Daily Cardiology Research Analysis
Analyzed 180 papers and selected 3 impactful papers.
Summary
Three impactful cardiology studies stood out: a nonrandomized clinical analysis showed that monthly PCSK9 inhibition with lerodalcibep cuts LDL-C by ~50% in HeFH irrespective of LDL receptor variant function; a prospective cohort in cardiac sarcoidosis demonstrated that a specific late gadolinium enhancement (LGE) phenotype has 100% negative predictive value for future ventricular arrhythmias; and a Medicare cohort revealed substantial delays (median ~16 months) in diagnosing transthyretin cardiac amyloidosis after incident heart failure, with clear predictors of delay.
Research Themes
- Genotype-agnostic precision lipid lowering
- Imaging phenotypes guiding arrhythmic risk stratification
- Reducing diagnostic delays in infiltrative cardiomyopathies
Selected Articles
1. Response to PCSK9 Inhibition Based on LDL Receptor Function in Familial Hypercholesterolemia: A Nonrandomized Clinical Trial.
In a predefined pooled subanalysis of five phase 3 studies and an open-label extension, monthly lerodalcibep reduced LDL-C by ~50% at weeks 48 and 72 in 703 HeFH patients already on background therapy. Crucially, LDL-C reduction was independent of the functional activity of the LDLR pathogenic variant, and over 70% achieved both ≥50% LDL-C reduction and risk-based LDL-C goals.
Impact: This study supports genotype-agnostic PCSK9 inhibition in HeFH, simplifying treatment decisions irrespective of LDLR variant function and demonstrating durable, clinically meaningful LDL-C reductions.
Clinical Implications: For HeFH patients not achieving targets on statin/ezetimibe, lerodalcibep can be considered regardless of LDLR variant function. Payers and clinicians may adopt genotype-agnostic criteria for PCSK9 inhibitor access and intensification strategies in very-high-risk ASCVD.
Key Findings
- Monthly lerodalcibep reduced LDL-C by 50.3% at weeks 48 and 72 (absolute change ~−72 mg/dL).
- LDL-C reduction was independent of LDLR variant functional activity among genetically confirmed LDLR carriers.
- Over 70% achieved both ≥50% LDL-C reduction and risk-based LDL-C goals despite background lipid-lowering therapy.
Methodological Strengths
- Predefined pooled subanalysis across multiple phase 3 studies with standardized endpoints
- High genetic characterization rate (92.5%) enabling genotype-response assessment
Limitations
- Nonrandomized, open-label design without clinical outcome endpoints
- Potential selection and survivorship bias inherent to extension studies
Future Directions: Randomized head-to-head comparisons, longer-term outcomes, and cost-effectiveness analyses could refine placement of lerodalcibep within lipid-lowering algorithms and payer policies.
IMPORTANCE: In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the LDLR gene carrying the pathogenic variant. OBJECTIVE: To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH. DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep. This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025. Data were analyzed from March 2025 to February 2026. INTERVENTION: All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks. MAIN OUTCOME AND MEASURES: The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals. RESULTS: Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg/dL. Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, -72.6 [50.5] mg/dL and -71.8 [48.0] mg/dL) at weeks 48 and 72, respectively. Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the LDLR pathogenic variant. LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal. CONCLUSIONS AND RELEVANCE: These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of LDLR function of the pathogenic variant. These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type LDLR. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04798430.
2. Comparing the prognostic utility of late gadolinium enhancement burden and phenotype in patients with cardiac sarcoidosis; a prospective cohort study.
In 206 patients within a prospective multicenter cohort, the 'pathology-frequent' LGE phenotype was present in 41.3% and accounted for all sustained ventricular arrhythmias over ~5 years, yielding a 100% negative predictive value for those without this phenotype. LGE phenotyping matched LGE burden in discrimination, but was far more reproducible and five times faster.
Impact: The perfect NPV for the absence of the high-risk LGE phenotype offers a powerful rule-out tool for ventricular arrhythmia risk in cardiac sarcoidosis, with superior reproducibility and efficiency over quantitative burden measures.
Clinical Implications: LGE phenotyping can streamline risk stratification and ICD decision-making by identifying patients at near-zero arrhythmic risk, while focusing monitoring and therapies on pathology-frequent phenotypes.
Key Findings
- Among 206 patients (mean follow-up 5.1±2.8 years), all sustained ventricular arrhythmias occurred in those with the pathology-frequent LGE phenotype.
- LGE phenotyping achieved 100% negative predictive value and very high interobserver reproducibility, and was approximately five times faster than LGE burden quantification.
- LGE phenotype and categorical LGE% had similarly high discriminative accuracy for predicting future ventricular arrhythmias.
Methodological Strengths
- Prospective multicenter cohort embedded within an established registry (CHASM-CS)
- Direct comparison of phenotyping vs quantitative burden with reproducibility and efficiency metrics
Limitations
- Event numbers were modest (22 sustained VA), which may widen confidence intervals
- Phenotyping may require specialized CMR expertise; external validation in broader settings is needed
Future Directions: Multicenter validation and integration of LGE phenotyping into clinical risk scores and ICD decision algorithms; exploration of therapy tailoring by phenotype.
INTRODUCTION: Cardiac sarcoidosis (CS) is associated with a significant risk of ventricular arrhythmias (VAs). Recently, late gadolinium enhancement (LGE) phenotypes have been described; the 'pathology-frequent' phenotype has been shown to be strongly associated with future VA risk. The aim of our study was to compare the relative predictability of quantitative LGE burden and LGE phenotype. Secondary aims were to contrast the reproducibility and speed of LGE burden quantification and LGE phenotyping. METHODS AND RESULTS: This is a two-centre sub-study of the Cardiac Sarcoidosis Multi-Center Prospective Cohort Study (CHASM-CS; NCT01477359). All patients underwent CMR at baseline. A total of 206 patients (112/206 (54.4%) with CS and 94/206 (45.6%) with extra-cardiac sarcoidosis) were included in the study. Pathology-frequent LGE phenotype occurred in 85/206 (41.3%) and 22/206 (10.7%) patients had sustained VA during a mean follow-up period of 5.1 ± 2.8 years. All events occurred in patients with a pathology-frequent phenotype. LGE phenotype and categorical LGE% had similar high discriminative accuracy in predicting future VA; however, only LGE phenotyping had 100% negative predictive value (NPV). Interobserver reproducibility of LGE phenotype was very high (Cohen's CONCLUSION: Our study confirms, for the first time in a fully prospective cohort, the prognostic importance of the pathology-frequent phenotype of LGE. This phenotype had 100% NPV, indicating the absence of VA events among patients without a pathology frequent phenotype. LGE phenotyping showed much higher interobserver reproducibility than LGE quantification and was five-fold faster.
3. Timeliness of Transthyretin Cardiac Amyloidosis Diagnosis in the Medicare Population.
Among 7770 Medicare beneficiaries with HF and ATTR-CM, the median time from HF to ATTR-CM diagnosis was 494 days, and 840 days from loop diuretic initiation to diagnosis. Female sex and comorbid aortic stenosis, CAD, COPD, diabetes, and hypertension predicted diagnostic delay, whereas older age, atrial fibrillation, and carpal tunnel syndrome reduced delay.
Impact: Quantifies real-world diagnostic delay and identifies actionable predictors, informing targeted case-finding pathways and EHR-based alerts to accelerate ATTR-CM recognition.
Clinical Implications: Clinicians should maintain higher suspicion for ATTR-CM in HF—especially in women and those with competing cardiopulmonary diagnoses—and consider early scintigraphy/CMR or biomarker pathways; health systems can implement EHR prompts for at-risk phenotypes.
Key Findings
- Median time from first HF diagnosis to ATTR-CM diagnosis was 494 days (IQR, 63–1340).
- Median time from initial loop diuretic prescription to ATTR-CM diagnosis was 840 days (IQR, 252–1768).
- Female sex and comorbid AS, CAD, COPD, diabetes, and hypertension increased odds of delayed diagnosis; older age, atrial fibrillation, and carpal tunnel syndrome decreased delay.
Methodological Strengths
- Large national Medicare cohort with contemporary data (2016–2022)
- Multivariable modeling of demographic, clinical, and socioeconomic predictors
Limitations
- Claims-based ascertainment risks misclassification and lacks imaging/biopsy granularity
- Generalizability primarily to older fee-for-service beneficiaries
Future Directions: Implement and evaluate EHR alert systems and targeted diagnostic pathways; assess impact of earlier diagnosis on outcomes and equity, particularly in women.
IMPORTANCE: Timely diagnosis of transthyretin cardiac amyloidosis (ATTR-CM) is critical for early treatment to reduce morbidity and mortality, yet the timeliness of contemporary ATTR-CM diagnosis remains poorly understood. OBJECTIVE: To describe the time from incident heart failure (HF) diagnosis to ATTR-CM diagnosis and identify predictors of delayed diagnosis among Medicare beneficiaries. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study using US Medicare fee-for-service data from January 2016 to December 2022. Medicare fee-for-service beneficiaries with HF and ATTR-CM were included. Data were analyzed from November 2024 to July 2025. EXPOSURES: HF diagnosis with ATTR-CM diagnosis following HF diagnosis or within 1 year prior. MAIN OUTCOMES AND MEASURES: The primary outcome was time to ATTR-CM diagnosis, measured as the number of days between each patient's first HF diagnosis and first ATTR-CM diagnosis. Multivariable logistic regression assessed demographic, clinical, and socioeconomic factors associated with delayed ATTR-CM diagnosis (defined as >6 months from HF diagnosis to ATTR-CM diagnosis). RESULTS: A total of 7770 patients with HF and ATTR-CM were identified in the Medicare dataset. The median (IQR) age at the time of ATTR-CM diagnosis was 81 (76-86) years; 5995 enrollees (77%) were men. The median (IQR) time from HF diagnosis to ATTR-CM diagnosis was 494 (63-1340) days. For the 6175 patients with a loop diuretic prescription before ATTR-CM diagnosis, the median (IQR) time between initial loop prescription and ATTR-CM diagnosis was 840 (252-1768) days. After adjustment, older age (odds ratio [OR], 0.68; 95% CI, 0.63-0.74), history of atrial fibrillation (OR, 0.39; 95% CI, 0.33-0.49), and carpal tunnel syndrome (OR, 0.85; 95% CI, 0.74-0.97) were associated with lower odds of delayed diagnosis. Female sex (OR, 1.28; 95% CI, 1.13-1.45), a history of aortic stenosis (OR 1.39; 95% CI, 1.20-1.62), chronic obstructive pulmonary disease (OR, 1.18; 95% CI, 1.03-1.34), coronary artery disease (OR, 1.26; 95% CI, 1.13-1.40), diabetes (OR, 1.21; 95% CI, 1.07-1.37), and hypertension (OR, 1.28; 95% CI, 1.13-1.45) were associated with higher odds of delayed diagnosis. CONCLUSIONS AND RELEVANCE: There were substantial delays between incident HF and diagnosis of ATTR-CM found in this study. Female sex and having a history of aortic stenosis, coronary artery disease, diabetes, hypertension, or chronic obstructive pulmonary disease, which are each associated with cardiomyopathy and breathlessness, were associated with delayed diagnosis. These findings highlight the need for a heightened index of suspicion for ATTR-CM in patients with other possible etiologies of cardiomyopathy or HF symptoms.