BACKGROUND: Primary aldosteronism (PA) carries excess cardiovascular risk not fully explained by hemodynamic load. While aldosterone promotes fibroblast activation experimentally, in vivo evidence linking adrenocortical...BACKGROUND: Primary aldosteronism (PA) carries excess cardiovascular risk not fully explained by hemodynamic load. While aldosterone promotes fibroblast activation experimentally, in vivo evidence linking adrenocortical activity with myocardial remodeling remains limited. This study integrated CXCR4 (C-X-C chemokine receptor type 4)-targeted Ga-Pentixafor positron emission tomography (PET)/magnetic resonance and FAP (fibroblast activation protein)-targeted Ga-FAPI-04 PET/cardiac magnetic resonance to evaluate the adrenal-cardiac axis in PA. METHODS: Eighty-two participants (40 with PA [21 aldosterone-producing adenoma (APA), 19 idiopathic hyperaldosteronism], 21 with essential hypertension, and 21 normotensive controls) underwent Ga-FAPI-04 PET/cardiac magnetic resonance; 48 concurrently underwent Ga-Pentixafor PET/magnetic resonance. Adrenal CXCR4 and myocardial FAPI uptake, as well as integrated volumetric-uptake burdens, were quantified and correlated with clinical and cardiac magnetic resonance indices. Eight patients with APA underwent follow-up imaging postadrenalectomy. RESULTS: Adrenal volume-adjusted CXCR4 signal served as a reliable marker of in vivo aldosterone burden and was significantly associated with adverse left ventricular remodeling, independent of blood pressure levels or hypertension duration. Myocardial Ga-FAPI-04 uptake was detected in 55% of patients with PA (APA 71.4%, idiopathic hyperaldosteronism 36.8%), compared with 19% of patients with essential hypertension and 0% of controls (<0.001), localizing predominantly to the basal septum. Importantly, total adrenal volume-adjusted CXCR4 signal correlated with myocardial FAPI activity (=0.38-0.64; all <0.05) and cardiac magnetic resonance markers of remodeling, both of which were positively associated with aldosterone levels. At 5.2±1.2 months post-adrenalectomy, myocardial FAPI uptake in 8 patients with APA declined significantly (<0.01), whereas late gadolinium enhancement and global cardiac function showed no significant change. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06756737. CONCLUSIONS: Dual-tracer PET/magnetic resonance provided in vivo molecular evidence of a CXCR4-FAP-mediated adrenal-cardiac axis in PA, revealing cross-talk between adrenocortical function, aldosterone secretion, and myocardial fibroblast activation beyond blood pressure effects. FAPI PET demonstrated more severe myocardial activation in APA, with partial postadrenalectomy reversibility, underscoring the value of early diagnosis and timely surgical intervention.
Xiong Z, Li Y, Zhang Y
… +16 more, Ma Z, Qi M, Zhang H, Zhang X, Jiang M, Liu J, Gao E, Li C, Man W, Zhang M, Hu J, Lin J, Yang Z, Fan L, Chen Y, Sun D
Circulation
· 2026 Jun · PMID 42273734
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BACKGROUND: Metabolic disturbances are key contributors to myocardial ischemia-reperfusion (I/R) injury, yet the underlying molecular mechanisms remain largely unclear. RND3, a cytosolic small GTPase known to antagonize...BACKGROUND: Metabolic disturbances are key contributors to myocardial ischemia-reperfusion (I/R) injury, yet the underlying molecular mechanisms remain largely unclear. RND3, a cytosolic small GTPase known to antagonize ROCK1 (Rho-associated coiled-coil kinase 1), has been implicated in several cardiovascular disorders. However, its mitochondrial localization and functional role in cardiac energy metabolism and I/R injury remain unknown. METHODS: A murine model of myocardial I/R injury was established through left anterior descending coronary artery ligation. Mice with cardiomyocyte-specific knockout and overexpression of were generated. To investigate the role of RND3 in cardiac metabolism and I/R injury, we used C-nuclear magnetic resonance, F-fluorodeoxyglucose positron emission tomography/computed tomography scanning, seahorse mitochondrial energy metabolism assays, and C-metabolic flux tracing. Mechanistic studies were conducted using RNA sequencing, coimmunoprecipitation, mass spectrometry, and GST pulldown assays. RESULTS: Cardiomyocyte-specific deletion of () resulted in impaired glucose oxidation and compensatory upregulation of fatty acid oxidation, leading to pronounced cardiac dysfunction and increased mortality. hearts exhibited reduced pyruvate/malate-driven complex I respiration and marked uncoupling between glycolysis and the tricarboxylic acid cycle. Mechanistically, RND3 was identified as a novel mitochondrial matrix-localized small GTPase that directly binds to ACAT1 (acetyl-CoA acetyltransferase), disrupting its interaction with PDHA1 (pyruvate dehydrogenase E1α subunit) and thereby promoting PDHA1 acetylation and glucose oxidation. It is important to note that RND3 expression was significantly downregulated in both human and murine hearts after I/R insult. Loss of RND3 sensitized the hearts to I/R injury, as evidenced by reduced levels of phosphocreatine and ATP. Conversely, cardiac-specific overexpression of conferred protection against I/R injury, an effect that was abolished upon knockdown. CONCLUSIONS: Our results identify RND3 as a novel mitochondria-localized regulator of glucose oxidation that safeguards the heart against I/R injury. Therapeutic reconstitution of may represent a promising strategy to restore metabolic homeostasis and mitigate myocardial damage in the context of I/R.
Zeitouni M, Procopi N, Cayla G
… +33 more, Ferrari E, Rangé G, Puymirat E, Delarche N, Guedeney P, Cuisset T, Varenne O, Cador R, Motreff P, Christiaens LP, Bellemain-Appaix A, Fayard M, Bayet G, Quédillac JM, Goube P, Goralski M, Elhadad S, Heliot F, Caussin C, Aisenfarb JC, Litalien J, Rambaud G, Attias D, Dumaine R, Slama MS, El Kasty M, Payot L, Aacha K, Diallo A, Vicaut E, Montalescot G, Silvain J, AβYSS investigators of the ACTION Study Group
Circulation
· 2026 Jun · PMID 42267437
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BACKGROUND: Heart rate (HR) is a key prognostic factor after myocardial infarction (MI), but its relevance in the modern reperfusion era is uncertain. We aim to evaluate the association between HR and β-blocker interrupt...BACKGROUND: Heart rate (HR) is a key prognostic factor after myocardial infarction (MI), but its relevance in the modern reperfusion era is uncertain. We aim to evaluate the association between HR and β-blocker interruption on cardiovascular outcomes. METHODS: A prespecified secondary analysis of the ABYSS trial (Assessment of Beta-Blocker Interruption 1 Year After an Uncomplicted Myocardial Infarction), including 3698 stable post-MI patients (left ventricular ejection fraction ≥40%) randomized to continue or interrupt β-blockers, was conducted. Patients were grouped by prerandomization HR tertiles: <60 bpm (T1), 60 to <68 (T2), and ≥68 (T3). We examined associations between HR, treatment strategy, and the primary endpoint (death, MI, stroke, or cardiovascular rehospitalization), major secondary endpoints, and on-treatment HR. RESULTS: Median age in the study population was 63.5 years (55.9-71.1), and there were 621 women (17.1%). Baseline HR was not associated with the primary endpoint (22.4% versus 21.8% versus 21.6%; 0.867). Higher HR was associated with increased risk of death, MI, or stroke (5.5% versus 6.4% versus 9.2%; <0.001; T3 versus T1 adjusted hazard ratio, 1.55; 95% CI, 1.14-2.12) and death, MI, stroke, or heart failure (6.5% versus 7.1% versus 10.4%; 0.007; T3 versus T1 adjusted hazard ratio, 1.47; 95% CI, 1.11-1.97). All-cause mortality rose across tertiles (2.9% versus 3.4% versus 5.9%; 0.004; trend=0.008). β-Blocker interruption produced a dose-dependent HR increase of ≈10-13 bpm during follow-up. The association between interruption and worse outcomes was consistent across HR tertiles (no significant interaction) and LVEF categories (40% to 49% and >50%). CONCLUSIONS: In stabilized post-MI patients with preserved ejection fraction, higher HR remains associated with adverse cardiovascular events and mortality in the reperfusion era. Interrupting β-blockers substantially increases HR and is consistently linked with worse outcomes irrespective of baseline HR, supporting continuation of β-blocker therapy.
Wang Q, Tian J, Liu D
… +16 more, Zheng T, Liu X, Zhao Y, Li X, Zhong H, Pan J, Yuan C, Zhao Y, Wang S, Li J, Zhang W, Zhang M, Zhang C, Liu F, Zhang M, Dai S
Circulation
· 2026 Jun · PMID 42267432
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BACKGROUND: Pulmonary hypertension (PH) is a progressive, life-threatening disease characterized primarily by pulmonary vascular remodeling in which endothelial dysfunction plays a vital role. However, the molecular fact...BACKGROUND: Pulmonary hypertension (PH) is a progressive, life-threatening disease characterized primarily by pulmonary vascular remodeling in which endothelial dysfunction plays a vital role. However, the molecular factors contributing to this pathological process remain incompletely understood. Through proteomic analysis of hypoxia-treated human pulmonary artery endothelial cells, we identified serine hydroxymethyltransferase 2 (SHMT2) as a potential target in PH, but its role in disease pathogenesis and the underlying mechanisms remain unclear. METHODS: The expression and function of SHMT2 were assessed in lung samples from patients with PH and in rodent PH models, including hypoxia-exposed mice and monocrotaline- or Sugen 5416/hypoxia-induced rats. Endothelial cell-specific SHMT2 loss and gain of function were achieved by conditional knockout and adeno-associated virus 9-mediated gene modulation. In vitro studies were performed in hypoxia-treated human pulmonary artery endothelial cells and HEK-293T cells. Virtual screening was used to identify a small-molecule inhibitor targeting the nonmetabolic function of SHMT2, and its therapeutic potential was further evaluated in rodent PH models. RESULTS: SHMT2 was upregulated predominantly in pulmonary vascular endothelium of patients with PH and multiple rodent PH models. In vivo, endothelial cell-specific deletion of markedly attenuated pulmonary vascular remodeling and right ventricular dysfunction in PH mice, whereas endothelial cell-specific overexpression aggravated PH development. Consistently, adeno-associated virus 9-mediated endothelial knockdown alleviated PH phenotypes in rat models. Mechanistically, SHMT2 promoted hypoxia-induced endothelial barrier dysfunction mainly through a noncanonical function by blocking the K63-ubiquitin-mediated lysosomal degradation of ras homolog family member B (RhoB). Additional in vivo studies supported an important role of the endothelial SHMT2-RhoB axis in pulmonary vascular remodeling of PH. Through virtual screening, Namodenoson was identified as a small-molecule inhibitor targeting the SHMT2-RhoB pathway. In vivo, Namodenoson showed both preventive and therapeutic effects against PH. CONCLUSIONS: This study highlights endothelial SHMT2 as an important contributor to PH pathogenesis and reveals a noncanonical SHMT2-RhoB pathway that promotes endothelial dysfunction. Targeting this pathway may represent a potential therapeutic strategy for PH.
Uno K, Araki S, Nakamori S
… +12 more, Nakamura S, Kitano T, Omori T, Fujita M, Nakamura A, Ishida M, Kitagawa K, Shomura Y, Maruyama K, Kumagai N, Sakuma H, Dohi K
Ruberto FP, Lee CJM, Ackers-Johnson M
… +22 more, Sridharan P, Khanchandani V, Wu LH, Goh LX, Luu TDA, Pakkiri LS, Bonne I, Lu TB, Buss DJ, Lovelace T, Subramanian V, Villanueva E, Hu Y, Vidyasekar P, Gurung R, Lee JM, Yong WK, Li Z, Kappei D, Ho L, Drum CL, Foo RSY
Circulation
· 2026 Jun · PMID 42267405
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BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial D...BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]-AMP [adenosine monophosphate] synthase)-STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood. METHODS: We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47-amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of (-KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of -KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9-mediated gene restoration in the -KO mouse. RESULTS: STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS-STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type or STING inhibition significantly rescued cardiac function in vivo. CONCLUSION: Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.
Writing Committee Members, Ndumele CE, Rodriguez F
… +34 more, Dixon DL, Khan SS, Mukherjee D, Bajaj M, Bangalore S, Bozkurt B, Breathett K, Clarke SL, de Boer IH, Ellison DH, Evangelista LS, Heffron SP, Kazi DS, Kulshreshtha A, Lingvay I, Low Wang CC, Mercado CA, Morton JM, Neeland IJ, Pagidipati N, Powell-Wiley TM, Rangaswami J, Rao G, Reza N, Saeed A, St Peter W, Starks JB, Sterling M, Talbot AW, Tran AH, Tuttle KR, VanWagner LB, Vest AR, Virani SS
Circulation
· 2026 Jun · PMID 42263157
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AIM: The "2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome" retires, replaces, and expands upon the "2013 AHA/ACC/TOS Guideline for the...AIM: The "2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome" retires, replaces, and expands upon the "2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults." The primary intended audience for this guideline is clinicians who care for patients across the spectrum of cardiovascular-kidney-metabolic syndrome, an interrelated condition characterized by the interconnections among metabolic risk factors (including obesity and type 2 diabetes), chronic kidney disease, and cardiovascular disease. METHODS: A comprehensive literature search was conducted from October 29, 2024, to April 14, 2025, to identify clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human subjects that were published since 2015 in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: The focus of this clinical practice guideline is to create a living, working document that provides current knowledge in the field of cardiovascular-kidney-metabolic syndrome aimed at all practicing cardiologists, endocrinologists, nephrologists, and primary care and specialty clinicians who manage these patients.
Khan SS, Bhave N, Blumenthal RS
… +18 more, Coresh J, Huang X, Joseph JJ, Khera A, Ho JE, Lloyd-Jones DM, Low Wang CC, Lu Y, Morris PB, Nasir K, Natarajan P, Rangaswami J, Rodriguez F, Sperling LS, Virani SS, Zhang S, Ndumele CE, American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; and the American College of Cardiology
Circulation
· 2026 Jun · PMID 42263147
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Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart...Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of high blood pressure in adults and the 2026 American Heart Association/American College of Cardiology guideline on the management of dyslipidemia incorporate quantitative risk assessment, recommending the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations to guide initiation and intensification of antihypertensive and lipid-lowering therapies, respectively. Given the growing awareness of the clustering of cardiovascular-kidney-metabolic risk factors along with the expanding armamentarium of cardioprotective therapies for obesity, diabetes, and chronic kidney disease, a harmonized approach that comprehensively assesses and addresses risk across these interconnected conditions is needed. The 2026 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of cardiovascular-kidney-metabolic syndrome provides recommendations for the use of the PREVENT equations with outcome-specific risk thresholds for staging, detection of subclinical cardiovascular disease, and decision-making regarding initiation and intensification of cardiovascular-kidney-metabolic therapies. This approach integrates predicted risk (using PREVENT-CVD [cardiovascular disease], PREVENT-ASCVD [atherosclerotic cardiovascular disease], and PREVENT-HF [heart failure]) with the relative risk reduction expected from treatment for each outcome to estimate the expected benefit (ie, absolute risk reduction) from drug therapy. This scientific statement details the rationale for using outcome-specific PREVENT equations, the evidence base for selected risk thresholds, and the potential population-level impact of these recommendations. This scientific statement also offers practical guidance for applying risk assessment as the first step in shared decision-making and for addressing gaps in awareness, risk communication, and optimal implementation of evidence-based preventive therapies to improve outcomes in individuals with or at risk for cardiovascular-kidney-metabolic syndrome.
Chen Q, Wang X, Yin Z
… +8 more, Liu S, Chen T, Zhang Y, Xian X, Zhang T, Zhao H, Jiang W, Wang J
Circulation
· 2026 Jun · PMID 42261667
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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TP...BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. METHODS: We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell-derived cardiomyocytes, we investigated the role of TPM1 isoforms and its upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. RESULTS: We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. CONCLUSIONS: AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.
Desroches-Castan A, Beurier-Soulat L, Tusseau M
… +14 more, Coulet F, Azemard V, Logeart-Avramoglou D, Maillard H, Laffargue F, Nachury-Janel C, Giraud S, Lesca G, Grynblat J, Guilhem A, Tillet E, Dupuis-Girod S, Montani D, Bailly S
Circ Genom Precis Med
· 2026 Jun · PMID 42261662
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BACKGROUND: (encoding BMP9) variants have been described in pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia, as well as a few variants in PAH. The purpose of the present study was to dev...BACKGROUND: (encoding BMP9) variants have been described in pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia, as well as a few variants in PAH. The purpose of the present study was to develop a functional assay capable of discriminating benign from pathogenic variants and to characterize the underlying molecular mechanisms responsible for their loss of function. METHODS: We developed a single-step functional assay in which C2C12 cells stably expressing a BMP (bone morphogenetic protein)-responsive element upstream of a firefly luciferase reporter would be stimulated by the autocrine secretion of BMP9 or BMP10 variants produced by transfected expression plasmids. RESULTS: Using this functional assay, we reclassified all variants and 2 out of 5 variants identified in patients with PAH as likely pathogenic. In contrast, only 2 of the 4 variants identified in suspected patients with hereditary hemorrhagic telangiectasia were found to be likely pathogenic; nevertheless, none of the patients met the diagnostic criteria for hereditary hemorrhagic telangiectasia. We also showed, using ELISAs and Western blots, that the loss of function of and variants was mostly due to altered processing (folding/stability defects). Moreover, we found that loss-of-function variants impaired the secretion of BMP10, suggesting a potential dominant-negative mechanism. CONCLUSIONS: We developed a functional assay for and variants, enabling the reclassification of variants of unknown significance. Together, this study further supports the involvement of and as predisposing genes in PAH. This single-step assay will be transferable to clinical genetic laboratories and will improve diagnosis of patients with PAH and hereditary hemorrhagic telangiectasia.
BACKGROUND: The relationship between fetal aortic valvuloplasty procedural volume and outcomes is crucial to understand whether regionalization should be advised worldwide. This study utilizes the International Fetal Car...BACKGROUND: The relationship between fetal aortic valvuloplasty procedural volume and outcomes is crucial to understand whether regionalization should be advised worldwide. This study utilizes the International Fetal Cardiac Intervention Registry to examine the relationship between center volume for fetal aortic valvuloplasty and outcome metrics including procedure success, complications, and fetal death. METHODS: Data were included from institutions performing ≥3 procedures (2001-2018). The primary outcome was technical success, defined as ≥1 balloon inflation across the aortic valve, with increased antegrade flow across the valve and new aortic regurgitation. Secondary end points were procedural complications and fetal periprocedural death (within 48 hours). Univariable and Classification and Regression Tree analyses were performed. RESULTS: Eleven centers, with volumes ranging from 6 to 31 cases, performed 162 fetal aortic valvuloplasties with a technical success rate of 80.2%. Higher volume was not associated with better technical success or fewer complications but was associated with fewer periprocedural fetal deaths. Employing Classification and Regression Tree modeling, the largest drivers of improved outcomes for all measures were greater estimated fetal weight and gestational age. A single cardiac puncture was associated with greater technical success and fewer procedural complications after accounting for fetal estimated fetal weight and gestational age. CONCLUSIONS: In this registry cohort, higher-volume centers did not have greater fetal aortic valvuloplasty technical success or fewer complications but did have fewer periprocedural fetal deaths. Fetal gestational age and number of cardiac punctures influenced outcomes, suggesting that unmeasured fetal selection criteria, such as different referral patterns, and technical expertise, indicative of overall center/team experience, may influence fetal survival.