibe and use in high-risk subgroups.
OBJECTIVES: Oral PCSK9 inhibitors show promise for the management of hypercholesterolemia, but a systematic review and network meta-analysis (NMA) is needed to inform clinical practice; we aimed to fill this gap. METHODS: Multiple databases were searched through November 14, 2025, to identify randomized controlled trials (RCTs) comparing oral PCSK9i with placebo in adults with hypercholesterolemia. Primary outcomes were adverse events (AEs) and percent change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included LDL-C goal attainment and changes in other lipids. Meta-analyses were conducted using RevMan and NMA in R, employing a frequentist approach and random-effects models. RESULTS: Four multicenter, low-bias RCTs (N=1387, follow-up 8-52 weeks) were included. Oral PCSK9i showed a safety profile similar to placebo, except for a higher risk of diarrhea (risk ratio: 3.25). All oral PCSK9i outperformed placebo in the percent reduction of LDL-C, with enlicitide high dose (HiD) (MD -62.6%, P score = 0.88) and NNC0385-0434 HiD (MD -61.8%, P score = 0.88) being the most effective, followed by enlicitide medium dose (MeD) (MD -59.1%, P score = 0.77). A higher proportion of patients receiving enlicitide (any dose) achieved LDL-C targets. All oral PCSK9i also improved total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B, and lipoprotein(a). NNC0385-0434 HiD increased HDL-C; NNC0385-0434 HiD, enlicitide HiD, and MeD reduced TG. CONCLUSIONS: Limited short-term data suggest that oral PCSK9i are reasonably safe and effective, reducing LDL-C and improving other lipids. Longer, larger RCTs are required to confirm safety, efficacy, and cardiovascular benefits before broader use.
2. Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
In a double-blind RCT of sedentary older adults (n=64), 12 weeks of oral sodium nitrite did not improve skeletal muscle mitochondrial respiration, exercise capacity, or physical function. An acute dose increased plasma nitrite 16–30-fold but only 1.6-fold in skeletal muscle, while platelet bioenergetics changed, indicating tissue-specific pharmacokinetics and pharmacodynamics with aging.
Impact: This rigorously designed RCT challenges extrapolation from younger cohorts, highlighting that tissue delivery and responsiveness limit nitrate–nitrite strategies in older adults. It refines therapeutic hypotheses and prioritizes delivery-focused approaches.
Clinical Implications: Oral nitrite should not be used to enhance exercise capacity or skeletal muscle bioenergetics in sedentary older adults based on current evidence. Strategies to improve skeletal muscle delivery or alternative NO-donor approaches warrant evaluation, potentially in combination with exercise training.
Key Findings
- No improvement in skeletal muscle CI&II MaxOXPHOS after 12 weeks of oral sodium nitrite versus placebo
- No gains in exercise capacity or physical function with nitrite supplementation
- Acute oral nitrite increased plasma nitrite 16–30-fold but only 1.6-fold in skeletal muscle
- Platelet mitochondrial respiration changed acutely after nitrite, indicating tissue-specific effects
Methodological Strengths
- Randomized, placebo-controlled, double-blind design with predefined primary outcome
- Objective bioenergetic phenotyping across tissues and standardized dosing over 12 weeks
Limitations
- Modest sample size (n=64) and sedentary older adult population limit generalizability
- Short intervention (12 weeks) and no long-term clinical outcomes assessed
Future Directions: Develop delivery systems to enhance skeletal muscle nitrite/nitrate bioavailability, test age-adapted dosing or alternative NO donors, and evaluate synergy with exercise training in adequately powered trials.
BACKGROUND: Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear. METHODS: Randomized, placebo controlled, double-blind, 2-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed. RESULTS: 64 adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16 to 30-fold in plasma following an acute dose, levels increased only 1.6 fold in skeletal muscle. CONCLUSIONS: The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggest tissue-specific pharmacokinetics and pharmacodynamics that likely impact on the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to nitrite/nitrate previously demonstrated in younger adults.
3. Adverse Events During Catheter Ablation in Patients with Cardiac Implantable Electronic Devices.
Across 433 adverse events from MAUDE and the literature (2020–2025), most complications in CIED patients undergoing ablation were energy-related, including thermal myocardial injury, generator dysfunction, oversensing, and VF induction. Technology-specific risks emerged—lattice-tip RF near Biotronik ICD leads triggered most RF-related VFs, PF accounted for all confirmed generator failures, and remote (>2 cm) thermal injury frequently necessitated lead or leadless pacemaker interventions.
Impact: This is the largest contemporary synthesis linking specific ablation energy modalities to distinct device-related complications, delivering immediately actionable safety guidance for EP labs and manufacturers.
Clinical Implications: Avoid lattice-tip RF near Biotronik ICD leads; anticipate remote thermal injury with RF and perform thorough post-ablation device assessments; be vigilant for PF-related generator failures; consider cryoablation when feasible; refine workflows and shielding/programming to reduce preventable events.
Key Findings
- Energy sources caused 97% of AEs (RF 89%; PF 8%); mechanical issues accounted for 32% (mostly dislodgements).
- Electromagnetic interactions included thermal injury (34%), generator dysfunction (20%), oversensing (9%), and VF induction (5%).
- Lattice-tip RF near Biotronik ICD leads induced 14 of 15 RF-related VFs.
- PF accounted for all 6 confirmed generator failures.
- Remote thermal injury (>2 cm from lead tip) frequently necessitated lead or leadless pacemaker intervention; 56% required generator/lead replacement or repositioning.
Methodological Strengths
- Largest contemporary synthesis integrating MAUDE surveillance with peer-reviewed reports focused on new ablation technologies
- Technology-specific analyses yielding actionable, mechanism-oriented safety insights
Limitations
- Reporting and selection biases inherent to adverse event databases and literature; lack of denominators precludes incidence estimation
- Not a prospective registry; potential underreporting and heterogeneous event adjudication
Future Directions: Prospective registries with denominators, bench testing of device–energy interactions, standardized EP lab workflows, and design modifications to improve CIED resilience during ablation.
BACKGROUND: Reviews of adverse events (AEs) in patients with cardiac implantable electronic devices (CIEDs) during catheter ablation predate newer devices, procedures, and ablation technologies (e.g., pulsed field [PF], lattice-tip radiofrequency [RF]). OBJECTIVE: To characterize AEs in contemporary CIED patients undergoing ablation and identify implications for safer practice. METHODS: We analyzed 433 AEs from the FDA's Manufacturer and User Facility Device Experience (MAUDE) database and peer-reviewed literature (2020-2025), focusing on newer technologies. RESULTS: Ablation catheters/energy caused 97% of AEs (RF: 89%; PF: 8%). Mechanical interactions caused 32% of AEs (30% dislodgements). Electromagnetic interactions (68%) included myocardial thermal injury (34%), generator dysfunction (20%), oversensing (9%), and induction of ventricular fibrillation (VF) (5%). Interventions (generator/lead replacement/repositioning) occurred in 56% of cases. Thermal injury with loss of capture necessitated replacement/repositioning of 53 transvenous leads and 32 leadless pacemakers, often when ablation sites were ≥2 cm from tip electrodes. Lattice-tip RF near Biotronik ICD leads induced 14 of 15 RF-related VFs. PF accounted for all 6 confirmed generator failures. No cryoablation AEs were reported. CONCLUSION: This first and largest comprehensive series of ablation-related complications in contemporary CIED patients underscores underappreciated risks of older technology and highlights novel risks of evolving technologies. A notable finding is that most threshold elevations requiring intervention occurred at ablation sites remote from CIED tip electrodes. More than 40% of AEs appeared largely preventable, suggesting gaps in procedural workflows. Our results suggest opportunities to improve clinical practices and CIED design to safeguard patients.