Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease, but its role in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations and shown to independently associate with prevalent AF following adjustment for risk factors. Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X) supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO diet had more inducible AF via a transesophageal pacing study compared with chow-fed controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice. Iodomethylcholine (IMC) reduced circulating TMAO levels and choline-induced AF onset. Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibited muscarinic receptor 2, resulting in autonomic dysfunction that promotes AF. In summary, TMAO, independently associated with AF risk in subjects, enhanced AF in multiple mouse models via autonomic dysfunction and is a therapeutic target for preventing AF.

Background:Ventricular tachycardia (VT) ablation in patients with ischemic cardiomyopathy (ICM) continues to be a challenging procedure with variable outcomes. Most current ablations are done using radiofrequency ablation (RFA). The new pulsed field ablation (PFA) technology may be able to achieve similar or superior procedural outcomes but potentially over shorter periods of time with less intravascular fluid infusion, but this possibility has never been tested. Objective:This study aimed to compare the procedural efficacy and safety of VT ablation in patients with ICM using focal PFA vs RFA catheters. Methods:This ASCEND-VT pilot study is a single-center trial randomizing patients to RFA vs PFA VT ablation in a 1:1 fashion. The new focal PFA catheter will be used under an investigational device exemption granted by the US Food and Drug Administration. Patients with mechanical valves will be excluded. The primary ablation target will be homogenization of endocardial late abnormal ventricular activity. Patients will be followed for 6 months after the procedure. Results:40 individuals will be randomized. The primary efficacy metric will be the ablation time needed to eliminate late abnormal ventricular activities in each patient. Additional efficacy and safety endpoints will be interrogated after the procedure and during outpatient follow-up. Conclusion:This is the first pilot randomized controlled trial comparing the safety and efficacy of focal PFA vs RFA VT ablation in ICM. Its results will inform the design of future larger studies that will further establish the clinical utility of PFA in the context of scar-related VT ablation.

Background: Patients with non-ischemic dilated cardiomyopathy (NIDCM) and ventricular tachycardia (VT) typically have a basal perivalvular substrate with predominant antero-septal or infero-lateral distribution. Isolated apical substrate responsible for VT in NIDCM has not been previously characterized. Objectives: The purpose of this study is to characterize the prevalence, characteristics and catheter ablation outcomes of NIDCM with isolated apical VT substrate. Methods: Patients with NIDCM and VT from an isolated apical scar were identified from a prospective registry of consecutive patients with NIDCM undergoing VT ablation between 2018 and 2023. Isolated apical scar was defined as apical abnormal bipolar low voltage area (LVA, <1.5 mV for the endocardium, <1.0 mV for the epicardium with abnormal electrograms) demonstrated to participate in VT with activation, entrainment and/or pace mapping in the absence of abnormal electroanatomic substrate in other LV segments. Patients with hypertrophic cardiomyopathy were excluded. Results: Out of 208 patients with NIDCM and VT undergoing catheter ablation during the study period, 5 (2.4%; age 52±10 years, LVEF 37±12%) had isolated apical substrate and underwent a total of 8 ablation procedures (2 endocardial, 6 endo-epicardial). One patient had isolated apical scar on pre-procedural cardiac MRI. All patients had both endocardial and epicardial scar identified. At the end of the procedure, non-inducibility of any VTs was achieved in all cases. After a median follow-up of 11 months (range 6-14 months) after the last procedure, there were no deaths and all patients remained free from recurrent VT. Conclusion: In patients with NIDCM, isolated apical VT substrate is rare. Endo-epicardial catheter ablation is typically needed in these patients and is associated with good VT control over follow-up.

ABSTRACT Aim Phenylacetylglutamine (PAGln) is a phenylalanine‐derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)‐relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Methods and results Fasting plasma PAGln levels were measured by stable‐isotope‐dilution liquid chromatography–tandem mass spectrometry (LC‐MS/MS) in patients with stable HF from two large cohorts. All‐cause mortality was assessed at 5‐year follow‐up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3‐year follow‐up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4–6.9) μM. Highest quartile of PAGln was associated with 3.09‐fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5‐year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07–2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0–4.8] μM), and PAGln levels were associated with a 1.92‐fold increase in 3‐year HF hospitalization or all‐cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02‐3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N ‐oxide levels. Conclusion High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio‐renal risk markers.

HeartMate 3 (HM3) is a fully magnetically levitated continuous flow left ventricular assist device (LVAD). In patients with HM3 and recurrent ventricular tachycardia (VT), data on the outcomes of catheter ablation (CA) are insufficient. We report our institutional experience with CA of VT in patients with the HM3.Consecutive patients with HM3 and recurrent drug-refractory VT undergoing CA were included. Ablation sites were identified using activation/entrainment mapping (stable VTs) and/or late/fractionated potential ablation and pace-mapping (unstable VTs). Between 2016-2023 a total of 431 patients (age 58±13, INTERMACS 3±0.98, 44% ischemic cardiomyopathy) received an HM3 LVAD at our institution. Of these, 15 (3.4%) underwent CA for recurrent VT despite therapy with 1.3±0.8 antiarrhythmic drugs a median of 700 days from the LVAD surgery (2 patients <1 month from the surgery). The LV access was transseptal in 12 (80%) cases, retrograde aortic in 2 (13%) and both in 1 (7%). A total of 23 distinct VTs were targeted. Of these, 21 (91%) were mapped with activation/entrainment mapping, always utilizing an intracardiac RV reference due to excessive surface ECG noise, and 2 (9%) were hemodynamically unstable with reduced LVAD flows and targeted with substrate-based ablation. A total of 3 (13%) VTs were targeted adjacent to the HM3 inflow cannula, and 20 (87%) from substrate remote from the HM3 cannula. At post-procedural programmed ventricular stimulation, non-inducibility of all targeted VTs was achieved in 13 (87%) patients, 1 patient had residual inducible clinical VT, and in 1 patient no post-procedural programmed stimulation was performed. Periprocedural complications occurred in 1 (7%) case (small pericardial effusion not requiring intervention). At 12 months follow-up following the index procedure, no death occurred and one patient received heart transplantation. Of the remaining 14 patients, 6 (42%) remained free from VT (2 with VT ablation <1 month post-LVAD and 12 with VT ablation >=1 month post-LVAD). In this large single-center HM3 registry, a minority of patients underwent CA for recurrent drug-refractory VT (3.4% over a 7-year period). CA of VT in HM3 recipients is feasible and appears safe also when performed soon after LVAD surgery. Myocardial scar from the underlying cardiomyopathic process rather than the apical cannula is the dominant substrate responsible for VT in these patients.

Excel file containing source data for "Prognostic Value of Gut Microbe-Generated Metabolite Phenylacetylglutamine in Patients with Heart Failure", by Tang et al, published in European Journal of Heart Failure.

Despite the advent of catheter ablation and antiarrhythmic medications, atrial fibrillation (AF) remains a significant source or morbidity and mortality. The gut microbiome and microbial derived trimethylamine N-oxide (TMAO) have been increasingly recognized as having a novel role in cardiovascular disease.

The heightened cardiovascular disease (CVD) risk observed among omnivores is thought to be linked, in part, to gut microbiota-dependent generation of trimethylamine-N-oxide (TMAO) from l-carnitine, a nutrient abundant in red meat. Gut microbial transformation of l-carnitine into trimethylamine (TMA), the precursor of TMAO, occurs via the intermediate γ-butyrobetaine (γBB). However, the interrelationship of γBB, red meat ingestion and CVD risks, as well as the gut microbial genes responsible for the transformation of γBB to TMA, are unclear. In the present study, we show that plasma γBB levels in individuals from a clinical cohort (n = 2,918) are strongly associated with incident CVD event risks. Culture of human faecal samples and microbial transplantation studies in gnotobiotic mice with defined synthetic communities showed that the introduction of Emergencia timonensis, a human gut microbe that can metabolize γBB into TMA, is sufficient to complete the carnitine → γBB → TMA transformation, elevate TMAO levels and enhance thrombosis potential in recipients after arterial injury. RNA-sequencing analyses of E. timonensis identified a six-gene cluster, herein named the γBB utilization (gbu) gene cluster, which is upregulated in response to γBB. Combinatorial cloning and functional studies identified four genes (gbuA, gbuB, gbuC and gbuE) that are necessary and sufficient to recapitulate the conversion of γBB to TMA when coexpressed in Escherichia coli. Finally, reanalysis of samples (n = 113) from a clinical, randomized diet, intervention study showed that the abundance of faecal gbuA correlates with plasma TMAO and a red meat-rich diet. Our findings reveal a microbial gene cluster that is critical to dietary carnitine → γBB → TMA → TMAO transformation in hosts and contributes to CVD risk. The gbu gene cluster, present in the human gut microbiota member Emergencia timonensis, converts γ-butyrobetaine (γBB) to trimethylamine in the conversion of dietary l-carnitine, which is found in red meat, to the proatherosclerotic metabolite trimethylamine-N-oxide. Individuals with high plasma γBB levels had increased risk of cardiovascular events.

Introduction: The gut microbiota is a metabolically active, endocrine-like organ which contributes to cardiovascular health and disease. Dietary carbon fuel sources (choline, PC, and L-carnitine) a...

L -Carnitine, a nutrient in red meat, accelerates atherosclerosis in a gut microbiota-dependent pathway by the formation of trimethylamine- N -oxide (TMAO). We now show that a novel compound, crotonobetaine (crotono), identified in a metabolomics study, is a product of L -carnitine gut microbial

Hypoattenuating leaflet thickening/thrombosis (HALT) is a known complication post transcatheter aortic valve replacement (TAVR). No pathophysiologic mechanism has been identified to date. We aimed to evaluate the association between stasis within the non-coronary aortic sinus (NCC) and HALT. We

BACKGROUND. L-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota-dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, gamma-butyrobetaine (gamma BB). The contribution of gamma BB in gut microbiota-dependent L-carnitine metabolism in humans is unknown. METHODS. Omnivores and vegans/vegetarians ingested deuterium-labeled L-carnitine (d(3)-L-carnitine) or gamma BB (d(9)-gamma BB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (>= 2 months) L-carnitine supplementation. Human fecal commensals capable of performing each step of the L-carnitine ->gamma BB -> TMA transformation were identified. RESULTS. Studies with oral d(3)-L-carnitine or d(9)-gamma BB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal L-carnitine ->gamma BB -> TMA -> TMAO pathway in subjects. Moreover, a striking increase in d(3)-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d(3)-L-carnitine ingestion, whereas fasting endogenous plasma L-carnitine and gamma BB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic L-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to gamma BB, whereas the second gut microbial transformation, gamma BB -> TMA, was diet inducible (L-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of L-carnitine -> TMA transformation, multiple community members that converted L-carnitine to gamma BB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted gamma BB to TMA. In coculture, E. timonensis promoted the complete L-carnitine -> TMA transformation. CONCLUSION. In humans, dietary L-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate gamma BB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota gamma BB -> TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic L-carnitine exposure.

Aims Carnitine and choline are major nutrient precursors for gut microbiota-dependent generation of the atherogenic metabolite, trimethylamine N-oxide (TMAO). We performed randomized-controlled dietary intervention studies to explore the impact of chronic dietary patterns on TMAO levels, metabolism and renal excretion. Methods and results Volunteers (N=113) were enrolled in a randomized 2-arm (high- or low-saturated fat) crossover design study. Within each arm, three 4-week isocaloric diets (with washout period between each) were evaluated (all meals prepared in metabolic kitchen with 25% calories from protein) to examine the effects of red meat, white meat, or non-meat protein on TMAO metabolism. Trimethylamine N-oxide and other trimethylamine (TMA) related metabolites were quantified at the end of each diet period. A random subset (N=13) of subjects also participated in heavy isotope tracer studies. Chronic red meat, but not white meat or non-meat ingestion, increased plasma and urine TMAO (each >two-fold; P<0.0001). Red meat ingestion also significantly reduced fractional renal excretion of TMAO (P<0.05), but conversely, increased fractional renal excretion of carnitine, and two alternative gut microbiota-generated metabolites of carnitine, gamma-butyrobetaine, and crotonobetaine (P<0.05). Oral isotope challenge revealed red meat or white meat (vs. non-meat) increased TMA and TMAO production from carnitine (P<0.05 each) but not choline. Dietary-saturated fat failed to impact TMAO or its metabolites. Conclusion Chronic dietary red meat increases systemic TMAO levels through: (i) enhanced dietary precursors; (ii) increased microbial TMA/TMAO production from carnitine, but not choline; and (iii) reduced renal TMAO excretion. Discontinuation of dietary red meat reduces plasma TMAO within 4 weeks.

Introduction: L-carnitine potentially contributes to atherosclerosis via gut microbe-dependent formation of trimethylamine N-oxide (TMAO). Microbiota-dependent conversion of L-carnitine to TMAO in ...