Daily Cardiology Research Analysis
Three impactful cardiology papers span clinical devices, mechanistic biology, and imaging biomarkers: a multicenter randomized trial shows a bioresorbable occluder is noninferior to metallic devices for ASD closure with near-complete degradation by 2 years; a Circulation Research study uncovers an estrogen–cardiomyocyte GC1–VEGF signaling axis preserving right ventricular function under pressure overload; and a JCI Insight study identifies FAP PET as an early imaging biomarker of doxorubicin car
Summary
Three impactful cardiology papers span clinical devices, mechanistic biology, and imaging biomarkers: a multicenter randomized trial shows a bioresorbable occluder is noninferior to metallic devices for ASD closure with near-complete degradation by 2 years; a Circulation Research study uncovers an estrogen–cardiomyocyte GC1–VEGF signaling axis preserving right ventricular function under pressure overload; and a JCI Insight study identifies FAP PET as an early imaging biomarker of doxorubicin cardiotoxicity preceding functional decline.
Research Themes
- Bioresorbable device validation for transcatheter ASD closure
- Sex-specific right ventricular remodeling mechanisms (estrogen–GC1–VEGF axis)
- Early detection of chemotherapy cardiotoxicity using FAP PET imaging
Selected Articles
1. Bioresorbable vs Metallic Occluders for Transcatheter Atrial Septal Defect Closure: A Randomized Clinical Trial.
In a multicenter noninferiority RCT of 229 patients with secundum ASD, a bioresorbable occluder achieved similar closure success and device-related safety to a metallic occluder at 6 months and 2 years, with ~99.8% device degradation by 2 years. The trial supports bioresorbable occluders as a viable alternative that may preserve future transseptal access.
Impact: This is the first randomized validation of a fully bioresorbable ASD occluder with 2-year outcomes, addressing long-standing concerns about permanent metal implants.
Clinical Implications: Bioresorbable occluders can be considered for secundum ASD closure with noninferior efficacy and safety to metallic devices, potentially facilitating future left atrial access and reducing long-term device-related risks.
Key Findings
- ASD closure success at 6 months: 96.5% (bioresorbable) vs 97.4% (metallic), meeting noninferiority (P < .001).
- Two-year closure success and device-related adverse events were similar between groups (P = .75 and P = .72, respectively).
- Bioresorbable occluder degraded by ~99.8% at 2 years, indicating near-complete resorption.
Methodological Strengths
- Multicenter randomized noninferiority design with core clinical endpoints at 6 months and 2 years
- Prospective assessment of device degradation profile with standardized imaging follow-up
Limitations
- Open-label design and enrollment limited to 10 sites in China may affect generalizability
- Two-year follow-up may not capture very late outcomes beyond device resorption
Future Directions: Longer-term surveillance for late arrhythmia, erosion, or thromboembolism after full resorption; evaluation in broader anatomies and age ranges; and health-economic analyses.
IMPORTANCE: The permanent metallic occluders used for atrial septal defect (ASD) closure are associated with risks of late complications and may impede access to the left atrium. Bioresorbable occluders have the potential to address these limitations but have yet to be validated in randomized clinical trials. OBJECTIVE: To evaluate whether a bioresorbable occluder is noninferior to a metallic occluder based on its efficacy and safety for transcatheter ASD closure. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, noninferiority, open-label randomized clinical trial included participants with secundum ASD. Enrollment occurred from May 8, 2021, to August 3, 2022, at 10 hospital sites in China. The 2-year follow-up period ended in September 2024. INTERVENTIONS: Participants were randomized in a 1:1 ratio to receive a bioresorbable occluder (n = 116) or a metallic occluder (n = 114). MAIN OUTCOMES AND MEASURES: The primary outcome was the success rate of ASD closure at 6 months (closure success was defined as procedural success with a residual shunt diameter of ≤2 mm, which was assessed using transthoracic echocardiography). At the 2-year follow-up, the occluder groups were compared regarding the success of ASD closure and the device-related adverse events. The degradation profile of the bioresorbable occluder was assessed at 2 years. RESULTS: Of the 230 participants randomized, implantation was not attempted in 1 participant in the bioresorbable occluder group due to a small femoral vein, leaving 229 (median age, 14.1 years [IQR, 7.0 to 37.3 years]; 68% were female). At 6 months, the success rate of ASD closure was 96.5% (111 of 115 patients) for the bioresorbable occluder group vs 97.4% (111 of 114 patients) for the metallic occluder group (between-group difference, -0.8 percentage points [95% CI, -5.0 to 3.7]; P < .001 for noninferiority). At 2 years, there were no statistically significant between-group differences in ASD closure success (94.8% [109/115] in the bioresorbable occluder group vs 96.5% [110/114] in the metallic occluder group; P = .75), or in device-related adverse events (2.6% [3/115] vs 3.5% [4/114], respectively; P = .72). The rate of degradation at 2 years was approximately 99.8% for the bioresorbable occluder. CONCLUSIONS AND RELEVANCE: A bioresorbable occluder is noninferior to a metallic occluder for ASD closure, with near-complete degradation by 2 years. These findings suggest that a bioresorbable occluder could be a valuable addition to the options for transcatheter ASD closure. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2100044408.
2. Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling.
Using sex-stratified cardiomyocyte-specific GC1 knockout mice under pulmonary artery banding, the study shows that estrogen and cardiomyocyte NO-sensitive GC1 sustain VEGF-mediated capillarization, preserving RV–PA coupling during pressure overload. Loss of cardiomyocyte GC1 or estrogen leads to capillary rarefaction, fibrosis, and RV dysfunction.
Impact: This work mechanistically deciphers a sex-specific, cardiomyocyte-to-endothelium signaling axis that explains better RV adaptation in females and highlights GC1 as a potential therapeutic node.
Clinical Implications: Targeting the GC1–cGMP–VEGF pathway or leveraging estrogenic signaling may offer sex-attentive therapies for RV failure in pulmonary hypertension and right-sided heart disease.
Key Findings
- Female control mice preserved RV–PA coupling under pressure overload, unlike males, ovariectomized females, or cardiomyocyte-GC1 knockouts.
- Capillary-to-cardiomyocyte ratio strongly correlated with RV function; cardiomyocyte GC1 maintained capillarization via VEGF–VEGFR signaling.
- Loss of cardiomyocyte GC1 led to RV dysfunction, hypertrophy, interstitial fibrosis, and capillary rarefaction.
Methodological Strengths
- Cardiomyocyte-specific genetic knockout with sex-stratified analysis and rigorous hemodynamic phenotyping
- Integration of single-nucleus RNA sequencing and endothelial coculture to define cell–cell signaling
Limitations
- Preclinical mouse model limits direct clinical generalizability
- Hormonal manipulations and genetic deletion may not fully recapitulate human disease complexity
Future Directions: Validate GC1–VEGF signaling in human RV tissue; test GC activators or cGMP-enhancing agents in sex-specific RV failure models; explore biomarkers reflecting capillary-to-cardiomyocyte ratio.
BACKGROUND: Right ventricular (RV) dysfunction increases mortality in heart failure and pulmonary hypertension. However, women demonstrate better RV function and survival than men. This difference is attributed to estrogen, though mechanistic details remain unclear. Given estrogen's stimulation of NO production, we investigated whether and how cardiomyocyte NO-sensitive GC1 (soluble guanylyl cyclase) mediates female-specific, adaptive RV pressure-overload remodeling. METHODS: Adult male and female mice with cardiomyocyte-specific GC1 deficiency (cardiomyocyte-specific knockout) and littermate controls underwent pulmonary artery banding (PAB) or thoracotomy (Sham). At 6-week postsurgery, RV function was assessed via echocardiography, pressure-volume loops, and treadmill testing. RV function, histopathology, and transcript profiles were compared across sex, genotype, and surgical group. Single-nucleus RNA sequencing of RV tissue was performed to identify putative cardiomyocyte GC1-mediated cell-cell communication in adaptive RV pressure-overload remodeling. Endothelial coculture assays with controls versus cardiomyocyte-specific knockout cardiomyocytes evaluated estrogen and cardiomyocyte GC1-dependence of the identified intercellular signaling. RESULTS: Female control PAB mice adapted RV contractility to overcome RV pressure-overload, thereby preserving RV-PA coupling. In contrast, female cardiomyocyte-specific knockout, ovariectomized female controls, and male PAB developed severe RV dysfunction with RV-PA uncoupling. These groups with maladapted RVs had marked cardiomyocyte hypertrophy, interstitial fibrosis, and capillary rarefaction; female control PAB had minimal changes. Among histological features, the capillary-to-cardiomyocyte ratio showed the strongest correlation with RV function. Ratios were similar between female control PAB and Sham, but abnormally low in all other PAB. Single-nucleus RNA sequence and coculture analyses revealed that cardiomyocyte GC1 is central to Vegf (vascular endothelial growth factor)-Vegfr (Vegf receptor) proangiogenic signaling from cardiomyocytes to endothelial cells in the adaptively remodeled, pressure-overloaded RV. CONCLUSIONS: We identified a novel estrogen- and cardiomyocyte GC1-dependent pathway that mitigates capillary rarefaction, maintaining normal capillary-to-cardiomyocyte ratio and preserving RV-PA coupling under RV pressure-overload. This proangiogenic, estrogen- and cardiomyocyte GC1-dependent mechanism contributes to sex-specific differences in RV remodeling and may inform the development of targeted therapies for RV dysfunction.
3. FAP PET identifies earlycardiac molecular changesinduced by doxorubicin chemotherapy.
In a mouse model of doxorubicin cardiotoxicity, [68Ga]FAPI-04 PET uptake increased by 2 weeks—well before measurable functional deficits (≈10 weeks) and fibrosis (≈16 weeks)—and correlated with FAP expression and remodeling markers. Alternative tracers (TSPO, NET) did not differentiate DOX from controls, highlighting FAP PET’s specificity for early fibroblast activation.
Impact: This study provides translational evidence that FAP PET detects cardiotoxic remodeling before functional decline, enabling earlier risk stratification in oncology patients.
Clinical Implications: FAP PET could be integrated into cardio-oncology surveillance to identify anthracycline-treated patients at risk before LVEF decline, guiding early cardioprotective interventions and therapy modification.
Key Findings
- [68Ga]FAPI-04 cardiac uptake rose by 2 weeks post-DOX, preceding functional impairment (~10 weeks) and fibrosis (~16 weeks).
- FAP PET signal correlated with FAP expression/activity and canonical remodeling markers.
- TSPO ([18F]DPA-714) and NET ([18F]MFBG) tracers did not distinguish DOX-exposed from control hearts.
Methodological Strengths
- Longitudinal design with multiple time points linking imaging to histology and function
- Comparator PET tracers to demonstrate specificity of FAP targeting
Limitations
- Preclinical male mouse model; sex differences and human validation are pending
- PET biomarker thresholds and clinical workflows require prospective studies
Future Directions: Prospective human studies to validate FAP PET for early cardiotoxicity, define thresholds, integrate with troponin/strain monitoring, and assess intervention triggers.
Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein α (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18 kDa and the norepinephrine transporter, respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.