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.
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Subclinical Primary Aldosteronism and Major Adverse Cardiovascular Events: A Longitudinal Population-Based Cohort Study
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.
The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20-Center Retrospective Cohort Study
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.
Cellular Reprogramming by PHF7 Enhances Cardiac Function Following Myocardial Infarction
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.
Highlights From the Circulation Family of Journals
Circulation, Volume 152, Issue 1, Page 74-78, July 8, 2025.
Correction to: Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia
Circulation, Volume 152, Issue 1, Page e22-e22, July 8, 2025.
The State of Cardiovascular Care in Peru: Needs for System Strengthening
Circulation, Volume 152, Issue 1, Page 7-10, July 8, 2025.
Correction to: Does Coronary Calcium Mean the Same in Active and Sedentary Individuals?
Circulation, Volume 152, Issue 1, Page e23-e23, July 8, 2025.
Cardiovascular Effects of COVID-19: Legacy and Future Insights
Circulation, Volume 152, Issue 1, Page 24-26, July 8, 2025.
Navigating Uncertainty in PAH Classification: Wedge Pressure Versus Disease Phenotypes
Circulation, Volume 152, Issue 1, Page 4-6, July 8, 2025.
Letter by Chen and Xu Regarding Article, “Effects of Sedentary Behavior Reduction on Blood Pressure in Desk Workers: Results From the RESET-BP Randomized Clinical Trial”
Circulation, Volume 152, Issue 1, Page e1-e2, July 8, 2025.
Circulation Editors and Editorial Board
Circulation, Volume 152, Issue 1, Page 1-3, July 8, 2025.
Cardiac Xenotransplantation: Current State and Future Directions
Circulation, Volume 152, Issue 1, Page 58-73, July 8, 2025. The increasing demand for donor hearts presents both a critical challenge and a significant opportunity for innovation in cardiac transplantation. Advancements in immunosuppressive regimens and genetic engineering have reignited recent interest in xenotransplantation. Notably, 2 human patients have received genetically modified pig hearts under expanded-access authorization. They survived for 40 and 60 days, with xenograft failure preceding death in both cases. Concurrently, decedent studies have focused on monitoring the short-term physiological function of genetically modified cardiac xenografts in legally brain-dead recipients, representing a novel experimental paradigm for preclinical testing to help bridge the gap between nonhuman primate studies and clinical trials. These contemporary achievements build on a large body of exploratory efforts in cardiac xenotransplantation in nonhuman primates. Despite significant progress in overcoming hyperacute rejection, adaptive cellular and humoral immunological barriers remain. This review aims to critically evaluate the current advancements in xenotransplantation, to explore ongoing challenges, and to discuss the future potential of this innovative approach in addressing the growing demand for donor organs in cardiac transplantation.
Letter by Zhang and Chen Regarding Article, “Effects of Sedentary Behavior Reduction on Blood Pressure in Desk Workers: Results From the RESET-BP Randomized Clinical Trial”
Circulation, Volume 152, Issue 1, Page e3-e4, July 8, 2025.
From the Literature
Circulation, Volume 152, Issue 1, Page 79-80, July 8, 2025.
Anti-TRPV2 Autoantibody Linked to Sudden Infant Death Syndrome
Circulation, Volume 152, Issue 1, Page 81-84, July 8, 2025.