Daily Cardiology Research Analysis
Three impactful studies span translational therapeutics, prevention, and regeneration. An optimized epigenetic regulator achieved >90% and year-long PCSK9 silencing in macaques via lipid nanoparticles, foreshadowing durable LDL-C lowering without genome edits. A binational cohort analysis found nearly all first CHD, heart failure, and stroke events were preceded by at least one nonoptimal traditional risk factor, underscoring primordial prevention. A Nature Cardiovascular Research study identifi
Summary
Three impactful studies span translational therapeutics, prevention, and regeneration. An optimized epigenetic regulator achieved >90% and year-long PCSK9 silencing in macaques via lipid nanoparticles, foreshadowing durable LDL-C lowering without genome edits. A binational cohort analysis found nearly all first CHD, heart failure, and stroke events were preceded by at least one nonoptimal traditional risk factor, underscoring primordial prevention. A Nature Cardiovascular Research study identifies oxidative phosphorylation as required for cardiomyocyte re-differentiation and long-term cardiac regeneration in fish.
Research Themes
- Durable epigenetic silencing therapeutics for lipid lowering
- Primordial prevention: traditional risk factors precede nearly all CVD
- Metabolic control of cardiac regeneration via oxidative phosphorylation
Selected Articles
1. Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.
Optimized TALE-based epigenetic regulators delivered by lipid nanoparticles achieved >90% and 343-day PCSK9 silencing in macaques, lowering LDL-C with minimal off-target effects. The platform is modular and retargetable, outperforming initial dCas9-based designs and advancing epigenetic editing toward clinical translation.
Impact: Demonstrates durable, non-editing epigenetic silencing of a validated cardiovascular target in nonhuman primates with systemic delivery. Establishes a blueprint for long-acting lipid lowering and broader therapeutic epigenetic editing.
Clinical Implications: If safety and efficacy translate to humans, infrequent-dosing LDL-C lowering could complement or replace PCSK9 antibodies/siRNA for high-risk hypercholesterolemia. The platform could extend to other hepatic and extrahepatic gene targets.
Key Findings
- TALE-based EpiReg achieved 98% silencing in mice, outperforming dCas9-based constructs (64%).
- Single-dose lipid nanoparticle delivery yielded >90% and 343-day hepatic PCSK9 silencing in macaques with LDL-C lowering.
- Integrative multiomic analyses across monkeys, mice, and human-derived cells showed minimal off-target effects.
- The DNA-binding domain can be reengineered to retarget EpiReg to other genes.
Methodological Strengths
- Translational in vivo validation in nonhuman primates with long-term follow-up (343 days).
- Comprehensive multi-omic off-target assessment across species and cell systems.
- Direct comparison of TALE- vs dCas9-based architectures and fusion designs.
- Clinically relevant delivery via lipid nanoparticles.
Limitations
- Preclinical study; human safety, immunogenicity, and durability beyond 1 year remain unknown.
- Focused on PCSK9; generalizability to extrahepatic targets and repeated dosing not established.
Future Directions: First-in-human trials to assess safety, pharmacodynamics, dose, and durability; expansion to additional cardiovascular and metabolic targets; evaluation of re-dosing, immunogenicity, and extrahepatic delivery strategies.
Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.
2. Oxidative phosphorylation is required for cardiomyocyte re-differentiation and long-term fish heart regeneration.
Comparative zebrafish studies reveal that oxidative phosphorylation, fueled via the malate–aspartate shuttle, rises as proliferation wanes and is required for cardiomyocyte re-differentiation and sustained regeneration. Cavefish lacking adequate OXPHOS upregulation fail to engage sarcomere gene programs, challenging the idea that OXPHOS hinders regeneration.
Impact: Identifies a metabolic switch as a necessary driver of cardiomyocyte re-differentiation and regeneration, offering tractable metabolic targets for post-MI repair strategies.
Clinical Implications: Suggests testing metabolic interventions that enhance OXPHOS or malate–aspartate shuttle activity during the repair phase after MI in mammalian models as a route to improve remodeling and function.
Key Findings
- Among zebrafish strains, regenerative outcomes correlated with OXPHOS upregulation post-cryo-injury.
- OXPHOS increased as proliferation declined and was required for cardiomyocyte re-differentiation and long-term regeneration.
- Malate–aspartate shuttle drove OXPHOS; cavefish lacking adequate OXPHOS upregulation failed to activate sarcomere gene programs.
- Challenges the dogma that OXPHOS inhibits regeneration; identifies metabolic targets for heart repair.
Methodological Strengths
- Inter- and intra-species comparative design with single-cell and bulk RNA-seq integration.
- Mechanistic linkage of glycolytic shuttling to OXPHOS and functional regeneration outcomes.
- Temporal mapping of proliferation, re-differentiation, and metabolic states.
Limitations
- Findings derived from fish; translational relevance to mammalian post-MI repair remains to be demonstrated.
- Intervention studies modulating OXPHOS in mammals were not presented.
Future Directions: Test pharmacologic or genetic augmentation of OXPHOS or malate–aspartate shuttle in mammalian MI models; integrate metabolic imaging/omics with functional outcomes; explore timing-specific metabolic interventions.
In contrast to humans, fish can fully regenerate their hearts after cardiac injury. However, not all fish have the same regenerative potential, allowing comparative inter-species and intra-species analysis to identify the mechanisms controlling successful heart regeneration. Here we report a differential regenerative response to cardiac cryo-injury among different wild-type zebrafish strains. Correlating these data with single-cell and bulk RNA sequencing data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by glycolysis through the malate-aspartate shuttle, increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. Reduced upregulation of OXPHOS in Astyanax mexicanus cavefish results in the absence of a dynamic temporal sarcomere gene expression program during cardiomyocyte re-differentiation. These findings challenge the assumption that OXPHOS inhibits regeneration and reveal targetable pathways to enhance heart repair in humans after myocardial infarction.
3. Very High Prevalence of Nonoptimally Controlled Traditional Risk Factors at the Onset of Cardiovascular Disease.
Across KNHIS and MESA, >99% of first CHD, HF, and stroke events were preceded by at least one nonoptimal level of BP, cholesterol, glucose, or smoking, with ≥2 risk factors common. Findings refute the notion of frequent CVD without antecedent risk factors and reinforce primordial prevention.
Impact: Defines the near-universal antecedent burden of modifiable risk exposures before CVD across populations, directly informing prevention policy and clinical risk communication.
Clinical Implications: Strengthens justification for aggressive primordial prevention (lifecourse BP, lipids, glycemia, tobacco control), earlier thresholds for intervention, and population-level strategies targeting multiple risk factors simultaneously.
Key Findings
- In both KNHIS and MESA, ≥1 nonoptimal traditional risk factor preceded >99% of first CHD, HF, and stroke events.
- ≥2 nonoptimal risk factors were present before 93–97% of CVD events.
- Patterns were consistent across sexes and age strata, with slightly lower but still high prevalence (>95%) for HF/stroke <60 years in women.
- Findings counter claims that CHD commonly occurs without major risk factors.
Methodological Strengths
- Two large population-based prospective cohorts with long follow-up and harmonized definitions.
- Event-wise assessment of antecedent risk factor exposure at any prior visit.
- Consistency across distinct populations (East Asian national cohort and US multi-ethnic cohort).
Limitations
- Observational design cannot prove causality; residual confounding possible.
- Reliance on clinical measurements and records may introduce misclassification; generalizability beyond studied settings needs caution.
Future Directions: Quantify risk reductions from earlier multifactorial interventions; evaluate communication strategies to counter “risk-factor–free” narratives; integrate primordial prevention into policy with equity focus.
BACKGROUND: Recent studies suggest that coronary heart disease (CHD) may frequently occur in the absence of traditional cardiovascular disease (CVD) risk factors. However, it is unclear whether this could reflect missed clinical diagnoses or subthreshold nonoptimal risk factor exposure preceding CHD, and whether similar patterns are observed for heart failure (HF) or stroke. OBJECTIVES: The purpose of this study was to determine the antecedent occurrence of nonoptimal levels of 4 traditional risk factors (blood pressure [BP], cholesterol, glucose, and tobacco smoking) before first CHD, HF, or stroke. METHODS: We analyzed 2 population-based prospective cohorts: KNHIS (Korean National Health Insurance Service) (n = 9,341,100; baseline age ≥20 years; follow-up, 2009-2022) and MESA (Multi-Ethnic Study of Atherosclerosis) (n = 6,803; baseline age 45-84 years; follow-up, 2000-2019). Among individuals who developed incident CHD, HF, or stroke during follow-up, we determined the prevalence of ≥1 traditional risk factor above optimal level-systolic BP ≥120 mm Hg or diastolic BP ≥80 mm Hg or BP-lowering treatment; total cholesterol ≥200 mg/dL or lipid-lowering treatment; fasting glucose ≥100 mg/dL or diagnosis of diabetes or glucose-lowering treatment; or past or current smoking-at any visit before CVD. RESULTS: Analyses were based on 601,025 and 1,188 CVD events in KNHIS and MESA, respectively. Prevalence of ≥1 nonoptimal risk factor was high (99.7% and 99.6%) before CHD, with similar patterns before HF (99.4% and 99.5%) and stroke (99.3% and 99.5%) in both KNHIS and MESA, respectively. Prevalence of ≥1 risk factor before CVD was consistently high (>99%) across age groups in both men and women, with the lowest proportion observed for HF and stroke (>95%) when occurring at ages <60 years in women. Prevalence of ≥2 risk factors was also common (93.2% to 97.2%) before CVD events. CONCLUSIONS: In this binational study of 2 prospective cohorts, the presence of nonoptimal levels of ≥1 traditional risk factor was nearly universal before CVD. These results not only challenge claims that CHD events frequently occur without antecedent major risk factors but also demonstrate that other CVD events, including HF or stroke, rarely occur in the absence of nonoptimal traditional risk factors, highlighting the importance of primordial prevention efforts.