Aaron Isaacs

Background and Aims: Atrial cardiomyopathy (AtCM) is associated with atrial fibrillation (AF). While histological studies describe underlying mechanisms of AtCM, these insights remain disconnected from clinical AtCM. This study determines the histological basis of non-invasive AtCM markers and assess their prognostic value in patients undergoing cardiac surgery. Methods and results: Left and right (LA/RA) atrial tissue samples were obtained in patients undergoing cardiac surgery (n = 136) in the RACE V Tissue Bank study. Pre-operative rhythm history, digital ECG, transthoracic echocardiography (TTE) and biomarker levels were used to group patients in AtCM stages: AF: history of paroxysmal, persistent or permanent AF, Severe (LAVi>50 mL/m2 or LAEF250 pg/mL), Mild (no AF, LAVi≤34 mL/m2 AND P-terminal Force V1 > 5 mV*ms OR P wave duration > 120 ms), and no AtCM. Tissue was stained (WGA/CD31/Vimentin) to quantify fibrosis, fibroblast density, myocyte diameter and vascularization. Post-operative rhythm was monitored continuously (2.5 years) using implantable loop recorders. Patients with severe AtCM had extended endomysial fibrosis (LA: +0.82µm, pFDR,LA < 0.001; RA: +0.64µm, pFDR,RA = 0.010) and larger left atrial cardiomyocytes (LA: +0.92µm, pFDR,LA = 0.026). Moderate AtCM patients showed LA myocyte hypertrophy (LA: +1.35µm, pFDR,LA = 0.007). Mild AtCM patients had similar histological features to patients without AtCM. Moderate (β = 3.56, pFDR = 0.045) and severe (β = 3.74, pFDR = 0.034) AtCM patients had a higher AF burden late after cardiac surgery. Conclusion: Clinical AtCM markers reflect pro-fibrotic and pro-hypertrophic remodelling in the moderate to severe AtCM stages and are associated with a higher AF burden late after surgery.

Background and Aims: To elucidate the genetic architecture of blood pressure (BP) and heart rate (HR) during early life and assess their potential relevance to adult health outcomes. Methods: The largest genome-wide association study (GWAS) meta-analyses to date of childhood systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (n = 28 425) and HR (n = 22 565) were conducted in children of European ancestry aged 4–17 years. Follow-up analyses included comparisons with adult GWAS results, polygenic risk score (PRS) analyses in independent cohorts of diverse ancestries, and a phenome-wide association study in the UK Biobank. Results: Eight genome-wide significant loci were identified for childhood BP (KIAA2013, CACNB2, PLCE1, PAX2, COL4A2, RP11-236L14.1, CFDP1, TPX2) and three loci for childhood HR (CCDC141, ACHE, MYH6); all novel in children but previously reported in adults. Childhood PRSs explained up to 1.6% of BP variance and 5.2% of HR variance among children of European ancestry. Genetic correlations between childhood and adulthood BP traits were moderate (rg = 0.4–0.7), suggesting age-specific genetic effects on BP. In the UK Biobank, higher childhood BP PRS levels were significantly associated with a broad range of adult health outcomes, particularly cardiometabolic outcomes such as hypertension, angina, myocardial infarction, and cardiovascular disease-related mortality. Conclusions: These findings advance the understanding of the genetic architecture of childhood BP and HR and provide compelling genetic evidence linking childhood BP to a broad spectrum of adult health outcomes—particularly cardiometabolic conditions—which may inform targeted prevention strategies from a young age.

Aims: Atrial fibrillation (AF) is conventionally classified as paroxysmal or persistent. AF burden might better reflect response to rhythm-control interventions. This study evaluated the association between estimated pre-procedural time spent in AF and recurrences after AF ablation, compared with conventional AF classification. Methods and results: In patients scheduled for AF ablation, clinical characteristics were collected before ablation, and 60-second single-lead ECGs were recorded three times daily (with additional symptom-triggered recordings) for four weeks. Pre-procedural time spent in AF was estimated as the number of days with detected AF divided by total monitoring days. The primary endpoint was AF recurrence between 3 and 12 months post-ablation. Of 302 patients (mean age 64 ± 9 years; 33% female), 201 (67%) had paroxysmal AF and 101 (33%) had persistent AF. After 12 months, recurrence rates were higher in persistent than in paroxysmal AF (37.6% vs. 24.4%, P & 0.01) and in patients with a higher (>32%) vs. lower (≤32%) percentage of time spent in AF (36.4% vs. 24.0%, P < 0.01). Notably, paroxysmal AF patients with a higher percentage of time in AF had recurrence rates comparable to those of patients with persistent AF. Pre-procedural percentage of time in AF independently predicted arrhythmia recurrence at 12-month follow-up (HR: 1.06; 95% CI: 1.0–1.1; P & 0.025). Conclusion: A higher pre-procedural percentage of time spent in AF derived from 60-second single-lead ECGs is independently associated with atrial arrhythmia recurrence after ablation. Assessing the percentage of pre-procedural time spent in AF might help identify paroxysmal AF patients with a high AF recurrence risk in future studies.

Aims: Several clinical factors, such as ageing and atrial dilatation, are associated with post-discharge atrial fibrillation (late-POAF) after cardiac surgery, but it is currently unknown if atrial histological characteristics are linked to late-POAF. Therefore, the aim of this study was to determine the association of atrial histological characteristics with POAF incidence and burden during 2.5 years of continuous rhythm monitoring after cardiac surgery. Methods and results: Consecutive patients with and without AF history were prospectively included. Intraoperatively, biopsies were taken of left (LAA) and right atrial appendages (RAA), and all patients received an implantable loop recorder for 2.5 years. Biopsies were analysed for overall and endomysial fibrosis, cardiomyocyte diameter, capillary density and size, and fibroblast density. POAF incidence was defined as any AF episode during the follow-up, while POAF burden was the percentage of time in AF. A total of 133 patients were included (90 without and 43 with AF history). Late-POAF occurred in 53 patients (40.8%). While several histological traits were associated with POAF incidence in the unadjusted analyses, none of the histological traits were significantly associated with POAF incidence after adjustments for clinical confounders. Increased RAA endomysial fibrosis was the only histological trait significantly associated with increased overall (St. Beta = 0.32, 95% CI: 0.06–0.58, P = 0.017) and late-POAF burden (St. Beta = 0.43, 95% CI: 0.13–0.72, P = 0.006) after adjusting for age, sex, type of surgery, reduced LV function, RA volume, and AF history. Conclusion: Increased RAA endomysial fibrosis appears to be associated with increased late-POAF persistence, reflected by increased burden, but not with incidental late-POAF recurrences.

BACKGROUND: Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation. METHODS: Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort. RESULTS: A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript ( P _FDR ≤0.05 for 579 regions). These “transcription disequilibrium” blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated. CONCLUSIONS: These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.

Background: Atrial endomysial fibrosis, rather than overall connective tissue content, determines the complexity of conduction in human atrial fibrillation (AF). Moreover, the AF-specific blood biomarker BMP10 is associated with atrial endomysial fibrosis, but not overall connective tissue content. It is unclear whether pre-operative atrial endomysial fibrosis predicts post-operative AF (POAF) incidence and burden. Objective: To determine the predictive value of atrial fibrosis for early and late POAF burden. Methods: Patients with and without AF history were included in the RACE V tissue bank study (n=134). Post-operative rhythm was monitored continuously for 2.5 years with implantable loop recorders. Late POAF-burden was investigated following a 90-day blanking period. Left (n=89) and/or right (n=92) atrial appendage biopsies (LAA/RAA) were snap-frozen and histologically investigated following WGA-staining. Results: Logistic regression, corrected for age, sex and AF history, showed that left (st.β = 0.54 [0.23-0.85], p=0.001) and right (st.β=0.35 [0.07-0.64], p=0.017) atrial endomysial fibrosis were associated with early POAF burden in the blanking period. Only right atrial endomysial fibrosis, however, predicted late POAF-burden (st.β=0.44 [-], p=0.009). Adjusted Cox proportional hazards analyses indicated that patients in the highest tertile of right atrial endomysial fibrosis, in particular, are at risk for late POAF (HR T3 vs T1: 2.47 [1.18-5.17], p=0.016, Fig 1). Overall connective tissue content in both atria was not associated with POAF-burden. Conclusion: Patients with higher levels of right atrial endomysial fibrosis are at risk for developing late POAF with a higher POAF-burden.Figure 1

Background: In patients with atrial fibrillation (AF), significant advances have been made in identifying biomarkers representing diverse pathophysiological pathways, such as inflammation, myocyte injury, collagen deposition, and fatty-fibrotic infiltration. Data on clinical determinants of biomarkers in patients with AF, however, are lacking. Objective: Our primary aim was to explore the relationships between clinical determinants and biomarker levels in AF patients scheduled for catheter ablation. Methods: A cross-sectional analysis was conducted in AF patients undergoing catheter ablation included in the prospective multicenter ISOLATION study between July 2020 and May 2022. Clinical characteristics, routine tests and blood samples were collected before ablation. Blood samples were analyzed for known and novel cardiovascular biomarkers, including Bone morphogenetic protein 10 (BMP10), Angiopoietin-2 (Ang-2), Fibroblast growth factor 23 (FGF-23), Dickkopf-related protein 3 (DKK-3), Endocan (ESM-1), Insulin-like growth factor-binding protein 7 (IGFBP-7), B-type natriuretic peptides (proBNP, NTproBNP), High sensitive Troponin-T (hsTnT)< Growth differentiation factor 15 (GDF-15), interleukin 6 (IL-6), Fatty acid binding protein 3 (FABP3), Cancer antigen-125 (Ca-125) (Table 1). For each biomarker we trained a lasso regression model to identify the most important clinical determinants out of all the 60 available determinants (including anthropometry, ECG, comorbidities). The strongest associations are summarized in figure 1. Results: Blood samples of 508 patients were analyzed. The mean age was 63 ±9 years, and 31.1% were female. 354 patients (69.7%) had paroxysmal AF and 154 patients (30.3%) had persistent AF. Heart failure was reported in 77 patients (15.2%). 355 (72.3%) patients were in sinus rhythm during sample collection. The following clinical determinants of biomarker levels were frequently identified as important: rhythm during blood phlebotomy, age, heart failure, decreased kidney function and female sex (Figure 1). Most notably, rhythm at the time of sampling was strongly associated with various biomarker levels. Female sex was positively associated with BMP10 and FGF23 (atrial fibrosis), but negatively associated with hsTNT (cardiac injury). Conclusion: In patients with AF scheduled for catheter ablation, we identified several clinical determinants of biomarker levels with potential implications for disease mechanisms. In women, pro-fibrotic biomarkers were frequently higher, while male patients more often showed signs of myocardial injury. Importantly, rhythm during blood draw is a very strong determinant of many biomarkers and should be taken into account in future biomarker studies.Figure 1.Table 1.

Background: Non-invasive quantification of electrophysiological properties of the atria is increasingly used for outcome prediction in atrial fibrillation (AF) patients. Data on the benefit of the current classification of AF compared to AF burden based on single lead ECG measurements to predict AF recurrences are scarce. Objective: This study sought to assess the predictive performance of low versus high AF burden compared to the conventional AF classification for predicting recurrences after AF catheter ablation. Methods: A cross-sectional analysis was conducted in AF patients scheduled for catheter ablation included in the prospective multicenter ISOLATION cohort study between July 2020 and November 2022. Clinical characteristics, routine tests, blood tests and rhythm monitoring through single lead ECGs were collected prior to ablation. ECGs were recorded three times daily for four weeks, with additional measurements in case of the onset or relief of symptoms. The primary endpoint was "ablation success" defined as freedom from documented arrhythmia after the blanking period. Of 650 included patients, pre-procedural rhythm monitoring was available in 580. 261 patients had at least 14 days of ECG measurements and completed 12 months of follow-up. In these patients, we compared the recurrences after 12 months between paroxysmal and persistent AF and high versus low AF burden through survival analysis. Maximally selected rank statistics were used to determine the best cut-off value for AF burden. Results: In 261 patients, the mean age was 64 ± 9 years, and 33.7% were female. Physicians classified 170 patients (65.1%) as paroxysmal AF and 91 (34.9%) as persistent AF based on medical history. The AF burden is shown in Figure 1. The optimal calculated cut-off value for AF burden was 42%. Out of 170 patients with paroxysmal AF, 17 (10%) had a burden of > 42%. Of the 91 patients with persistent AF, 35 (38%) had a burden of < 42%. After 12 months, a significant difference in recurrences was observed between patients with paroxysmal AF versus persistent AF (p= 0.015). Patients with high AF burden, had more recurrences after 12 months, than patients with a low AF burden (p= 0.006) (Figure 2). Conclusion: Our preliminary results suggest that the addition of a new classification of AF based on burden might provide additional benefit in predicting AF recurrences after catheter ablation compared to the current existing classification and may improve prognostication. Completion of patient follow-up is necessary to determine the predictive value of AF burden derived from single lead ECGs for the prediction of AF recurrence.Figure 2.

Background: Serum bone morphogenetic protein 10 (BMP10) levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in AF-patients, including stroke, recurrence after catheter ablation, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphological properties of atrial tissue are unknown. Objective: To study the correlation between BMP10 levels and pre-operative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. Methods: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n=147). Pre-operative blood biomarkers were analyzed, left (n=114) and right (n=125) atrial appendage biopsies were histologically assessed following WGA-staining, and post-operative rhythm was monitored continuously with implantable loop recorders (n=134, 2.5yrs). Results: Multiple logistic regression indicated that BMP10 accurately predicts a history of persistent AF (OR=1.24, 95%CI: 1.10-1.40, p=4.32e-4), similar to NT-pro-BNP. BMP10 levels were associated with increased late-POAF90 occurrence after adjusting for age, sex, AF history, and early-POAF occurrence (HR=1.07 [per 0.1ng/ml increase], 95%CI: 1.00-1.14, p=0.04). Left atrial endomysial fibrosis (St.β=0.22, p=0.04), but not overall fibrosis (St. β= , p=), was associated with circulating BMP10, after adjusting for age, sex, AF history, reduced LVF, and valvular surgery indication. Conclusion: Increased BMP10 levels were associated with persistent AF-history, increased late-POAF incidence, and LAA endomysial fibrosis in a diverse population of patients undergoing cardiac surgery.