Daily Cardiology Research Analysis
Analyzed 179 papers and selected 3 impactful papers.
Summary
Analyzed 179 papers and selected 3 impactful articles.
Selected Articles
1. Severe obesity in human HFpEF alters contractile protein function and organization.
In human HFpEF with severe obesity, cardiomyocytes show markedly impaired contractile reserve with reduced calcium- and length-dependent tension, power, and myosin activation, correlating with BMI and exercise hemodynamics. A selective increase in troponin-I Thr181 phosphorylation appears specific to HF with obesity and may drive sarcomere dysfunction; deficits may be reversible with weight loss, suggesting therapeutic opportunities with weight reduction and sarcomere enhancers.
Impact: This study provides a human, mechanistic link between obesity and HFpEF sarcomere dysfunction via site-specific troponin-I phosphorylation, reframing therapeutic targets toward myofilaments and metabolic interventions.
Clinical Implications: For obese HFpEF, structured weight reduction may restore myocyte function, and sarcomere-targeted therapies (e.g., myosin modulators or phosphorylation-state modulators) warrant clinical testing, especially in obesity-driven phenotypes.
Key Findings
- Obese HFpEF cardiomyocytes exhibit markedly reduced calcium- and length-stimulated tension, power, and myosin activation.
- Defects correlate with BMI and exercise hemodynamics in HFpEF, not in non-failing controls, and appear reversible with weight loss.
- Troponin-I Thr181 phosphorylation increases only in HF with obesity, implicating it in sarcomere dysfunction.
- Findings suggest benefits of weight reduction and sarcomere enhancers in obesity-related HFpEF.
Methodological Strengths
- Use of human patient-derived cardiomyocytes with direct biomechanical and myosin activation assessments.
- Integrative correlation with BMI and exercise hemodynamics, and phospho-site specificity (troponin-I Thr181).
Limitations
- Sample size and detailed cohort composition are not specified in the abstract, limiting generalizability.
- Causality and therapeutic efficacy of sarcomere enhancers were not tested in interventional human studies.
Future Directions: Prospective interventional trials of weight loss strategies and sarcomere-targeted modulators in obesity-driven HFpEF; phospho-switch targeting of troponin-I Thr181 to test causal reversibility.
Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared to less-obese HFpEF and non-failing (NF) controls ±obesity, but similar to advanced HF with reduced EF. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin-I phosphorylation at Thr181 occurs only in HF+obesity contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity.
2. The N-terminus of Apolipoprotein B mediates the interaction of atherogenic lipoproteins with endothelial cells.
The APOB N-terminus contains receptor-specific interfaces with SR-BI and ALK1 on endothelial cells. An 18% N-terminal fragment (APOB18) reduced endothelial uptake and transcytosis of chylomicrons and LDL, and its overexpression lowered atherosclerosis in hypercholesterolemic mice, nominating APOB18-mimetic strategies to therapeutically limit lipoprotein entry into the arterial wall.
Impact: By mapping functional receptor-binding sites on APOB and demonstrating in vivo atherosclerosis reduction via an APOB fragment, this work opens a tractable, mechanistically precise avenue to impede endothelial lipoprotein entry.
Clinical Implications: Therapeutics that mimic APOB18 or selectively disrupt APOB–SR-BI/ALK1 interactions could reduce atherogenic lipoprotein flux into the vessel wall, complementing lipid-lowering therapies.
Key Findings
- Distinct APOB regions interact with SR-BI and ALK1 on endothelial cells; APOB48 is internalized only via SR-BI.
- APOB18 (N-terminal 18%) reduces endothelial uptake and transport of chylomicrons and LDL, whereas APOB12 blocks ALK1-mediated uptake of APOB100 lipoproteins.
- APOB18 overexpression decreases atherosclerosis in hypercholesterolemic mice, validating the endothelial uptake mechanism in vivo.
Methodological Strengths
- Integration of molecular modeling, site-directed mutagenesis, and cell-based receptor assays.
- In vivo validation with hypercholesterolemic mouse models demonstrating atherosclerosis reduction.
Limitations
- Therapeutic translation relies on achieving effective APOB18-mimetic delivery and specificity in humans.
- Human clinical validation of endothelial uptake blockade and long-term safety are not yet established.
Future Directions: Develop APOB18-mimetic peptides/biologics, test in large animals, and evaluate safety/efficacy of selective SR-BI/ALK1 disruption; explore combinatorial strategies with LDL-C lowering.
Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.
3. Randomized Trial of Left Bundle Branch Pacing vs Right Ventricular Pacing in Vulnerable Cardiac Function.
In a multicenter RCT of 160 high pacing burden patients at risk for dysfunction, LBBP reduced the composite of all-cause death, HF hospitalization, or PICM versus RVP (HR 0.31), primarily by lowering PICM (6.5% vs 18.2%). LBBP also improved LVEF, LV dimensions, and NYHA class over 36 months, supporting conduction system pacing to preserve ventricular function.
Impact: Provides randomized evidence that conduction system pacing prevents adverse remodeling and PICM compared with conventional RVP, informing device strategy in high-burden pacing populations.
Clinical Implications: For patients anticipating high ventricular pacing burden, LBBP should be considered to minimize PICM and preserve LV function; guideline updates and implementation pathways are warranted.
Key Findings
- Primary composite (death, HF hospitalization, or PICM) reduced with LBBP vs RVP (11.6% vs 33.9%; HR 0.31).
- PICM incidence significantly lower with LBBP (6.5% vs 18.2%).
- LBBP improved LVEF (+5.34%), reduced LVEDD/LVESD, and yielded better NYHA class at 36 months.
Methodological Strengths
- Prospective, multicenter randomized controlled design with 36-month follow-up.
- Predefined clinical and echocardiographic endpoints demonstrating structural and functional benefits.
Limitations
- Moderate sample size; mortality and HF hospitalization differences were not individually significant.
- Blinding and adjudication details are not specified in the abstract; generalizability to broader populations remains to be validated.
Future Directions: Larger RCTs powered for mortality/HF hospitalization, subgroup analyses (e.g., intrinsic conduction disease), cost-effectiveness, and standardized implantation/programming protocols.
BACKGROUND: Right ventricular pacing (RVP) is associated with an increased risk of pacing-induced cardiomyopathy (PICM) in high pacing burden patients. Left bundle branch pacing (LBBP), a more physiological pacing modality, may better preserve cardiac function. OBJECTIVES: This randomized trial aimed to evaluate the clinical outcomes of LBBP versus RVP in high pacing burden patients with high risk of cardiac dysfunction. METHODS: In this prospective, multicenter, randomized controlled trial, 160 high pacing burden patients with high risk of cardiac dysfunction were randomly assigned in a 1:1 ratio to either LBBP or RVP. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization (HFH), or PICM. Secondary endpoints included the individual components of the primary endpoints, echocardiographic parameters, and New York Heart Association (NYHA) functional class. RESULTS: During a median follow-up duration of 36 months, the primary endpoint occurred in 9 patients in the LBBP group and in 25 patients in the RVP group (11.6% vs. 33.9%; HR 0.310, 95% CI 0.145-0.664; P=0.001), mainly driven by PICM (6.5% vs. 18.2%; sHR 0.324, 95% CI 0.119-0.883; P=0.028). No significant differences were observed in all-cause mortality (P=0.391) and HFH (P=0.100) between two groups. LBBP showed superior improvements than RVP in left ventricular ejection fraction (LVEF) (mean difference: 5.34, 95% CI: 3.18-7.50; P <0.001), left ventricular end-diastolic diameter (LVEDD) (mean difference: -3.06, 95% CI: -4.38- -1.73; P <0.001) and left ventricular end-systolic diameter (LVESD) (mean difference: -3.74, 95% CI: -5.07- -2.41; P <0.001) from baseline to 36 months. Patients in the LBBP group also showed favored NYHA functional class compared with those in the RVP group at 36-month follow-up (1.66 ± 0.60 vs. 1.90 ± 0.56, P = 0.014). CONCLUSIONS: In high pacing burden patients with high risk of cardiac dysfunction, LBBP significantly reduced the risk of the composite outcome, driven primarily by a decreased risk of PICM, and is associated with better echocardiographic improvements and clinical function. CONDENSED ABSTRACT: This LBBP-FAVOUR randomized trial is the first multi-center, prospective, randomized controlled trials to evaluate the clinical efficacy of left bundle branch pacing (LBBP) vs right ventricular pacing (RVP) in patients with high risk of cardiac dysfunction. During a median follow-up of 36 months, LBBP significantly reduced the risk of the composite endpoint including pacing-induced cardiomyopathy (PICM), heart failure hospitalization, and all-cause mortality compared with RVP, and this benefit was mainly driven by the reduction in PICM risk. This work lays a solid foundation for future larger randomized trials in specific patient populations to further validate these findings.