Circulation, Volume 151, Issue 18, Page 1309-1311, May 6, 2025.
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Evidence Generation and Implementation of Transcatheter Interventions for Atrioventricular Valvular Heart Disease in Heart Failure: Current Status and Future Directions
Circulation, Volume 151, Issue 18, Page 1342-1363, May 6, 2025. Mitral regurgitation and tricuspid regurgitation are the most common valvular heart diseases in patients with heart failure and have independent prognostic value. Transcatheter interventions are now available for the treatment of valvular heart disease, and their efficacy and safety have been tested in randomized controlled trials. However, evidence is still limited and sometimes inconclusive because several aspects of these trials limit their interpretation or consistency. These include heterogeneity in the pathogenesis and clinical characteristics of patients, the dynamic nature of secondary atrioventricular valve disease severity, the role of heart failure medications and devices, dependency on procedural results and operators’ skills, smaller number of patients enrolled and the power to detect differences in trials, and limitations to use patients’ reported outcomes with unblinded study protocols. These specific aspects of trials in patients with atrioventricular valve disease are reviewed in this article with a focus on possible solutions to generate further evidence for the efficacy and safety for transcatheter treatments of atrioventricular valve disease in patients with heart failure.
CD206+IL-4Rα+ Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy
Circulation, Ahead of Print. BACKGROUND:The role of cardiac CD (cluster of differentiation) 206+macrophages in chronic heart failure (HF) is unknown. We examined whether CD206+macrophages expressing IL (interleukin)–4Rα are key drivers of adverse left ventricular (LV) remodeling in HF.METHODS:Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of M[IL-4] macrophages. Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice.RESULTS:CD206+macrophages steadily expanded in hearts after myocardial infarction, such that at 8 weeks after myocardial infarction, they comprised ≈85% of all macrophages. These macrophages were proliferative, predominantly CCR2–(C-C motif chemokine receptor) and MHC (major histocompatibility complex) IIhi, and correlated with LV dysfunction and fibrosis. Nearly half of CD206+macrophages expressed IL-4Rα, and the majority of CD206+IL-4Rα+macrophages coexpressed profibrotic FIZZ (found in inflammatory zone) 1. IL-4–polarized bone marrow–derived CD206+macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of both cardiac mesenchymal stem cells and cardiac fibroblasts, in part related to DLL-4/Jagged1-Notch1 signaling in cardiac mesenchymal stem cells. Intramyocardial adoptive transfer of M[IL-4], but not M[IL-10], CD206+macrophages to naïve mice induced progressive LV remodeling over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, and apoptosis. Myeloid-specific IL-4Rα gene deletion in HF (initiated 4 weeks after myocardial infarction) in IL-4Rαf/fLysM-CreERT2mice significantly reduced CD206+macrophage proliferation and effectively depleted CD206+IL-4Rα+cardiac macrophages. This was associated with abrogation of LV remodeling progression, reduction of cardiac fibrosis, and improved neovascularization. In vivo IL-4Rα gene silencing in mice with established HF effectively depleted cardiac CD206+IL-4Rα+macrophages and reversed LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressed both local and systemic inflammation. Last, alternatively activated CD206+and CD163+macrophages were significantly expanded in human failing hearts and correlated with fibrosis. The majority of CD163+macrophages expressed IL-4Rα and FIZZ3, the human homolog of FIZZ1.CONCLUSIONS:Cardiac CD206+IL-4Rα+macrophages proliferate and expand in HF and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206+macrophage IL-4Rα signaling alleviates LV remodeling in ischemic cardiomyopathy.
Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study
Circulation, Ahead of Print. BACKGROUND:Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain.METHODS:We measured plasma levels of Lp(a) in a nested case–control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia.RESULTS:In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of myocardial infarction and IS, but not with ICH. In genome-wide association analysis, we identified 29 single nucleotide polymorphisms independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese individuals. In UK Biobank, the lead Chinese variants identified in CKB were replicated in 1260 Chinese individuals, but explained only 10% of variance in Lp(a) in European individuals. In Mendelian randomization analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all cardiovascular disease outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically predicted Lp(a) levels for myocardial infarction were 3-fold greater than for total IS (rate ratio, 0.78 [95% CI, 0.76–0.81] versus 0.94 [0.92–0.96]), but were similar to those for large-artery IS (0.80 [0.73–0.87]; n=8134). There were weaker associations with cardioembolic IS (0.92 [95% CI, 0.86–0.98]; n=11 730), and no association with small-vessel IS (0.99 [0.91–1.07]; n=12 343) or with intracerebral hemorrhage (1.08 [0.96–1.21]; n=5845).CONCLUSIONS:The effects of Lp(a) on risk of myocardial infarction and large-artery IS were comparable in East Asian and European individuals, suggesting that people with either ancestry could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.
Suppression of the Prostaglandin I2–Type 1 Interferon Axis Induces Extramedullary Hematopoiesis to Promote Cardiac Repair After Myocardial Infarction
Circulation, Ahead of Print. BACKGROUND:Immune cells are closely associated with all processes of cardiac repair after myocardial infarction (MI), including the initiation, development, and resolution of inflammation. Spleen extramedullary hematopoiesis (EMH) serves as a crucial source of emergency mature blood cells that are generated through the self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs). However, how EMH responds to MI and the role of EMH in cardiac repair after MI remains unclear.METHODS:To assess the role of spleen EMH in MI, aTcf21CreERScfflox/floxMI mouse model with inhibited EMH was constructed. GFP+(green fluorescent protein) hematopoietic stem cells were sorted from eGFP (enhanced green fluorescent protein) mouse spleen by flow cytometry and injected intoTcf21CreERScfflox/floxmice to test the sources of local inflammatory cells during MI. Using highly specific liquid chromatography–tandem mass spectrometry and single-cell RNA sequencing, we analyzed the lipidomic profile of arachidonic acid metabolites and the transcriptomes of HSPCs in the spleen after MI.RESULTS:We found that MI enhanced EMH, as reflected by the increase in spleen weight and volume and the number of HSPCs in the spleen. The lack of EMH inScf-deficient mice exacerbated tissue injury after MI. Analysis of the transcriptome of spleen HSPCs after MI revealed that the type 1 interferon pathway was substantially inhibited in hematopoietic stem cell/multipotent progenitor subclusters, and the absence of type 1 interferon signaling enhanced the MI-induced spleen EMH. Lipidomics analysis revealed that prostaglandin I2 (PGI2) was markedly reduced in the spleen. PGI2 suppressed MI-induced EMH through a PGI2 receptor (IP)–cyclic adenosine monophosphate–453p-SP1 cascade in spleen HSPCs. Hematopoietic cell–specific IP-deficient mice exhibited enhanced EMH and improved cardiac recovery after MI.CONCLUSIONS:Together, our findings revealed that a PGI2–IFN axis was involved in spleen EMH after MI, providing new mechanistic insights into spleen EMH after MI and offering a new therapeutic target for treating ischemic cardiac injury.
Splenic CD169+Tim4+ Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction
Circulation, Ahead of Print. BACKGROUND:Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6Chi(lymphocyte antigen 6 complex, locus C) blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear.METHODS:We used a variety of in vivo murine models and orthogonal approaches, including surgical MI, flow cytometry and single-cell RNA sequencing, lineage tracing and cell tracking, splenectomy, parabiosis, cell adoptive transfer, and functional characterization, to establish an essential role for splenic CD169+Tim4+(cluster of differentiation 169+; T cell immunoglobulin– and mucin-domain–containing molecule 4) marginal metallophilic macrophages (MMMs) in post-MI wound healing in mice. Flow cytometry was used to measure circulating CD169+Tim4+monocytes in humans with ST-segment–elevation MI and control participants with stable coronary artery disease undergoing elective percutaneous coronary intervention.RESULTS:Splenic CD169+Tim4+MMMs circulate in blood as Ly6Clowmonocytes expressing macrophage markers and help populate CD169+Tim4+CCR2−LYVE1lowmacrophages in the naive heart. After acute MI, splenic MMMs augment phagocytosis and CCR (C-C motif chemokine receptor) 3 and CCR4 expression, and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169+Tim4+LYVE1lowmacrophages with an immunomodulatory and proresolving gene signature. These macrophages are obligatory for apoptotic neutrophil clearance, suppression of inflammation, and induction of a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing, and limit late pathological remodeling. Liver X receptor-α agonist–induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Humans with acute ST-segment–elevation MI also exhibit expansion of circulating CD169+Tim4+cells, primarily within the intermediate (CD14+CD16+) monocyte population.CONCLUSIONS:Splenic CD169+Tim4+MMMs are required for proresolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.
Letter by Dong et al Regarding Article, “Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation”
Circulation, Volume 151, Issue 17, Page e962-e963, April 29, 2025.
Interplay Between Epicardial Adipose Tissue and Left Ventricular Stiffness in Heart Failure With Preserved Ejection Fraction
Circulation, Volume 151, Issue 17, Page 1294-1296, April 29, 2025.
New Tools for Precision Targeting of Origin-Specific Vascular Smooth Muscle Cells Using Intersectional Genetics
Circulation, Volume 151, Issue 17, Page 1268-1271, April 29, 2025.
A Plea for a Genetics-First Approach in Arrhythmogenic Cardiomyopathies
Circulation, Volume 151, Issue 17, Page 1231-1234, April 29, 2025.
Correction to: BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension
Circulation, Volume 151, Issue 17, Page e967-e967, April 29, 2025.
Correction to: Core Components of Cardiac Rehabilitation Programs: 2024 Update: A Scientific Statement From the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation
Circulation, Volume 151, Issue 17, Page e965-e966, April 29, 2025.
Palpitations After Leadless Pacemaker Implantation
Circulation, Volume 151, Issue 17, Page 1291-1293, April 29, 2025.
Response by Bonnesen et al to Letter Regarding Article, “Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation”
Circulation, Volume 151, Issue 17, Page e964-e964, April 29, 2025.
COnventional vs. Optimized PERiprocedural Analgosedation vs. Total IntraVEnous Anesthesia for Pulsed-Field Ablation: a Three-Arm Randomized Controlled Trial (COOPERATIVE-PFA)
Circulation, Ahead of Print. Background: Deep analgosedation (DAS) or general anesthesia (GA) is mandatory for pulsed-field ablation (PFA) of atrial fibrillation (AF). In contrast to DAS, GA (conventional or total intravenous anesthesia [TIVA]) requires airway management. To find the optimal sedation regimen, this study compared ketamine-remimazolam DAS and propofol-opioid TIVA to propofol-opioid DAS, focusing on sedation-related adverse events.Methods: Patients indicated for AF catheter ablation were randomly assigned in a 1:1:1 ratio to (1) DAS using intermittent propofol-opioid boluses (arm P), (2) continuous remimazolam-ketamine DAS (arm R), or (3) continuous propofol-opioid TIVA with secured airways (arm TIVA). Catheter ablation was performed using the FARAPULSE system (Boston Scientific, MA, USA). The major exclusion criterion was obstructive sleep apnea syndrome. The primary endpoint was defined as a composite of hypoxemia, hypotensive, or hypertensive events requiring intervention or leading to procedure discontinuation. Secondary endpoints included hemodynamic instability events, procedure time, serious adverse events, and patient satisfaction.Results: One-hundred and twenty-seven patients (mean age 62.9 ± 10.3 years, 35.1% female, 47.2% with paroxysmal AF) were enrolled and randomized to the P (N = 42), R (N = 43) or TIVA (N = 42) arms. The primary endpoint occurred in 85.7% of P pts., 27.9% of R pts., and 66.7% of TIVA pts. (P < 0.001), driven by hypoxemia in the P arm (100% of pts. with the primary endpoint) and by hypotension in the TIVA arm (100%). The R arm showed a similar distribution of hypoxemia (50%) and hypotensive (66.7%) events. No differences were observed in mean procedural times, rates of serious adverse events, and assessment of patient satisfaction.Conclusions: In PFA procedures for AF, remimazolam-ketamine DAS was superior to propofol-opioid regimens (either boluses or continuous) and had the lowest risk of hypoxemia and hypotensive events. More than 80% of patients undergoing conventional propofol-opioid analgosedation experienced hypoxemia.
Stepwise Anatomical Approach to Ablation of Intramural Outflow Tract Ventricular Arrhythmias Guided by Septal Coronary Venous Mapping
Circulation, Ahead of Print. Background: Intramural site of origin is a major cause of ablation failure of ventricular arrhythmias and the optimal strategy is unclear. This study investigated the efficacy of a stepwise ablation approach for intramural outflow tract (OT) premature ventricular complexes (PVCs) guided by mapping of the septal coronary venous system.Methods: Consecutive patients with OT PVCs were included in which an intramural origin was confirmed by demonstration of earliest activation in a septal coronary vein. Radiofrequency ablation was performed from the closest endocardial site in the left (LVOT) and/or right ventricular OT (RVOT) independent of the local activation time. If there was no suppression by endocardial ablation, retrograde transvenous ethanol infusion with a single or double balloon technique was performed, targeting the earliest septal coronary vein. If venous anatomy was not suitable for ethanol ablation or if this failed, bipolar ablation was performed.Results: Sixty patients (age 61±12 years, 78% male) were included. The mean QRS duration of the PVC was 150.8±17.6 ms with a maximum deflection index of 0.51±0.11, and the most common ECG pattern was a left bundle branch block with inferior axis and V3 transition (63%) followed by a right bundle branch block with inferior axis and no transition (27%). Earliest ventricular activation (28.6±11.2 ms pre-QRS) was recorded in the left ventricular annular vein in 15 cases and a septal perforator vein in 45 cases. Acute PVC suppression at the end of the procedure was achieved in all cases. In 87% of cases (n=52), endocardial ablation from the endocardial LVOT, RVOT or both was successful in eliminating the PVC. In the remaining 8 patients, the PVC was eliminated with ethanol infusion (n=7) and bipolar ablation (n=1). Complications included one case of pericardial effusion related to venous mapping. During follow-up (17±24 months), the PVC burden was reduced from 28±12% to 2.3±4.7% and long-term success (≥80% burden reduction) was 88%.Conclusions: Most intramural OT PVCs can be successfully eliminated with endocardial ablation adjacent to the earliest intramural activation site. A high success rate is achieved when following a stepwise approach, with bailout ablation strategies required in a minority of cases.