Daily Cardiology Research Analysis
Three impactful cardiology studies stood out today: a Nature Cardiovascular Research study uncovers a heart failure–specific fibroblast program (MYC–CXCL1–CXCR2) that impairs cardiomyocyte function; a network meta-analysis challenges the class-effect assumption among TAVI devices, finding mortality differences across platforms; and an RCT substudy shows aficamten outperforms metoprolol on echocardiographic measures in obstructive HCM.
Summary
Three impactful cardiology studies stood out today: a Nature Cardiovascular Research study uncovers a heart failure–specific fibroblast program (MYC–CXCL1–CXCR2) that impairs cardiomyocyte function; a network meta-analysis challenges the class-effect assumption among TAVI devices, finding mortality differences across platforms; and an RCT substudy shows aficamten outperforms metoprolol on echocardiographic measures in obstructive HCM.
Research Themes
- Fibroblast-driven mechanisms and therapeutic targets in heart failure
- Comparative effectiveness and device selection in TAVI
- Cardiac myosin inhibition as monotherapy in obstructive HCM
Selected Articles
1. Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC-CXCL1-CXCR2 axis.
Using single-cell transcriptomics and functional studies, the authors identify a heart failure–specific fibroblast state driven by MYC that secretes CXCL1, signaling via cardiomyocyte CXCR2 to depress contractility. Genetic or pharmacologic interruption of the MYC–CXCL1–CXCR2 axis improved cardiac function in preclinical models and human relevance was supported by failing-heart fibroblast profiles.
Impact: This study shifts focus from cardiomyocytes to fibroblasts and delineates a tractable signaling axis linking fibroblast reprogramming to cardiomyocyte dysfunction, opening a new therapeutic avenue.
Clinical Implications: Targeting CXCL1–CXCR2 signaling or upstream MYC programs in cardiac fibroblasts could yield anti-remodeling therapies for heart failure. Biomarkers from this axis may aid patient stratification.
Key Findings
- Single-cell RNA-seq identified a heart failure–specific fibroblast subcluster with high MYC expression.
- MYC directly upregulates CXCL1 in fibroblasts; CXCL1 signals via cardiomyocyte CXCR2 to depress contractility.
- Genetic deletion of Myc in fibroblasts or pharmacologic blockade of CXCL1–CXCR2 improved cardiac function in pressure overload models and human relevance was confirmed in failing-heart fibroblasts.
Methodological Strengths
- Integration of single-cell transcriptomics with in vivo genetic manipulation and in vitro human iPSC-cardiomyocyte assays
- Cross-species validation including human failing-heart fibroblasts
Limitations
- Preclinical models; clinical efficacy and safety of targeting MYC/CXCL1–CXCR2 remain untested
- Potential off-target and systemic effects of chemokine pathway modulation
Future Directions: Develop selective inhibitors or delivery strategies targeting fibroblast-specific MYC–CXCL1 signaling; validate axis-related biomarkers and conduct early-phase trials to assess safety and remodeling impact.
Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Single-cell RNA sequencing of mouse hearts under pressure overload identified six CF subclusters, with one specific to the HF stage. This HF-specific CF population highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-specific CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes, and blocking the CXCL1-CXCR2 axis mitigates HF. CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls. These findings reveal that HF-specific CFs contribute to HF via the MYC-CXCL1-CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes.
2. Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM.
In MAPLE-HCM, aficamten monotherapy led to significantly greater reductions in resting and Valsalva LVOT gradients versus metoprolol over 24 weeks, with concurrent improvements in left atrial volume index, diastolic function, and mitigation of SAM/MR; a modest LVEF reduction was observed.
Impact: Head-to-head randomized evidence against standard beta-blockade supports cardiac myosin inhibition as a superior monotherapy for obstructive HCM on key echocardiographic markers.
Clinical Implications: Aficamten may be favored as first-line pharmacotherapy in symptomatic obstructive HCM to rapidly lower LVOT gradients and improve diastolic parameters, with monitoring for LVEF reduction.
Key Findings
- Aficamten reduced resting LVOT gradient by −30 mm Hg and Valsalva gradient by −35 mm Hg versus metoprolol (both P < 0.001).
- Left atrial volume index and diastolic function measures improved more with aficamten; SAM and mitral regurgitation were reduced.
- A modest decrease in LVEF occurred with aficamten compared to metoprolol.
Methodological Strengths
- Randomized, head-to-head comparison with standardized serial echocardiography
- Dose-titration protocol reflecting clinical practice
Limitations
- Echocardiographic surrogate endpoints over 24 weeks; not powered for hard clinical outcomes
- Modest sample size and exploratory imaging analyses
Future Directions: Confirm clinical outcome benefits and safety in longer trials, define optimal sequencing with other HCM therapies, and refine monitoring strategies for LVEF.
BACKGROUND: Beta-blockers have formed the mainstay of first-line therapy for symptomatic obstructive hypertrophic cardiomyopathy (HCM) for decades. Aficamten, compared with placebo, lowered left ventricular outflow tract gradients (LVOT-G), improved measures of left ventricular (LV) diastolic function, and showed evidence of favorable remodeling when added to standard of care medical therapy in SEQUOIA-HCM. The comparative effectiveness of monotherapy with aficamten vs metoprolol was investigated in MAPLE-HCM. OBJECTIVES: This study evaluated the effect of monotherapy with aficamten compared with metoprolol on cardiac structure and function in participants enrolled in the MAPLE-HCM study. METHODS: Serial echocardiograms and other clinical measures were collected over 24 weeks in participants receiving escalating doses of aficamten 5 to 20 mg or metoprolol 50 to 200 mg. RESULTS: The study enrolled 175 participants (mean age 58 ± 13 years, 42% women, 80% White, 14% Asian). Mean left ventricular ejection fraction (LVEF) was 68% ± 4% with resting and Valsalva LVOT-G of 47 ± 29 mm Hg and 74 ± 33 mm Hg, respectively. Compared with metoprolol, aficamten decreased resting LVOT-G (-30 mm Hg [95% CI: -37 to -23 mm Hg]; P < 0.001) and Valsalva LVOT-G (-35 mm Hg [95% CI: -44 to -26 mm Hg]; P < 0.001); reduced left atrial volume index (left atrial volume index -7.0 mL/m
3. Comparative Effectiveness of TAVI Platforms and Surgical Aortic Valve Replacement: A Network Meta-Analysis of Randomized Controlled Trials.
Across 11 RCTs (n=9,946), CoreValve–Evolut showed mortality comparable to SAVR, whereas SAPIEN and ACURATE neo were associated with higher all-cause and cardiovascular mortality versus SAVR and versus CoreValve–Evolut. All TAVI platforms increased pacemaker and reintervention rates compared with SAVR.
Impact: This challenges the widely held class-effect assumption for TAVI and directly informs device selection and guideline recommendations with long-term randomized evidence.
Clinical Implications: Device choice matters: CoreValve–Evolut may be preferred when mortality is prioritized, while clinicians should balance reintervention/pacemaker risks. Findings argue against assuming equivalence across TAVI platforms.
Key Findings
- CoreValve–Evolut had similar all-cause and cardiovascular mortality to SAVR (moderate certainty).
- SAPIEN and ACURATE neo increased all-cause and cardiovascular mortality versus SAVR and versus CoreValve–Evolut (moderate to high certainty).
- All TAVI platforms showed higher pacemaker implantation and reintervention rates than SAVR.
Methodological Strengths
- Network meta-analysis of randomized trials with GRADE assessment and 1–10 year follow-up
- Head-to-head and indirect comparisons across commercially available platforms
Limitations
- Assumptions of transitivity/consistency inherent to network meta-analysis
- Evolving device generations and operator experience may introduce heterogeneity
Future Directions: Prospective head-to-head RCTs across current-generation platforms, stratified by anatomy and risk, and post-market surveillance to validate mortality signals.
BACKGROUND: Evidence informing clinical guidelines assumes that all transcatheter aortic valve implantation (TAVI) devices have similar effectiveness, in other words, displaying a class effect across TAVI valves. We aimed to assess the comparative effectiveness of different TAVI platforms relative to other TAVI counterparts or surgical aortic valve replacement (SAVR). METHODS: MEDLINE/Embase/CENTRAL were searched from inception until April 2025, for randomized controlled trials comparing outcomes with different commercially available TAVI devices relative to other TAVI counterparts or SAVR. The certainty of the evidence was assessed following the Grading of Recommendations, Assessment, Development, and Evaluations approach. We performed a frequentist network meta-analysis to generate treatment effect estimates. All-cause, cardiovascular mortality, and stroke were considered critically important patient-centered outcomes. RESULTS: We identified 11 randomized controlled trials with 9946 participants and reporting outcomes between 1 to 10 years. TAVI with CoreValve-Evolut was associated with a similar risk of all-cause (absolute risk difference [ARD], 31/1000 from -12 to 79), and cardiovascular mortality (ARD, -8/1000 from -39 to 28) compared with SAVR (moderate certainty). Compared with SAVR, TAVI with SAPIEN and ACURATE neo were associated with an increased risk of all-cause (ARD, 109/1000 from 56 to 169, high certainty and ARD, 123/1000 from 9 to 277, moderate certainty, respectively) and cardiovascular mortality (ARD, 58/1000 from 18 to 105, high certainty and ARD, 105 from 7 to 247, moderate certainty, respectively). Moderate and high-certainty evidence showed that all TAVI platforms were associated with an increased risk of reinterventions and pacemaker implant versus SAVR. Compared with TAVI with CoreValve-Evolut, SAPIEN was associated with higher all-cause (ARD, 75/1000 from 13 to 147, high certainty) and cardiovascular mortality (ARD, 66/1000 from 15 to 130, high certainty), same scenario for ACURATE neo (ARD 113/1000 from 13 to 259, high certainty). CONCLUSIONS: TAVI with CoreValve-Evolut is probably associated with similar mortality to SAVR. TAVI with SAPIEN and ACURATE neo were associated with increased risk of mortality compared with SAVR and CoreValve-Evolut. The current body of evidence from randomized controlled trials goes against the hypothesis of a class effect across TAVI valves. REGISTRATION: URL: https://www.crd.york.ac.uk; Unique identifier: CRD42024512026.