Search Results for: Circulation

Circulation, Ahead of Print. BACKGROUND:Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers.METHODS:This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency

Circulation, Ahead of Print. BACKGROUND:Proteomic signatures might improve disease prediction and enable targeted disease prevention and management. We explored whether a protein risk score derived from large-scale proteomics data improves risk prediction of atrial fibrillation (AF).METHODS:A total of 51 680 individuals with 1459 unique plasma protein measurements and without a history of AF were included from the UKB-PPP (UK Biobank Pharma Proteomics Project). A protein risk score was developed with lasso-penalized Cox regression from a random subset of 70% (36 176 individuals, 54.4% women, 2155 events) and was tested on the remaining 30% (15 504 individuals, 54.4% women, 910 events). The protein risk score was externally replicated with the ARIC study (Atherosclerosis Risk in Communities; 11 012 individuals, 54.8% women, 1260 events).RESULTS:The protein risk score formula developed from the UKB-PPP derivation set was composed of 165 unique plasma proteins, and 15 of them were associated with atrial remodeling. In the UKB-PPP test set, a 1-SD increase in protein risk score was associated with a hazard ratio of 2.20 (95% CI, 2.05–2.41) for incident AF. The C index for a model including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), NT-proBNP (N-terminal B-type natriuretic peptide), polygenic risk score, and protein risk score was 0.816 (95% CI, 0.802–0.829) compared with 0.771 (95% CI, 0.755–0.787) for a model including CHARGE-AF, NT-proBNP, and polygenic risk score (C-index change, 0.044 [95% CI, 0.039–0.055]). Protein risk score added to CHARGE-AF, NT-proBNP, and polygenic risk score resulted in a risk reclassification of 5.4% (95% CI, 2.9%–7.9%) with a 5-year risk threshold of 5%. In the decision curve, the predicted net benefit before and after the addition of protein risk score to a model including CHARGE-AF, NT-proBNP, and polygenic risk score was 3.8 and 5.4 per 1000 people, respectively, at a 5-year risk threshold of 5%. External replication of a protein risk score in the ARIC study showed consistent improvement in risk stratification of AF.CONCLUSIONS:Protein risk score derived from a single plasma sample improved risk prediction of AF. Further research using proteomic signatures in AF screening and prevention is needed.

Circulation, Ahead of Print. BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.METHODS:The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell–derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography–tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2.RESULTS:Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the Ca2+/CaMKII (calmodulin protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury.CONCLUSIONS:Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.

Stroke, Ahead of Print. BACKGROUND:For patients with acute ischemic stroke due to a large vessel occlusion admitted in primary stroke centers, helicopter transfer to comprehensive stroke centers is often used to expedite access to mechanical thrombectomy. Some studies have suggested that vibrations generated during helicopter transport might enhance intravenous thrombolysis (IVT) efficacy. We aimed to evaluate the impact of helicopter transfer, compared with ground transportation, on interhospital recanalization and functional outcomes.METHODS:We conducted a retrospective analysis of 2 prospectively collected cohorts of anterior circulation acute ischemic stroke due to a large vessel occlusion patients transferred to 2 comprehensive stroke centers (Stanford, CA, November 2019 to January 2023, and Montpellier, France, January 2015 to January 2017) for mechanical thrombectomy consideration with arterial imaging both at the primary stroke center and on comprehensive stroke center arrival. The primary outcome was interhospital recanalization, determined by comparison of the baseline and posttransfer arterial imaging and defined as revised arterial occlusive lesion scores of 2b to 3. The association between transportation mode (helicopter versus ground) and interhospital recanalization was studied in logistic regression analysis, adjusting for pretransfer IVT use, occlusion site, and transfer duration.RESULTS:Among 520 included patients, 315 (61%) were transferred by helicopter and 259 (50%) received IVT before transfer. Interhospital recanalization rates were similar between helicopter and ground transfers in both the overall cohort (23% versus 19%;P=0.30) and the IVT subgroup (36% versus 33%;P=0.61). Adjusted analyses confirmed no association between helicopter transport and interhospital recanalization (adjusted odds ratio, 1.23 [95% CI, 0.72–2.11];P=0.44). Favorable 3-month functional outcome (modified Rankin Scale score, 0–2) rates were also similar between helicopter and ground transfers in both unadjusted (35% versus 40%;P=0.29) and adjusted analyses (adjusted odds ratio, 1.12 [95% CI, 0.67–1.88];P=0.67).CONCLUSIONS:In this multicenter observational cohort study, helicopter transfer was not associated with improved interhospital recanalization or favorable functional outcomes compared with ground transport. These findings do not support the hypothesis that vibrations during helicopter transport enhance IVT efficacy.

Circulation, Ahead of Print. BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is a genetic disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C) present from birth, leading to early-onset and progressive atherosclerotic cardiovascular disease. Early treatment initiation is crucial for cardiovascular risk reduction; however, many patients do not reach LDL-C treatment goals. Inclisiran, a small interfering RNA targeting hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9), is effective and well tolerated in adult patients with hyperlipidemia; however, it has not yet been studied in pediatric patients.METHODS:Herein we report results of the 1-year, double-blind, placebo-controlled part of the phase 3 study ORION-13 (Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia) in adolescents with HoFH. This 2-part multicenter study included 13 patients ≥12 to 130 mg/dL) on maximally tolerated statin treatment, with or without other lipid-lowering therapies. Eligible patients were randomized 2:1 to receive either 300 mg of inclisiran sodium or placebo, administered on days 1, 90, and 270. The primary end point was the mean percentage change in LDL-C from baseline to day 330.RESULTS:The mean age of patients was 14.8 years, and mean baseline LDL-C was 272 mg/dL. The placebo-adjusted mean (95% CI) percentage change in LDL-C from baseline to day 330 was −33.3% (−59.2% to −7.3%). Six of 9 (66.7%) inclisiran-treated patients (versus 1 of 4 [25%] on placebo) achieved a >15% reduction in LDL-C, and 5 of 9 (55.6%) inclisiran-treated patients (versus none on placebo) achieved a >20% reduction. The placebo-adjusted mean (95% CI) percentage change in PCSK9 from baseline to day 330 was −60.2% (−79.8% to −40.7%); corresponding changes in apoB (apolipoprotein B), non–high-density lipoprotein cholesterol, and total cholesterol were −23.0%, −32.7%, and −27.8%, respectively. No serious adverse events, treatment discontinuations because of adverse events, or deaths occurred. No new safety findings were reported.CONCLUSIONS:In a 1-year randomized controlled study (part 1 of ORION-13), inclisiran was effective in lowering LDL-C in adolescents with HoFH and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HoFH and a minimum of LDLR residual activity.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT04659863.

Circulation, Volume 151, Issue 20, Page 1477-1490, May 20, 2025. Heart valve replacement in children is fraught with long-term morbidity and mortality rates, largely because conventional implants lack the capacity to grow with the child. Partial heart transplantation presents a potential solution by transplanting only specific segments of a donor heart, thereby providing a living and growing heart valve implant. This approach harnesses the full spectrum of cardiac tissues, which, when freshly procured and supported by immunosuppression, can integrate as functional and potentially growth-capable tissue. This state-of-the-art review discusses the history and development of partial heart transplantation, its indications, recent clinical experiences, regulation, and future directions.

Circulation, Volume 151, Issue 20, Page e1004-e1005, May 20, 2025.

Circulation, Volume 151, Issue 20, Page e1002-e1003, May 20, 2025.

Circulation, Volume 151, Issue 20, Page 1491-1493, May 20, 2025.

Circulation, Volume 151, Issue 20, Page 1449-1450, May 20, 2025.

Circulation, Volume 151, Issue 20, Page 1433-1435, May 20, 2025.

Circulation, Ahead of Print. Background:Vascular smooth muscle cells (vSMCs), the predominant cell type in the aortic wall, play a crucial role in maintaining aortic integrity, blood pressure, and cardiovascular function. vSMC contractility and function depend on smooth muscle alpha-actin 2 (ACTA2). The pathogenic variantACTA2 c.536G >A(p. R179H) causes multisystemic smooth muscle dysfunction syndrome (MSMDS), a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and high-risk early mortality from aneurysms or stroke. No effective treatments exist for MSMDS.Methods:To develop a comprehensive therapy for MSMDS, we utilized CRISPR-Cas9 adenine base editing to correct theACTA2R179H mutation. We generated isogenic human induced pluripotent stem cell (iPSC) lines and humanized mice carrying this pathogenic missense mutation. iPSC-SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor (ABE) ABE8e-SpCas9-VRQR under control of either a SMC-specific promoter or a CMV promoter, and an optimized single guide RNA (sgRNA) under control of U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 (AAV9) and phenotypic outcomes were evaluated.Results:The R179H mutation causes a dramatic phenotypic switch in human iPSC-SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2R179H/+mutation caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function.Conclusions:This study demonstrates the effectiveness of adenine base editing to treat MSMDS and restore aortic smooth muscle function. By correcting theACTA2R179H mutation, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.

Circulation, Ahead of Print. Cardiac intensive care units are witnessing a demographic shift, characterized by patients with increasingly complex or end-stage cardiovascular disease with a greater burden of concomitant comorbid noncardiovascular disease. Despite technical advances in care that may be offered, many critically ill cardiovascular patients will nevertheless experience significant morbidity and mortality during the acute decompensation, including physical and psychological suffering. Palliative care, with its specialized focus on alleviating suffering, aligns treatments with patient and caregiver values and improves overall care planning. Integrating palliative care into cardiovascular disease management extends the therapeutic approach beyond life-sustaining measures to encompass life-enhancing goals, addressing the physical, emotional, psychosocial, and spiritual needs of critically ill patients. This American Heart Association scientific statement aims to explore the definitions and conceptual framework of palliative care and to suggest strategies to integrate palliative care principles into the management of patients with critical cardiovascular illness.

Circulation, Ahead of Print. The “open vein hypothesis” postulates that early thrombus clearance and restoration of venous blood flow may prevent postthrombotic syndrome after proximal deep vein thrombosis. Since its proposal several decades ago, new insights from basic and clinical studies have motivated a re-evaluation and refinement of this hypothesis. According to data from these studies, susceptibility to postthrombotic syndrome occurs as a result of differences in genetic composition, thrombophilic conditions, predilection to inflammation and fibrosis, endogenous fibrinolytic capability, timing of s ymptom presentation and treatment initiation, and efficacy of antithrombotic therapy. Although initial restoration of an open vein appears to be beneficial for selected patient groups, freedom from postthrombotic syndrome is more likely in the setting of long-term venous patency, reduced recurrent thrombotic episodes, and reduced perithrombotic (eg, vein wall and valve) inflammation. These underlying biological mechanisms need further elucidation, with a long-term goal of personalizing treatment by mapping the individuals’ clinical presentation with their underlying risk factors and assessing time-dependent biological processes that occur as a clinical venous thrombosis resolves. This scientific statement (1) highlights historical fundamentals of the open vein hypothesis and then showcases new research insights into the pathophysiological factors driving postthrombotic syndrome; (2) discusses advantages and disadvantages of imaging modalities for deep vein thrombosis used in clinical practice, including the potential to depict thrombus chronicity and status of vein wall injury; (3) proposes measures to develop integrated multidisciplinary care for deep vein thrombosis focused on the reduction of postthrombotic syndrome; and (4) identifies priority areas and questions for further research.

Circulation, Ahead of Print. BACKGROUND:Hypothyroidism leads to multiple organ dysfunction, with the heart the most affected. However, the pathologic mechanism of hypothyroidism-induced heart failure remains to be completely elucidated. Thyroid hormone replacement therapy enhances myocardium systolic function but increases the occurrence of arrythmias. There is an urgent need to explore these mechanisms in detail and to discover and develop drugs that can target and manage heart failure in patients with hypothyroidism.METHODS:In this study, a mouse model of hypothyroidism-induced heart failure was established through the administration of propylthiouracil.Dusp14knockout mice were generated, and adeno-associated virus–mediated cardiomyocyte-specific overexpression of Dusp14 (dual specificity phosphatase 14) was used in combination with related cellular experiments to investigate the protective effects of Dusp14 on hypothyroidism-induced heart failure. Further analyses confirmed the crucial involvement of necroptosis in the pathogenesis of hypothyroidism-induced heart failure, and demonstrated the protective role of Dusp14 in modulating necroptosis. In addition, a novel small molecule compound that effectively regulates Dusp14 activity in vitro was identified through molecular docking, providing a potential therapeutic avenue.RESULTS:Dusp14 regulates necroptosis and mitigates hypothyroidism-induced heart failure. Myocardial tissue sections from mice in the hypothyroidism group showed positive Evans blue dye staining, and the serum levels of the myocardial injury marker lactate dehydrogenase were significantly higher compared with the euthyroid group (n=8). In addition, phosphorylation levels of the necroptosis marker MLKL (mixed lineage kinase domain-like protein) were significantly elevated, indicating the activation of necroptosis (n=8). These findings suggest that myocardial necroptosis is activated during hypothyroidism. Myocardial-specific overexpression of Dusp14 reduced myocardial necroptosis and improved myocardial contractile function in hypothyroid mice (n=8). In contrast,Dusp14knockout exacerbated myocardial contractile dysfunction and necroptosis in these mice (n=5–7). These results indicate that Dusp14 alleviates hypothyroidism-induced heart failure by inhibiting necroptosis. P077-0472, a small molecule compound, was identified as an activator of Dusp14, which could inhibit cardiomyocyte necroptosis from hypothyroidism (n=6).CONCLUSIONS:Dusp14 inhibits cardiomyocyte necroptosis from hypothyroidism and consequently rescues damaged cardiomyocytes. P077-0472, a novel small molecule compound that activates the dephosphorylation function of Dusp14, could inhibit cardiomyocyte necroptosis from hypothyroidism.

Circulation, Ahead of Print. BACKGROUND:Exercise improves functional outcomes in patients with diabetic cardiomyopathy (DiaCM). The molecular mechanism underlying cardiac benefits of exercise in DiaCM remains incompletely understood. N6-methyladenosine (m6A) is the most common form of messenger RNA modification in eukaryotes and has been implicated in cardiac development and disease. However, the role of m6A in DiaCM and in the mitigating effects of exercise on this disease are unclear.METHODS:Cardiomyocyte-specific N6-adenosine-methyltransferase-like 3 (METTL3, an m6A methyltransferase) knockout mice and their wild-type littermates were subjected to either chow diet or high-fat diet feeding and injection of streptozotocin to induce DiaCM, followed by an 8-week exercise training and assessment of cardiac function. Some of the mice were injected with adeno-associated viral vector encoding METTL3 to overexpress METTL3 in cardiomyocytes. Cardiac METTL3 expressions were assessed in patients with nonischemic primary dilated cardiomyopathies without or with diabetes. Potential METTL3 downstream effector YBX1 (Y-box binding protein 1) was identified through RNA sequencing. The functional role of YBX1 was examined through adeno-associated viral vector overexpression or knockdown in cardiomyocytes in DiaCM mice.RESULTS:We showed that cardiac METTL3 protein expression and m6A level were downregulated in patient with dilated cardiomyopathy and further downregulated in patients with dilated cardiomyopathy and diabetes. Consistently, cardiac METTL3 and m6A were downregulated in mouse with DiaCM, whereas they were upregulated by exercise. Cardiomyocyte-specific METTL3 knockout eliminated the cardiac benefits of exercise on DiaCM. Conversely, cardiomyocyte-specific METTL3 overexpression improved systolic and diastolic function in 2 DiaCM mouse models. We demonstrated that exercise enhanced cardiac METTL3 expression in DiaCM through signal transducer and activator of transcription 3. Moreover, METTL3 attenuated DiaCM through m6A-depdendent YBX1 upregulation and the subsequent activation of Nrf2. Cardiomyocyte-specific YBX1 overexpression promoted Nrf2 activation and attenuated oxidative stress, resulting in an improvement in cardiac function in DiaCM. In contrast, cardiomyocyte-specific YBX1 gene knockdown abolished the effect of METTL3 on cardiac improvement in mice with DiaCM. Further, pharmacological activation of METTL3 using a small molecule attenuated cardiac dysfunction in DiaCM.CONCLUSIONS:These studies reveal an essential role of METTL3 in the cardiac benefits of exercise and identify METTL3 and YBX1 as promising therapeutic targets for treating DiaCM.