Search Results for: Circulation

Circulation, Ahead of Print. BACKGROUND:Vascular aging is an important phenotype characterized by structural and geometric remodeling. Some individuals exhibit supernormal vascular aging, associated with improved cardiovascular outcomes; others experience early vascular aging, linked to adverse cardiovascular outcomes. The aorta is the artery that exhibits the most prominent age-related changes; however, the biological mechanisms underlying aortic aging, its genetic architecture, and its relationship with cardiovascular structure, function, and disease states remain poorly understood.METHODS:We developed sex-specific models to quantify aortic age on the basis of aortic geometric phenotypes derived from 3-dimensional tomographic imaging data in 2 large biobanks: the UK Biobank and the Penn Medicine BioBank. Convolutional neural ne2rk–assisted 3-dimensional segmentation of the aorta was performed in 56 104 magnetic resonance imaging scans in the UK Biobank and 6757 computed tomography scans in the Penn Medicine BioBank. Aortic vascular age index (AVAI) was calculated as the difference between the vascular age predicted from geometric phenotypes and the chronological age, expressed as a percent of chronological age. We assessed associations with cardiovascular structure and function using multivariate linear regression and examined the genetic architecture of AVAI through genome-wide association studies, followed by Mendelian randomization to assess causal associations. We also constructed a polygenic risk score for AVAI.RESULTS:AVAI displayed numerous associations with cardiac structure and function, including increased left ventricular mass (standardized β=0.144 [95% CI, 0.138, 0.149];P

Circulation, Ahead of Print. BACKGROUND:Neurodevelopmental and functional impairments are among the most consequential morbidities for survivors of hypoplastic left heart syndrome after staged single ventricle surgical palliation. The SVRIII trial (Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type) enrolled adolescents, who were randomized to different surgical shunt types at the time of Norwood procedure as neonates, for multifaceted in-person evaluation. This study reports their neurodevelopmental outcomes.METHODS:Transplant-free survivors from SVRIII were invited to complete an in-person comprehensive neurodevelopmental evaluation in early adolescence. Outcomes across domains of cognition, academics, learning, memory, and attention, as well as social, emotional, behavioral, adaptive, and executive function, were compared with those of normative populations. Associations with demographic and medical covariates, including Norwood shunt type, were also assessed.RESULTS:Among 549 participants enrolled in the SVR trial (Single Ventricle Reconstruction), 200 of the 237 SVRIII participants (84%) completed a neurodevelopmental evaluation at a mean age of 11 years (range, 10 to 14 years). SVRIII participants who did versus did not undergo evaluation were more likely to be male (63% versus 51%), to be White (87% versus 76%), and to have a higher Childhood Opportunity Index score (61±26 versus 46±39). Full-scale intelligence quotient (88±18) was significantly lower than in the normative population, with 39% >1 and 15% >2 SD below the normative mean. Similar patterns were seen for reading (38% >1 SD and 16% >2 SD below the normative mean) and math (38% >1 SD and 19% >2 SD below the normative mean) scores. Attention, executive functioning, social development, visual memory, and adaptive functioning were all more impaired than in the normative population. Measures of socioeconomic status, number of medical complications, and requirement for a gastrostomy tube were each independent predictors of neurodevelopment, with socioeconomic status the most consistently significant factor across models. Group differences by shunt type were inconsistent across neurodevelopmental domains without a clear benefit of one surgical strategy.CONCLUSIONS:In early adolescence, transplant-free survivors of surgical palliation for hypoplastic left heart syndrome show concerning impairments across all domains of neurodevelopment. The distribution of affected outcomes is broad and associated with demographic, medical, and, most frequently, socioeconomic factors. Our findings support recommendations for neurodevelopmental evaluation during adolescence to guide individualized interventions to promote educational success and psychosocial well-being.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT02455531.

Circulation, Ahead of Print. BACKGROUND:Hereditary hemorrhagic telangiectasia is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function variations in activin receptor-like kinase 1 (ALK1) cause type 2 hereditary hemorrhagic telangiectasia, andAlk1knockout mice develop AVMs, along with overactivation of vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. The full spectrum of signaling alterations resulting fromALK1variations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed.METHODS:Single-cell RNA sequencing of endothelial-specificAlk1knockout mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human type 2 hereditary hemorrhagic telangiectasia lesions. Genetic and pharmacological PIEZO1 inhibition was tested inAlk1knockout mice, along with downstream PIEZO1 signaling.RESULTS:A cluster ofAlk1mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle, and vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling.Piezo1deletion and pharmacological inhibition inAlk1-deficient mice mitigated AVM formation, whereasPiezo1overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated vascular endothelial growth factor receptor 2/AKT, ERK5-p62-KLF4, endothelial nitric oxide synthase, hypoxia, proliferation, and inflammation in ALK1-deficient endothelium.CONCLUSIONS:PIEZO1 expression and signaling are elevated in type 2 hereditary hemorrhagic telangiectasia. PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.

Circulation, Ahead of Print. BACKGROUND:β-Adrenergic receptors (βARs) are prototypical G protein–coupled receptors that regulate contractility in the normal heart and pathological remodeling in disease. Canonical βAR signaling originates at the plasma membrane, but functional βARs have been localized to intracellular membranes such as the endosome, sarcoplasmic reticulum, Golgi, and nuclear envelope. The functional significance of these intracellular receptors remains unclear, including whether they regulate cellular processes distinct from those regulated by plasma membrane receptors and whether they can be independently targeted for therapeutic benefit.METHODS:Live cell imaging of rat and human cardiomyocytes expressing novel compartment-specific modulators of βAR activity and fluorescent biosensors was used to study the compartment-specific βAR regulation of second messengers and to target enzyme activity. Compartmentalized signaling was compared with myocyte gene expression and hypertrophy. Adeno-associated virus gene delivery conferring gain and loss of perinuclear βAR activity was studied in wild-type mice and a mouse model of familial dilated cardiomyopathy.RESULTS:We demonstrate here that intracellular β1ARs present on Golgi membrane facing the outer nuclear membrane regulate a perinuclear cAMP compartment containing the A-kinase anchoring protein 6β signalosome, conferring selective regulation of perinuclear cAMP-dependent protein kinase activity independently of βARs at the plasma membrane or endosome. The A-kinase anchoring protein 6β compartment is shown to be of nanometer scale and dependent on local restriction of cAMP diffusion. In addition, perinuclear βARs are shown to be sufficient and necessary for activation of the Ca2+-dependent calcineurin–nuclear factor of activated T cells pathway and myocyte hypertrophy in vitro. Accordingly, adeno-associated virus 9–based delivery of an outer nuclear membrane–localized pepducin, which selectively activated perinuclear βARs in vitro, induced dilated cardiomyopathy in wild-type mice. Conversely, in vivo delivery of an outer nuclear membrane–localized nanobody, which selectively inhibited perinuclear βARs in vitro, improved cardiac function and inhibited pathological remodeling in a mouse model of familial dilated cardiomyopathy with established disease.CONCLUSIONS:These results demonstrate that β1ARs localized to Golgi membranes facing the outer nuclear membrane regulate A-kinase anchoring protein 6β signalosomes required for the induction of pathological cardiac remodeling, defining an intracellular nanocompartment. Proof of concept is provided for a novel therapeutic approach for familial dilated cardiomyopathy, with potential application to other forms of cardiovascular disease.

Circulation, Ahead of Print. BACKGROUND:The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.METHODS:We calculated the American Heart Association’s Life’s Essential 8 score to reflect CVH in 5 cohorts with diverse backgrounds (mean age 54 years, 55% women, and enrollment year ranging from 1989 to 2012). Epigenome-wide association studies (EWAS) for Life’s Essential 8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with Life’s Essential 8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident cardiovascular disease (CVD), cardiovascular disease–specific mortality, and all-cause mortality.RESULTS:We identified 609 cytosine-phosphate-guanines (CpGs) associated with Life’s Essential 8 score at false discovery rate

Circulation, Volume 152, Issue 2, Page 126-128, July 15, 2025.

Circulation, Volume 152, Issue 2, Page 85-86, July 15, 2025.

Circulation, Volume 152, Issue 2, Page 87-88, July 15, 2025.

Circulation, Volume 152, Issue 2, Page 89-91, July 15, 2025.

Circulation, Ahead of Print. BACKGROUND:Abdominal aortic aneurysms (AAA) present with high morbidity and mortality when they occasionally rupture. No medical therapy has successfully been proven to reduce AAA growth, though both metformin and statins have been identified as potential treatments in multiple meta-analysis. This study aimed to investigate a potential relationship between statin use and AAA growth rates and risk of undergoing repair, rupture, or death.METHODS:The study population included all men with screening-detected AAAs (30–55 mm) from the 2 large, population-based, randomized screening trials; the Viborg Vascular Screening trial (inclusion, 2008–2011) and the Danish Cardiovascular Screening trial (inclusion, 2014–2018). The clinical database was supplemented with data from the nationwide Danish Healthcare Registries, including prescription and outcome data. Statin exposure was quantified by defined daily doses (DDD). The primary outcome was AAA growth rate, whereas secondary outcomes included the need for repair and a composite of repair, rupture, and all-cause death. Growth rates were calculated using linear regression. To evaluate the risk of repair, patients were followed from inclusion until surgery, rupture, death, 5-year follow-up, or December 31, 2021.RESULTS:A total of 998 aneurysmal men (median age, 69.5 [interquartile range (IQR), 67–72] years; median AAA diameter, 35.4 [IQR, 32–41.2] mm) were included. Statin use was significantly associated with reduced AAA growth rate; an increase of 1 DDD statin per day was associated with an adjusted change in growth rate of −0.22 mm/year [95% CI, −0.39 to −0.06];P=0.009). The 5-year adjusted hazard ratio for undergoing repair per doubling of statin dose presented a significantly reduced adjusted hazard ratio (HR) of 0.82 ([95% CI, 0.70–0.97];P=0.023), which was significant after 2.5 years. Statin use was associated with a significantly lower risk of the composite outcome (surgery, rupture, and death) in a dose-dependent manner, with an adjusted HR of 0.83 ([95% CI, 0.73–0.94];P=0.003) per doubling of statin dose. Findings were robust in a variety of sensitivity analyses.CONCLUSIONS:High-dose statin use was associated with decreased AAA growth rates and lowered risk of undergoing repair, rupture, and death. This nonrandomized study suggests that patients with AAA could benefit from high-dose statin use, beyond only targeting associated risk factors.

Circulation, Ahead of Print. BACKGROUND:Primary aldosteronism (PA), an overt form of renin-independent aldosterone production, leads to a disproportionately high rate of major adverse cardiovascular events (MACEs). Mounting evidence suggests that milder forms of renin-independent aldosterone production (subclinical PA) are highly prevalent; however, the link between subclinical PA and MACE remains uncertain.METHODS:This prospective study included 2017 Canadian adults 40 to 69 years of age from the randomly sampled, population-based CARTaGENE cohort (Québec, Canada), in which aldosterone and renin concentrations at enrollment (2009–2010) were measured. Follow-up data were obtained via provincial health care administrative database linkage. MACE outcomes consisted of a composite of myocardial infarction, stroke, hospitalization for heart failure, and cardiovascular death. Multivariable linear and nonlinear Cox regression models measured the associations of concentrations of aldosterone, renin, and the aldosterone-to-renin ratio with MACE. Outcome-derived optimal thresholds for these markers were then determined.RESULTS:The mean (SD) age of participants was 56 (8) years, and 45% were women. Mean blood pressure was 129 (15)/76 (10) mm Hg, with hypertension being present in 27%. Over a median follow-up time of 10.8 years, 57 (3%) MACE outcomes occurred. Lower renin concentration (adjusted hazard ratio [aHR], 2.22 [95% CI, 1.02–4.76]) and higher aldosterone-to-renin ratio (aHR, 2.43 [95% CI, 1.15–5.12]) were associated with a higher risk for MACE, whereas no significant association was found with aldosterone concentration (aHR, 1.57 [95% CI, 0.42–5.90]). Renin concentration exhibited a nonlinear relationship with MACE risk. The outcome-derived optimal thresholds to discriminate a higher MACE risk were renin concentration ≤4.0 ng/L (aHR, 2.12 [95% CI, 1.21–3.72]) and aldosterone-to-renin ratio ≥70 pmol/L per ng/L (aHR, 2.03 [95% CI, 1.09–3.80]). All aforementioned associations were independent of blood pressure.CONCLUSIONS:Independent of blood pressure, the subclinical PA biochemical phenotype is associated with an increased risk of MACE. Future studies are necessary to determine whether early identification and targeted treatment of subclinical PA mitigates this risk.

Circulation, Ahead of Print. BACKGROUND:Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality rates, including heart failure, multisystem end-organ disease, and need for heart transplant. Specific FCF morbidities have not been rigorously defined, limiting study of how FCF morbidities affect pre–heart transplant and post–heart transplant outcomes. We hypothesized that FCF-related morbidities affect survival from heart transplant waitlisting through 1 year after heart transplant.METHODS:This 20-center, retrospective cohort study collected demographic, medical/surgical history, waitlist, and peri- and post–heart transplant data, and a priori defined FCF-specific morbidities, in Fontan patients who were listed for heart transplant from 2008 through 2022. Univariate 2-group statistics compared surviving individuals with those who died anytime from waitlisting to 1 year after heart transplant, died on the waitlist, or underwent transplant and died within 1 year after transplant. Using covariates from both univariate analyses, multivariable logistic regression determined the primary study outcome of independent FCF risk factors for death between waitlist and 1 year after heart transplant.RESULTS:Of 409 waitlisted patients, 24 (5.9%) died on the waitlist. Of the 341 (83.4%) who underwent transplant, 27 (8.5%) did not survive to 1 year. Univariate risk factors for waitlist death included higher aortopulmonary collateral burden, >1 hospitalization in the previous year, younger age, sleep apnea, higher New York Heart Association class, nonenrollment in school or work, and single-parent home. Risk factors for 1-year post–heart transplant mortality included hypoplastic left heart syndrome diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry 1 hospitalization in the year before waitlisting (adjusted odds ratio, 2.0 [95% CI, 1.0–4.1];P=0.05) and clinical cyanosis (adjusted odds ratio, 5.0 [95% CI, 1.8–13.4];P=0.002).CONCLUSIONS:Patients with Fontan palliation selected for heart transplant have substantial mortality rates from waitlisting through transplant. Among FCF-specific morbidities, cyanosis is associated with worsened survival and necessitates further study. Clinical morbidity of any type requiring repeated hospital admission also should prompt consideration of heart transplant.

Circulation, Ahead of Print. BACKGROUND:Direct reprogramming of fibroblasts to cardiomyocytes is a potentially curative strategy for ischemic heart disease. However, current reprogramming strategies require excessive factors due to epigenetic barriers of adult mouse and human fibroblasts. Recently, we identified the epigenetic factor PHF7 from a screen of gene-regulatory factors as the most potent activator of adult fibroblast-to-cardiomyocyte reprogramming in vitro.METHODS:Through in vitro assays coupled with genome-wide studies, we interrogated the ability of PHF7 to induce reprogramming events with minimal reprogramming factors. Using in vivo murine models of myocardial infarction and intramyocardial reprogramming factor delivery coupled with genetic fibroblast lineage tracing, we delivered retroviral PHF7 cocktails to the murine heart and interrogated reprogramming events as well as the acute and chronic functional impact of these cocktails. Deployment of 10X multiomics in vivo generated a combinatorial single-nucleus transcriptomic and epigenomic atlas of PHF7 reprogramming in the infarcted heart.RESULTS:Genome-wide in vitro transcriptomic analyses revealed that addition of PHF7 to Tbx5 or Mef2c and Tbx5 in fibroblasts induced global reprogramming through upregulation of unique cardiac transcriptomes. Further, PHF7 itself upregulated cardiac master regulators when overexpressed in dermal fibroblasts. Delivery of PHF7 cocktails to the infarcted murine heart induced in vivo reprogramming events and improved cardiac function and remodeling in both acute and chronic heart failure. When delivered as a single factor to the infarcted heart, PHF7 improved survival, function, and fibrosis up to 16 weeks after injury. Genetic lineage tracing analyses revealed that PHF7 induced bona fide fibroblast-to-cardiomyocyte reprogramming events in vivo. Comprehensive multiomics of PHF7 cocktails in the infarcted heart exposed the impact of PHF7 on chromatin structure, generating population-level shifts in nonmyocyte and cardiomyocyte cellular identity.CONCLUSIONS:Here, we report the ability of a single epigenetic factor, PHF7, to induce reprogramming and improve cardiac function in the mouse heart following myocardial infarction. Together, these data support the premise that a single factor, when deployed into the infarcted mouse heart, can induce reprogramming events and recover function in the ischemic heart.

Circulation, Volume 152, Issue 1, Page e3-e4, July 8, 2025.

Circulation, Volume 152, Issue 1, Page e22-e22, July 8, 2025.

Circulation, Volume 152, Issue 1, Page 24-26, July 8, 2025.