Daily Cardiology Research Analysis
Analyzed 186 papers and selected 3 impactful papers.
Summary
Three high-impact studies advance cardiology across mechanistic and clinical domains: 1) a Lancet multicenter cohort shows coronary microvascular dysfunction independently predicts adverse outcomes after invasive angiography; 2) Science Advances identifies soluble APP/APLP2 as endothelial KIT allosteric modulators essential for post-MI angiogenesis; 3) Nature Communications reveals brown adipose tissue–derived mitochondria-origin vesicles reprogram cardiac macrophage bioenergetics to attenuate post-MI remodeling.
Research Themes
- Coronary microvascular dysfunction as a prognostic determinant in invasive cardiology
- Endothelial APP/APLP2 signaling and KIT-mediated post-ischemic angiogenesis
- Inter-organ vesicular crosstalk (brown adipose tissue to heart) in myocardial repair
Selected Articles
1. Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis.
This mechanistic study demonstrates that endothelial APP/APLP2 are processed under hypoxia to soluble APPsα/APLP2sα, which positively allosterically modulate endothelial KIT to drive post-MI angiogenesis. Endothelial deletion worsened neovascularization, heart failure, and mortality, while endothelial APPsα expression rescued the phenotype.
Impact: It uncovers a previously unrecognized endothelial role for APP/APLP2 and reveals soluble APP fragments as endogenous allosteric KIT modulators in ischemic repair—opening a novel proangiogenic therapeutic avenue.
Clinical Implications: Therapeutic strategies enhancing APPsα/APLP2sα signaling or KIT positive allosteric modulation could augment post-MI revascularization. Caution may be warranted when targeting amyloid pathways to avoid compromising cardiac repair.
Key Findings
- Hypoxia upregulates endothelial α-secretases, generating soluble APPsα/APLP2sα via nonamyloidogenic processing.
- Endothelial APP/APLP2 loss reduces neovascularization and increases post-MI heart failure and mortality; endothelial APPsα expression rescues these deficits.
- APPsα/APLP2sα act as positive allosteric modulators of endothelial KIT to promote post-ischemic angiogenesis.
Methodological Strengths
- Endothelium-specific genetic loss-of-function and rescue approaches in MI models
- Mechanistic linkage to KIT established via functional modulation and phenotype rescue
Limitations
- Preclinical models without human clinical validation
- Potential off-target effects and safety of modulating APP/KIT signaling not addressed
Future Directions: Test APPsα/KIT-targeted interventions in large-animal MI models and evaluate safety-efficacy in early-phase clinical studies; explore interactions with anti-amyloid therapies.
Amyloid precursor protein (APP) gives rise to amyloid-β, a pathological factor in Alzheimer's disease. However, the physiological role of APP and its homolog amyloid precursor-like protein 2 (APLP2), which are also widely expressed outside the nervous system, is largely unknown. Here, we show that endothelial APP and APLP2 are required for postischemia angiogenesis after myocardial infarction (MI). We found that hypoxia induced the endothelial expression of α-secretases, resulting in nonamyloidogenic processing of APP and APLP2 into the soluble forms APPsα and APLP2sα. Loss of endothelial APP and APLP2 led to decreased neovascularization as well as increased heart failure and mortality after MI, a phenotype that could be rescued by endothelial expression of APPsα. APPsα and APLP2sα exerted their proangiogenic effect by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, which promotes postischemia neovascularization. Our data identify a function of APP and APLP2 in endothelial cells, which is required for postischemia tissue repair, and suggest approaches to improve regeneration after MI and other ischemic diseases.
2. Coronary microvascular dysfunction and cardiovascular outcomes (Multicenter FLOW-CMD Registry): a prospective, multicentre cohort study in South Korea.
In a prospective multicenter registry (n=1003), CMD (CFR <2.0 and IMR ≥25) was present in 21.5% with obstructive CAD and 9.3% without, and it independently doubled the risk of composite adverse events over ~2 years (HR 1.91). CMD frequently coexisted with epicardial disease, emphasizing its prognostic importance.
Impact: Provides prospective, invasive physiology-based evidence that CMD independently worsens outcomes, supporting integration of CFR/IMR assessment into routine cath lab practice.
Clinical Implications: Routine CFR and IMR assessment can identify high-risk patients beyond epicardial stenosis, informing intensification of preventive therapy and selection for trials targeting microvascular function.
Key Findings
- CMD prevalence: 21.5% with obstructive CAD and 9.3% without obstructive CAD at invasive angiography.
- CMD (CFR<2.0 and IMR≥25) associated with higher 2-year composite events (18.8% vs 10.5%; HR 1.91).
- Systematic invasive physiology in routine practice is feasible across seven tertiary centers.
Methodological Strengths
- Prospective, multicenter design with standardized invasive physiologic thresholds (CFR, IMR)
- Clinically relevant composite endpoints with near 2-year follow-up
Limitations
- Single-country (South Korea) tertiary-center cohort may limit generalizability
- Residual confounding and treatment heterogeneity cannot be excluded; follow-up duration modest
Future Directions: Evaluate CMD-guided management strategies in randomized trials and expand validation across diverse healthcare systems; refine CFR/IMR thresholds and integrate noninvasive surrogates.
BACKGROUND: Coronary microvascular dysfunction often coexists with epicardial coronary artery disease. Data regarding its prevalence and prognosis in patients undergoing invasive coronary angiography are scarce. This study aimed to evaluate the prevalence and prognosis of coronary microvascular dysfunction in patients undergoing clinically indicated invasive coronary angiography in routine practice. METHODS: In this prospective, multicentre cohort study done in seven tertiary medical hospitals in South Korea, consecutive patients aged 18 years and older who were referred for clinically indicated invasive coronary angiography were systematically screened and evaluated by coronary physiological assessment. Obstructive epicardial coronary artery disease was defined as an intermediate stenosis (40-90% diameter stenosis), with fractional flow reserve of 0·80 or less or severe stenosis (>90% of diameter stenosis) treated with revascularisation without fractional flow reserve measurement. Coronary microvascular dysfunction was identified as coronary flow reserve below 2·0 and index of microcirculatory resistance of ≥25. The primary endpoint was a composite of all-cause death, myocardial infarction, clinically driven repeat revascularisation, or hospitalisation for heart failure. The Multicenter FLOW-CMD Registry study is registered with ClinicalTrials.gov (NCT05369182). FINDINGS: Between April 22, 2022, and Nov 19, 2024, 5764 patients were screened and 1003 patients were enrolled (756 men and 247 women). Among these patients, coronary microvascular dysfunction was observed in 123 (21·5%) of 573 patients with obstructive epicardial coronary artery disease and in 40 (9·3%) of 430 patients without obstructive epicardial coronary artery disease. At a median follow-up of 1·9 years, the primary endpoint occurred in 26 patients (2-year Kaplan-Meier estimate 18·8%) with coronary microvascular dysfunction and 70 patients (2-year Kaplan-Meier estimate 10·5%) with preserved microvascular function (hazard ratio 1·91 [95% CI 1·22-2·99]; p=0·0047).
3. Mitochondria-derived vesicles with bioenergetic units from brown adipose tissue attenuate cardiac remodeling post-myocardial infarction.
Brown adipose tissue emits mitochondria-derived vesicles enriched in mitochondrial membranes and complex V that home to cardiac macrophages, reprogramming their oxidative metabolism and reparative cytokine output to mitigate post-MI remodeling. VPS35-dependent cargo loading and Becn1 integrity are required for this cardioprotection.
Impact: Reveals a previously unrecognized inter-organ, vesicle-mediated delivery of bioenergetic units that rewires immune cell metabolism to promote cardiac repair, suggesting a novel cell-free therapeutic strategy.
Clinical Implications: Engineered or purified BAT-derived vesicles could emerge as a biotherapeutic to modulate macrophage metabolism and reduce adverse remodeling post-MI; targets like VPS35/BECN1 pathways may optimize vesicle therapeutics.
Key Findings
- BAT-derived mitochondria-origin vesicles containing mitochondrial membranes and complex V traffic to the heart and reprogram cardiac macrophage metabolism.
- VPS35 mitochondrial translocation is required for cargo loading; Becn1 deficiency disrupts vesicle cargo and abrogates cardioprotection.
- Purified MDVs reduce pathological remodeling in vivo in male mice by enhancing reparative cytokines and oxidative phosphorylation in macrophages.
Methodological Strengths
- Multi-layered approach: vesicle biogenesis genetics (VPS35/Becn1), proteomics, and in vivo functional efficacy
- Cell-type targeting demonstrated with macrophage bioenergetic and cytokine reprogramming
Limitations
- Predominantly male mouse data; sex-dependent effects require clarification
- Translational dosing, biodistribution, and safety of vesicle therapy need rigorous evaluation
Future Directions: Define pharmacology and safety of MDVs in large-animal MI models; develop GMP-grade vesicles and assess efficacy in early human trials; explore combinatorial strategies with existing post-MI therapies.
Post-myocardial infarction remodeling is a major cause of heart failure, with contributions from multiple organs. Brown adipose tissue protects against cardiovascular disease, but the mediators of brown adipose tissue-heart crosstalk and their roles in cardiac remodeling remain elusive. Here, we show that mitochondria-derived vesicles from brown adipose tissue transfer to cardiac macrophages and attenuate pathological remodeling via anti-inflammatory effects. Vesicles containing mitochondrial membranes, rather than mitochondrial matrix, mobilize from brown adipose tissue to the heart in response to stress. VPS35 translocation to mitochondria drives protein packaging into mitochondria-derived vesicles for secretion through extracellular vesicle trafficking machinery. Becn1 deficiency impairs VPS35 translocation, alters mitochondria-derived vesicle cargo, and abolishes brown adipose tissue-mediated cardioprotection. Proteomics identifies mitochondrial respiratory chain complex V as a hallmark of protective mitochondria-derived vesicles. These vesicles enhance reparative cytokine production and oxidative phosphorylation rewiring in macrophages. Purified mitochondria-derived vesicles markedly improve remodeling in male mice. Our study uncovers an interorgan transfer of bioenergetic units that contributes to tissue repair.