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.

Physiology assessment of coronary lesion prepercutaneous coronary intervention (PCI) using hyperemic and nonhyperemic pressure ratios is useful to determine if a lesion requires treatment. Whether the physiology after PCI is superior to angiography guidance only is unknown. The study sought to investigate whether post-PCI physiology improves clinical outcomes compared with standard angiographic guidance.

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.

Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) provides an alternative treatment for high-risk patients with failed surgical bioprosthetic aortic valves. However, limited data exist on ViV-TAVR outcomes in patients with small aortic annuli, particularly among the relatively small-statured Japanese population.

Beyond pulmonary vein (PV) isolation, the optimal ablation strategy for persistent atrial fibrillation (AF) remains poorly defined. The purpose of this study was to compare 2 ablation strategies in the treatment of patients with persistent AF: a comprehensive ablation strategy based on anatomic considerations versus PV isolation alone.

Primary percutaneous coronary intervention (PCI) with stenting is recommended in ST-segment-elevation myocardial infarction. Immediate stenting may cause distal embolization, microvascular damage, and flow disturbances, leading to adverse outcomes. We report the 10-year clinical outcomes of deferred stenting versus conventional PCI in patients with ST-segment-elevation myocardial infarction.

Six-month results from the SPYRAL HTN-ON MED trial demonstrated that renal denervation (RDN) reduced office blood pressure (BP), and not 24-hour ambulatory systolic BP, compared with sham control in hypertensive patients. In this prespecified analysis of the ON MED trial, long-term changes in BP, antihypertensive drug use, and safety outcomes through 24 months are compared between RDN and sham control groups.

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.

Background: The sex-related prognosis of patients with cardiogenic shock (CS) undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) remains unclear. Our analyses aim to assess sex-specific outcomes in patients with CS receiving VA-ECMO and explored whether the effect of moderate hypothermia (MH) on clinical outcomes was modified by sex. Methods: In this post-hoc analysis of the HYPO-ECMO trial, clinical outcomes were compared by sex. The primary outcome was 30-day all-cause mortality (ACM). Key secondary outcomes included ACM and a composite outcome of ACM, heart transplant, escalation to left ventricular assist device implantation, or stroke at 30, 60 and 180 days. Results: Among the 334 patients enrolled in the trial, 81 (24%) were female. At 30 days, 45.7% of female and 46.6% of male patients experienced the primary outcome, with no sex differences (adjusted OR, 1.01 [0.57 - 1.78], p=0.98 and log-rank test, p=0.93). No significant sex differences were observed in all-cause mortality at 60 and 180 days (adjusted OR, 0.87 [0.49 - 1.52], p=0.61 and 0.83 [0.47 - 1.46], p=0.51, respectively) or in the composite outcome up to 180 days (p>0.2 for all). The effect of MH on the primary outcome (aOR, 0.73 [0.43 - 1.25], p=0.25 and 0.67 [0.26 - 1.76], p=0.41, in male and female respectively, interaction p-value = 0.88) and secondary outcomes (interaction p-value >0.3 for all) was not modified by sex. Conclusions: In this post-hoc analysis of the HYPO-ECMO trial, male and female experienced similar outcomes in CS treated with VA-ECMO. Sex did not significantly modify the effect of moderate hypothermia on outcomes. Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02754193.

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 variant ACTA2 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 the ACTA2 R179H 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 the ACTA2 R179H 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.

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.

Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were, first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification.

Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF) and is characterized by skeletal muscle (SkM) dysfunction with impaired oxidative capacity. To maintain oxidative capacity, the SkM secretes myokines such as musclin, which has been shown to potentiate NP (natriuretic peptide) signaling and induce PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1 alpha) signaling. We sought to investigate the role of musclin in SkM dysfunction in HFpEF. For this study, we selected the oxidative-predominant SkM soleus in HFpEF mice and vastus lateralis from patients with HFpEF.

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.

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.