Atrial Conduction Abnormalities Research Articles

High prevalence of atrial conduction abnormalities in Lewy body disease - a marker of cardiac complications?

Increasing evidence suggests that Lewy body disease (LBD) is associated with clinically important cardiac complications, including sick sinus syndrome, atrial fibrillation and sudden cardiac death. The high prevalence of sick sinus syndrome and atrial fibrillation in LBD suggests the presence of disease-related atrial conduction disorders. To explore whether LBD is associated with atrial conduction disorders, electrocardiographic (ECG) P wave parameters were analyzed in a cohort of LBD patients (n = 74), using age-matched Alzheimer's disease (AD) patients (n = 25) as controls. P wave terminal force in V1 and P wave duration were found to be significantly greater in the LBD group than in the AD group. In addition, 43 (58%) individuals in the LBD exhibited pathological P wave terminal force (> 4000µV*ms) vs 3 (12%) in the AD group, and 60 (81%) in the LBD group exhibited pathological P wave duration (≥ 120ms), vs 13 (52%) in the AD group. The difference could not be explained by atrial fibrillation or atrial enlargement on echocardiogram. The clinical significance of pathological P wave parameters in LBD is unknown, but their presence suggests an atrial cardiomyopathy that could be due to cardiac alpha-synuclein deposition, autonomic dysfunction, or a combination thereof. Future research is warranted to elucidate whether this proposed disease-related atrial cardiomyopathy is related to cardiac alpha-synuclein deposition, whether it is causally related to cardiac complications in LBD, and whether pathological P wave parameters hold potential as a screening tool for cardiac complications in LBD.

Quantifying DNA Lesions and Circulating Free DNA: Diagnostic Marker for Electropathology and Clinical Stage of AF.

Atrial fibrillation (AF) persistence is associated with molecular remodeling that fuels electrical conduction abnormalities in atrial tissue. Previous research revealed DNA damage as a molecular driver of AF. This study sought to explore the diagnostic value of DNA damage in atrial tissue and blood samples as an indicator of the prevalence of electrical conduction abnormalities and stage of AF. High-sensitivity long-run real-time PCR was performed on mitochondrial (ND1) and nuclear (P53) DNA from atrial tissue samples from paroxysmal (PAF), persistent (PeAF), and longstanding persistent (LS-PeAF) AF, and sinus rhythm (SR) patients (n=83). PicoGreen assay and quantitative polymerase chain reaction were used on circulating free DNA (cfDNA) markers (total cfDNA, β-globin, ND1, and P53) in blood samples of 70 patients with AF or SR. High-resolution epicardial mapping of the atria (n=48) was conducted to quantify electrical conduction abnormalities. The number of DNA lesions gradually and significantly increased in PAF and PeAF and in patients with<3years of AF compared with SR. In SR, the quantity of nuclear DNA damage significantly correlated with the proportion of fractionated potentials. Mitochondrial DNA lesions correlated with slower conduction velocity and lower potential amplitudes in AF samples. Also, mitochondrial cfDNA levels decreased in patients with >3 years of AF compared with<3 years of AF (P=0.004). The quantity of DNA lesions in atrial tissue samples is associated with atrial conduction abnormalities and stage of AF. Serum DNA damage markers discriminate short- from long-term AF. Therefore, the quantity of DNA damage may have diagnostic value in clinical AF management.

Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and Pwave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated Pwave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone,might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and Pwave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to Pwave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Selective blockade of interleukin 6 trans-signaling depresses atrial fibrillation

Atrial fibrillation (AF) has been accepted as an inflammatory atrial myopathy. Interleukin 6 (IL-6)-dependent inflammatory signaling pathways take context-dependent effects on cardiovascular diseases. IL-6 trans-signaling is predominantly pro-inflammatory. However, its effect on AF is unclear. The purpose of this study was to investigate the role of IL-6 trans-signaling in AF. Circulating levels of IL-6, soluble IL-6 receptor, and soluble glycoprotein 130 (sgp130) in patients with AF and controls were measured to estimate the activation of IL-6 trans-signaling. A mouse model of AF was established by transverse aortic constriction surgery. Sgp130Fc administration was used for the selective blockade of IL-6 trans-signaling. Studies were conducted to evaluate the effects and underlying mechanisms of sgp130Fc on AF inducibility and atrial conduction abnormalities and structural remodeling. In patients, the elevation of IL-6 trans-signaling level was positively associated with AF occurrence. IL-6 trans-signaling activation was recapitulated in the mouse model of AF. In transverse aortic constriction-challenged mice, the selective blockade of IL-6 trans-signaling with sgp130Fc attenuated AF inducibility, which was attributable to the amelioration of slow conduction and conduction heterogeneity induced by atrial dilation, fibrosis, and reduction in connexin 40 and redistribution of connexin 43. Sgp130Fc administration also reduced immune cell infiltration and oxidative stress in the mouse atrium and abrogated IL-6 trans-signaling activation-mediated connexin dysregulation and reactive oxygen species production in atrial myocytes. IL-6 trans-signaling activation contributes to AF development, and its selective blockade may promise a novel therapeutic strategy.

The relationship of plasma catestatin concentrations with the extension of left atrial fibrosis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atrial fibrosis is increasingly considered an important part of vulnerable substrates, with an essential function in the induction of left atrial (LA) conduction abnormalities underlying the transition from paroxysmal (PAF) to persistent atrial fibrillation (PeAF), contributing to disease continuation. A substantial number of studies suggest a correlation between atrial fibrosis and low voltage zones (LVZ) (1). Previous studies have shown that catestatin (CST) regulates cardiac remodeling. The CST inhibition of catecholamine inhibits the Ang II-induced cell proliferation, and the extracellular matrix (ECM) downregulation to protect the heart from fibrosis produces similar results inhibition of catecholamine and the regulation of the beta-adrenergic receptors (β-ARs) (2). From the results, it is clear that CST inhibits cardiac fibrosis by regulating nitric oxide (NO) and the reactive oxygen species (ROS) pathways via inhibiting catecholamine release and influencing the production of the downstream molecule (2). Purpose This study investigated the potential association of serum catestatin level and LA fibrosis in AF patients. Methods The current study enrolled 18 consecutive patients with PeAF who had undergone bipolar voltage mapping of the left atrium before catheter ablation. The proportion of the mapped LA surface exhibiting low voltage (&amp;lt;0.5mV) was expressed as a percentage of the overall mapped LA surface area. In all participants, fasting laboratory tests were drawn at admission. The primary outcome measure of the current study was the association of serum CST and low-voltage zones (%LVZ ≥ 10% as a reference for severe LVZ). Results The patient characteristics were summarized in Table 1. The LA was mildly dilated, and the median %LVZ was 4 (IQR 0.75-31.25). The lower degree of cardiac fibrosis (LVZ &amp;lt; 10%) is significantly associated with higher levels of catestatin compared to severe LVZ &amp;gt;10% (8.6 (interquartile range-IQR 4.6 – 25.0) vs. 21.9 (IQR 11.1-100.0), p= 0.040)(Figure 1). Conclusion The higher catestatin level was associated with the lower extension of atrial fibrosis (low LA voltage zones).

Voltage characterization of abnormal conduction zones in patients affected by atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background In case of persistent atrial fibrillation (AF), atrial substrate assumes a dominant role in sustaining the arrhythmia. Recent studies prove that low voltage areas (LVA, Voltage Amplitude &amp;lt; 0,5 mV) represent an additional target for ablation of AF patients. Purpose The purpose of this study is to analyse whether structural atrial conduction abnormalities (i.e., pivot sites and slow conduction corridors) may occur outside low voltage areas. Methods The study is based on the retrospective analysis of 31 consecutive maps of patients undergoing AF ablation (16 paroxysmal and 15 persistent cases). The clinical procedures have been performed with the support of a mapping system. Sinus rhythm activation maps and bipolar maps used for this analysis have been created with a multipolar mapping catheter. Map points were only acquired when the electrode was in contact with the endocardial tissue to avoid misleading voltage amplitude information. Slow conduction corridors and pivot sites have been analysed. At these sites, EGMs characterization included voltage amplitude (mV), signal duration (ms) and fractionation. Results The average value of EGMs amplitude reported at pivot sites and slow conduction zones, respectively, amounted to 2,08 ± 0,63 mV and 2,1 ± 0,66 mV in paroxysmal cases. In persistent cases, there were slight decreased values to 1,95 ± 0,93 mV and 1,89 ± 0,89 mV. Characterization at pivot sites documented a mean duration value of 45,4 ± 4,64 ms and 49,93 ± 5,51 ms in paroxysmal and persistent patients, respectively, while in slow conduction zones 41,53 ± 7,94 ms and 49,04 ± 6,41 ms have been reported. As for fractionation, more than five deflections per signal have been identified in all abnormal conduction areas. Conclusion Our study proves that functional electrophysiological phenomena can occur outside low voltage areas, even in persistent cases. According to this analysis, not all LVA represent the correct target for catheter ablation, encouraging the development of further methods for investigation of atrial substrate.

P57 VOLTAGE CHARACTERIZATION OF ABNORMAL CONDUCTION ZONES IN PATIENTS AFFECTED BY ATRIAL FIBRIALLATION

Abstract Background In case of persistent atrial fibrillation (AF), atrial substrate assumes a dominant role in sustaining the arrhythmia. Recent studies prove that low voltage areas (LVA, Voltage Amplitude &amp;lt; 0,5 mV) represent an additional target for ablation of AF patients. Purpose. The purpose of this study is to analyse whether structural atrial conduction abnormalities (i.e., pivot sites and slow conduction corridors) may occur outside low voltage areas. Methods The study is based on the retrospective analysis of 31 consecutive maps of patients undergoing AF ablation (16 paroxysmal and 15 persistent cases). The clinical procedures have been performed with the support of a mapping system. Sinus rhythm activation maps and bipolar maps used for this analysis have been created with a multipolar mapping catheter. Map points were only acquired when the electrode was in contact with the endocardial tissue to avoid misleading voltage amplitude information. Slow conduction corridors and pivot sites have been analysed. At these sites, EGMs characterization included voltage amplitude (mV), signal duration (ms) and fractionation. Results The average value of EGMs amplitude reported at pivot sites and slow conduction zones, respectively, amounted to 2,08 ± 0,63 mV and 2,1 ± 0,66 mV in paroxysmal cases. In persistent cases, there were slight decreased values to 1,95 ± 0,93 mV and 1,89 ± 0,89 mV. Characterization at pivot sites documented a mean duration value of 45,4 ± 4,64 ms and 49,93 ± 5,51 ms in paroxysmal and persistent patients, respectively, while in slow conduction zones 41,53 ± 7,94 ms and 49,04 ± 6,41 ms have been reported. As for fractionation, more than five deflections per signal have been identified in all abnormal conduction areas. Conclusion Our study proves that functional electrophysiological phenomena can occur outside low voltage areas, even in persistent cases. According to this analysis, not all LVA represent the correct target for catheter ablation, encouraging the development of further methods for investigation of atrial substrate.

Abstract P3016: Role Of AMPK/Sirtuin3 Signaling In HFpEF-associated Atrial Myopathy

Background: Patients with heart failure with preserved ejection fraction (HFpEF) are uniquely predisposed to atrial fibrillation (AF), which significantly worsens clinical outcomes. Pathological atrial remodeling, i.e. atrial myopathy, usually precedes clinical AF and is deemed to be an underlying cause of AF. However, little is known about its molecular features, and no effective treatments have been identified. Method: Wild type C57Bl6 mice were fed a high fat diet (HFD) and received L-NAME via drinking water (5-8 weeks). Atrial morphology and function were assessed by echocardiography. AF was induced by transesophageal pacing. Results: We discovered that HFpEF mice manifest prominent sinoatrial node (SAN) dysfunction and are highly susceptible to pacing-induced AF, suggesting that this is an ideal model for studying HFpEF-associated atrial changes. Our findings revealed that atrial hypertrophy, contractile dysfunction, and conduction abnormalities are key features of HFpEF-associated atrial myopathy. Interestingly, we did not observe significant atrial fibrosis in this model, a prominent feature of other AF models. Importantly, we discovered impaired AMPK/Sirt3 signaling in the atria of HFpEF mice, and similar atrial defects were observed in mice with cardiomyocyte-specific loss of sirtuin3 (Sirt3) or AMPK, indicating a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial myopathy. Lastly, we found that metformin, a widely used clinical AMPK agonist, significantly attenuated AF inducibility and SAN dysfunction in HFpEF mice. Conclusion: Our “two-hit” HFpEF model successfully recapitulates HFpEF-associated atrial phenotypes. Using this model, we unveiled molecular features of a distinct atrial myopathy. We identified a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial remodeling and demonstrated the therapeutic effect of metformin. As next steps, confirming this benefit in a clinical trial is warranted.

Polycystic Ovary Syndrome Triggers Atrial Conduction Disorders: A Systematic Review and Meta-Analysis.

Background: Polycystic ovary syndrome (PCOS) is closely related to various adverse cardiovascular manifestations and increased cardiovascular risk. However, atrial fibrillation (AF) development and atrial conduction abnormalities have not been thoroughly studied in patients with PCOS. Methods: This meta-analysis (CRD42021261375) was conducted in accordance with the PRISMA guidelines. Our aim was to investigate associations between PCOS and disorders in atrial conduction parameters linked with an increased risk for AF occurrence. Results: Five cohort studies with aggregate data on 406 adult women (229 with PCOS and 177 age-matched without PCOS) were included in this analysis. Our results showed a significantly increased mean difference in P-wave maximum duration (+7.63 ± 7.07 msec; p < 0.01) and P-wave dispersion (+11.42 ± 5.22 msec; p = 0.03) of patients with PCOS compared to healthy women. The mean difference in P-wave minimum duration (−2.22 ± 2.68 msec; p = 0.11) did not reach the statistical threshold between the compared groups. Echocardiographic measurements of atrial electromechanical delay (AED) also indicated a statistically significant mean difference in favour of the PCOS group in all assessed parameters, except for atrial electromechanical coupling (PA) in the tricuspid annulus. Particularly, PCOS was associated with increased lateral PA, septal PA, inter- and intra-AED durations (mean difference: +17.31 ± 9.02 msec; p < 0.01, +11.63 ± 7.42 msec; p < 0.01, +15.31 ± 9.18 msec; p < 0.01, +9.31 ± 6.85 msec; p < 0.01, respectively). Conclusions: PCOS is strongly associated with alterations in several electrocardiographic and echocardiographic parameters indicating abnormal atrial conduction. Therefore, PCOS could be considered as a causal or triggering factor of AF. Larger studies are needed to confirm these results and investigate direct associations between PCOS and AF.

The significance of widely split P waves: a case report

BackgroundP wave morphology on electrocardiogram is often overlooked but indicates abnormal cardiac conduction from various etiologies. Split P waves on electrocardiogram have been reported previously but not in a perioperative setting.Case presentationA 69-year-old Caucasian male patient with widely split P waves on his preoperative electrocardiogram was scheduled for a reimplantation right total hip replacement under a combined spinal–general anesthetic technique. The patient was evaluated prior to surgery by a cardiologist and the preoperative anesthesia clinic without any comment on the abnormal P wave morphology on electrocardiogram. The patient was cleared to proceed with anesthesia and surgery. Following induction of general anesthesia, his cardiac rhythm changed to a Mobitz type II pattern. The surgical procedure was cancelled, and a permanent cardiac pacemaker was inserted.ConclusionsAnesthesiologists should be aware that the presence of widely split P waves on electrocardiogram indicates the presence of atrial conduction abnormalities, likely from an ischemic or infiltrative process that can lead to more serious cardiac arrhythmias. P wave morphology should be observed and noted during the perioperative period for all patients.

Bariatric surgery reduces ventricular repolarisation gradients in obese patients - results from an electrocardiographic imaging study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research (NIHR) British Heart Foundation Background Obesity confers higher risks of atrial arrhythmias and is associated with abnormal ventricular repolarisation. Despite this, the proarrhythmic substrate in obesity and its reversibility with weight loss has not been studied in-depth. Purpose To characterise the proarrhythmic substrate in obese patients, and its reversibility with bariatric surgery, using electrocardiographic imaging (ECGi). Methods ECGi was performed in 8 obese patients before (PreOb) and after (PostOb) bariatric surgery (mean age 39+/-11years, 7 female), and in 8 age- and sex-matched non-obese controls (NOb) (40+/-11 years). ECGi recordings were made at rest, on exercise, and during recovery from exercise. For ECGi analysis, &amp;gt;2000 atrial and ventricular epicardial electrograms were calculated from body surface potential recordings from 256 sites and information from cardiac magnetic resonance imaging, by solving the inverse problem. Local atrial and ventricular epicardial activation times (AT) were calculated as the steepest downslope of their respective activation complexes, and local ventricular repolarisation times (RT) as the steepest upslope of the T-wave. Atrial activation gradients (ATG) and ventricular repolarisation gradients (RTG) were calculated as the maximum difference within 10mm radius divided by the corresponding Euclidean distance. Results BMI was greater in PreOb vs NOb (46.6+/-4.8 vs 23.8+/-2.6kg/m2, p&amp;lt;0.0001) and decreased with surgery (PostOb 35.3+/-4.2kg/m2, p&amp;lt;0.0001). Total atrial AT was prolonged in PreOb vs NOb (68+/-12 vs 45+/-10ms, p=0.016) and did not change post-surgery (PreOb vs PostOb: 68+/-12 vs 67+/-16ms, p=0.81). Atrial ATG were also greater in PreOb vs NOb: max 254+/-111 vs 106+/-58ms, p=0.035; mean 24+/-6 vs 12+/-6ms, p=0.0087) and did not change with weight loss (PreOb vs PostOb: max 254+/-111 vs 222+/-69ms/mm, p=0.61; mean 24+/-6 vs 21+/-7ms/mm, p=0.52). Ventricular RTG were greater in PreOb vs NOb (max: 287+/-73 vs 131+/-89ms/mm, p=0.012; mean: 33+/-10 vs 17+/-9ms/mm, p=0.0052). Ventricular RTG decreased with weight loss (PreOb vs PostOb: max 287+/-73 vs 151+/-54ms/mm, p=0.0070; mean: 33+/-10 vs 21+/-8ms/mm, p=0.018), and were similar between PostOb and NOb (max, p=0.81; mean p=0.58). Ventricular AT and RT were non-different in NOb, PreOb and PostOb. Conclusion Obesity is associated with pro-arrhythmic electrophysiological remodelling, including steeper ventricular repolarisation gradients and slower atrial activation. At 6 months post-bariatric surgery, there was a reduction in ventricular repolarisation gradients though atrial conduction abnormalities persisted. These findings provide a mechanistic insight into obesity-related arrhythmic risks and its potential reversibility with weight loss surgery.

Premature atrial stimulation accentuates conduction abnormalities in cardiac surgery patients that develop postoperative atrial fibrillation

Backgroundpostoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the association between presurgical atrial conduction abnormalities and POAF has not been investigated clinically during premature atrial S1S2 stimulation. This clinical study sought to examine whether intraoperative premature atrial stimulation reveals increased areas of slowed and/or blocked conduction in patients that develop POAF. MethodsHigh-density intraoperative epicardial left atrial mapping was conducted in 20 cardiac surgery patients with no prior history of atrial fibrillation (AF). In 20 patients, 6 (30%) developed POAF. A flexible-array of 240-electrodes was placed on the posterior left atrial wall in between the pulmonary veins. Activation maps were generated for sinus and premature atrial S1S2 stimulated beats. The area of conduction block (CB), conduction delay (CD) and the combination of both (CDCB) for conduction velocity < 0.1, 0.1 ≤ x < 0.2 and < 0.2 m/s, respectively were quantified. ResultsFor a premature atrial S2 beat with shortest cycle length captured, conduction velocity maps revealed a significantly higher area for CD (13.19 ± 6.59 versus 6.06 ± 4.22 mm2, p = 0.028) and CDCB (17.36 ± 8.75 versus 7.41 ± 6.39 mm2, p = 0.034), and a trend toward a larger area for CB (4.17 ± 3.66 versus 1.34 ± 2.86 mm2, p = 0.063) in patients who developed POAF in comparison to those that remained in the sinus. Sinus and S1 paced beats did not show substantial differences in abnormal conduction areas between patients with and without POAF. ConclusionIn comparison to sinus and S1 beats, premature atrial S2 beats accentuate conduction abnormalities in the posterior left atrial wall of cardiac surgery patients that developed POAF.

Atrial Fibrillation (AF) and Ibrutinib, a Monocentric Experience: Should Cardiological Evaluation be a Guide in Clinical Practice?

IntroductionReported prevalence of AF in patients with chronic lymphocytic leukemia (CLL) on ibrutinib is approximately 5-10%. Management of AF in ibrutinib treated patients represents a multidisciplinary and challenging clinical need. Despite therapeutic advances, substantial morbidity and mortality still remain, and preventive or therapeutic strategies need to be implemented. Older age, male gender, arterial hypertension (AH) and valvular heart disease have recently been recognized as strong predictors of AF on ibrutinib. A clear relationship exists between an enlarged left atrium (LA), assessed by transthoracic echocardiography (TTE), and incidence of AF. LA dysfunction at ibrutinib start has been suggested as a predictor of AF: it helps identifying a selected cohort of patients who may benefit from strict follow-up and preventive strategies to reduce incidence of AF and associated complications. To date no prospective clinical trials have been conducted.AimTo analyse cardiovascular predictors and incidence of AF in a monocentric population of CLL patients on ibrutinib and in regular cardio-oncologic follow-up.MethodsFrom June 2014 to June 2017 we prospectively evaluated CLL patients requiring ibrutinib treatment at our Institution. Before starting therapy a full cardiovascular evaluation including accurate history, clinical examination and assessment of concomitant cardiovascular risk factors and cardioactive therapy were performed by an expert cardio-oncologist. All patients underwent non-invasive instrumental investigations performed by the same clinician: baseline electrocardiography (ECG) was used for rhythm documentation and TTE was focused on studying LA size and function. In a selected group of patients a 24 hours ECG monitoring was performed.ResultsFourty-three patients on ibrutinib were evaluated for a median of 12 months (range 1-37). Male/female ratio was 2.07 (M/F 29/14) and median age was 71 years (range 54-86). AF occurred in 7 patients (16.3%) after a median period of 6 months from the beginning of ibrutinib. Before starting therapy 30 patients (69.8%) had at least one cardiovascular risk factor, with 23 (53.5%) suffering from AH and 27 (62.8%) having more than one cardiovascular comorbidity. Twenty-three patients (53.5%) were regularly taking at least one cardioactive drug. We observed male gender and AH (p=0.009) to be significantly related to incidence of AF (p=0.04). One or more pre-existent cardiovascular comorbidity was found to be a strong predictive factor for AF (p=0.03). Concomitant cardioactive therapy and incidence of AF failed to show a significant correlation. Analysing TTE data, a strong predictive value of increased LA linear dimensions (p 0.02) and area (p 0.03) clearly emerged. Sixteen patients (37.2%) were evaluated through prolonged ECG-monitoring. We observed a trend to significance (p=0.07) of a higher maximal heart rate (HR) (109,5±0,7) reached in AF patients compared to those in stable sinus rhythm (73,35±30,6): higher HR, uncovering an increased sympathetic tone, is known to be a risk factor for AF. No significant correlation emerged between occurrence of AF and atrial conduction abnormalities recorded by baseline ECG.ConclusionsDue to the widespread use of ibrutinib in CLL population prompt recognition of AF high risk patients represents an emerging issue.As reported in literature, male sex and AH significantly correlate with AF development. LA enlargement represents a strong predictive factor for AF and TTE can reliably be used as a non-invasive exam to detect early signs of atrial dysfunction. In our cohort AF has occurred in a slightly higher percentage of patients treated with Ibrutinib than in literature. This finding, especially if validated in a larger CLL cohort, can suggest that silent, undetected AF is a common and a often underdiagnosed event in older patients with multiple risk factors. These initial results support a systematic cardiologic monitoring and AF screening program. Proper cardiological evaluation aims to identify patients at higher risk of AF. Educating patients to early recognize adverse events and behave accordingly to clinician's instructions allow to avoid unnecessary drug suspension. Comorbidity control and implementation of cardioactive therapy by an expert cardio-oncologist, preventing LA dilation and dysfunction, could be pursued as a means of reducing AF on ibrutinib. DisclosuresNo relevant conflicts of interest to declare.

The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome.

Apamin-sensitive small-conductance calcium-activated potassium (SK) current (IKAS) plays an important role in cardiac repolarization under a variety of physiological and pathological conditions. The regulation of cardiac IKAS relies on SK channel expression, intracellular Ca2+, and interaction between SK channel and intracellular Ca2+. IKAS activation participates in multiple types of arrhythmias, including atrial fibrillation, ventricular tachyarrhythmias, and automaticity and conduction abnormality. Recently, sex dimorphisms in autonomic control have been noticed in IKAS activation, resulting in sex-differentiated action potential morphology and arrhythmogenesis. This review provides an update on the Ca2+-dependent regulation of cardiac IKAS and the role of IKAS on arrhythmias, with a special focus on sex differences in IKAS activation. We propose that sex dimorphism in autonomic control of IKAS may play a role in J wave syndrome.

Atrial Conduction Disorders.

Atrial conduction disorders result from impaired propagation of cardiac impulses from the sinoatrial node through the atrial conduction pathways. Disorders affecting interatrial conduction alter P-wave characteristics on the surface electrocardiogram. A variety of P-wave indices reflecting derangements in atrial conduction have been described and have been associated with an increased risk of atrial fibrillation (AF) and stroke. Interatrial block (IAB) is the most well-known of the different P-wave indices and is important clinically due to its ability to predict patients who are at risk of the development of AF and other supraventricular tachycardias. P-Wave Axis is a measure of the net direction of atrial depolarization and is determined by calculating the net vector of the P-wave electrical activation in the six limb-leads using the hexaxial reference system. It has been associated with stroke and it has been proposed that this variable be added to the existing CHA2DS2-VASc score to create a P2-CHA2DS2-VASc score to improve stroke prediction. P-Terminal Force in V1 is thought to be an epiphenomenon of advanced atrial fibrotic disease and has been shown to be associated with a higher risk of death, cardiac death, and congestive heart failure as well as an increased risk of AF. P-wave Dispersion is defined as the difference between the shortest and longest P-wave duration recorded on multiple concurrent surface ECG leads on a standard 12-lead ECG and has also been associated with the development of AF and AF recurrence. P-wave voltage in lead I (PVL1) is thought to be an electrocardiographic representation of cardiac conductive properties and, therefore, the extent of atrial fibrosis relative to myocardial mass. Reduced PVL1 has been demonstrated to be associated with new-onset AF in patients with coronary artery disease and may be useful for predicting AF. Recently a risk score (the MVP risk score) has been developed using IAB and PVL1 to predict atrial fibrillation and has shown a good predictive ability to determine patients at high risk of developing atrial fibrillation. The MVP risk score is currently undergoing validation in other populations. This section reviews the different P-wave indices in-depth, reflecting atrial conduction abnormalities.

Abstract 17255: Premature Atrial Stimulation Reveals Increased Conduction Slowing and Block in Cardiac Surgery Patients That Develop Postoperative Atrial Fibrillation

Introduction: Postoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is highly associated with increased morbidity and mortality. The relation of presurgical left atrial (LA) conduction abnormalities and POAF during intraoperative premature atrial stimulation (S1S2) pacing is investigated and reported. Hypothesis: Intraoperative premature atrial stimulation reveals increased areas of slowed or blocked conduction in patients that develop POAF. Methods: High-density intraoperative epicardial mapping was conducted in 20 cardiac surgery patients with no history of preoperative atrial fibrillation (AF) both in sinus rhythm (SR) and during S1S2 pacing. A flexible array comprised of 240 electrodes was placed on the posterior LA wall in between the pulmonary veins. For each patient, the area of conduction block (CB), conduction delay (CD) and combined conduction delay and block (CDCB) for conduction velocity &lt;0.1 m/s, 0.1 - 0.2 m/s and &lt;0.2 m/s, respectively were quantified. Results: In 20 patients, 6 (30%) developed POAF. As shown in the Figure, conduction maps revealed the presence of significantly higher areas of CD (13.2±6.6% vs. 6.1±4.2%, p=0.03) and CDCB (17.5±8.7% vs. 7.4±6.4%, p=0.03), and a trend toward larger CB (4.2±3.8% vs. 1.3±2.9%, p=0.09) in patients that developed POAF for premature atrial beat S2 compared to patients that remained in SR after cardiac surgery. S1 paced beats and SR did not show significant differences in abnormal conduction percentages between patients with and without POAF. Conclusions: Premature atrial stimulation accentuates conduction abnormalities in cardiac surgery patients that develop POAF, revealing a pre-surgical substrate that may indicate greater risk for post-surgical atrial arrhythmias.

Provocation testing is irreplaceable to uncover or refute Brugada syndrome – an electrocardiographic validation study during ajmaline provocation

Abstract Background A Brugada syndrome (BrS) diagnosis is made upon documenting its characteristic type-1 ECG abnormality, being either spontaneously present or provoked by drug challenge, in the absence of co-morbidities resulting in similar ECG characteristics. In patients without type-1 ECG but in whom a suspicion of BrS exists, several ECG characteristics have been proposed that could aid in distinguishing BrS from non-BrS, particularly in individuals with incomplete right bundle branch block. Purpose To validate the diagnostic value of ECG characteristics that were previously proposed. Methods For this retrospective study, ECGs were evaluated from consecutive patients suspected of BrS who underwent ajmaline testing (n=1392). Baseline ECG and peak-effect ECG were analyzed with the MEANS software. Parameters considered were P, PR, QRS, S, JT, QT and QTc durations (all in ms), J and S amplitudes (both in mV), and QRS and T axes (both in °). ECG evaluations also included b-angles (in °) and duration of the base of a triangle (DBT) at 0.5 mV from the r' (in ms) in right precordial leads (V1, V2, V1ic3, V2ic3). Results Diagnostic type-1 ECGs were uncovered in 345 subjects and 1047 subjects had a negative test. Patients with BrS had significantly more atrial and ventricular conduction abnormalities (P, PR, QRS, and S duration) at baseline; these differences, except in PR duration, were aggravated upon ajmaline administration. In particular, the b-angle (e.g., V1: 28° [20; 46.5] versus 18° [12; 24], p&amp;lt;0.01) and DBT (e.g., V1: 130 ms [89; 214] versus 65 ms [42; 92.3], p&amp;lt;0.01) were significantly larger at baseline in patients with BrS, however, only with modest diagnostic value (area-under-the-curve 0.67–0.80). The optimal b-angle cut-off value based on the ROC curves to rule out BrS was determined at an angle of &amp;gt;15°, negative predictive values ranged from 78.6–95.5 and sensitivities ranged from 80–98.1% among different leads. Conclusions Patients with BrS show more baseline ECG abnormalities and display more conduction slowing upon ajmaline infusion. The b-angle and DBT do not demonstrate strong enough diagnostic characteristics to serve as a stand-alone diagnostic tool. Drug provocation tests remain necessary for diagnosing BrS in patients without a spontaneous type-1 ECG. Funding Acknowledgement Type of funding source: None

Temporal Trends in the Incidence and Outcomes of Pacemaker Implantation After Transcatheter Aortic Valve Replacement in the United States (2012-2017).

BackgroundNationwide studies documenting temporal trends in permanent pacemaker implantation (PPMI) following transcatheter aortic valve replacement (TAVR) are limited.Methods and ResultsWe selected patients who underwent TAVR between 2012 and 2017 in the National Readmission Database. The primary end point was the 6‐year trend in post‐TAVR PPMI at index hospitalization and at 30, 90, and 180 days after discharge. The secondary end point was the association between PPMI and in‐hospital mortality, stroke, cost, length of stay, and disposition. Among the 89 202 patients who underwent TAVR, 77 405 (86.8%) with no prior pacemaker or defibrillator were included. Patients who required PPMI had a higher prevalence of atrial fibrillation (43.6% versus 38.7%, P<0.001) and conduction abnormalities (28.4% versus 15.3%, P<0.001). The incidence of PPMI during index admission increased from 8.7% in 2012 to 13.2% in 2015, and then decreased to 9.6% in 2017. The incidence of inpatient PPMI within 30 days after discharge increased from 0.5% in 2012 to 1.25% in 2017 (P trend<0.001). Inpatient PPMI beyond 30 days remained rare (<0.5%) during the study period. After risk adjustment, PPMI was not associated with in‐hospital mortality or stroke but was associated with increased nonhome discharge, longer hospitalization, and higher cost. The incremental expenditure associated with post‐TAVR PPMI during index admission increased from $9.6 million to $72.2 million between 2012 and 2017.ConclusionsAfter an upward trend, rates of PPMI after TAVR in the United States stabilized at ~10% in 2016 to 2017, but there was a notable increase in PPMI within 30 days after the index admission. PPMI was not associated with increased in‐hospital morbidity or mortality but led to longer hospitalization, higher cost, and more nonhome discharges.

Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality

BackgroundClinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. ObjectivesThe purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. MethodsPatients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. ResultsHigher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. ConclusionsThese findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.

Early Detection of Left Ventricular Subclinical Systolic Dysfunction in Hypertensive Patients: Speckle Tracking at Rest and after Dobutamine Stress Echocardiography Study

Abstract Background: Hypertension is one of the major cardiovascular risk factor that may result in heart failure. Two-D transthoracic echocardiography (2-D TTE) recognizes reduction in left ventricular systolic function in late stages of the disease course, so early detection is of paramount importance. Objective: Our study intended to evaluate feasibility of speckle-tracking echocardiography (STE) to provide additional perceptions for early detection of hypertension induced left ventricular systolic dysfunction. Patient and Methods: We enrolled 40 hypertensive patients, 21 women (52.5%) their mean age was 54.55±9 years and 20 normotensive age and gender matched control individuals (10 women, their mean age was 53.20±12.06 years). All had normal left ventricular systolic function by 2-D TTE. STE performed at rest and low dose dobutamine. Patients with significant ischemic or valvular heart disease as well as atrial fibrillation, conduction abnormalities and diabetes excluded. Results: Systolic blood pressure was significantly higher in the hypertensive group patients (138.50±10.27 mmHg vs. 120.50±7.76 mmHg, respectively; P = <0.001). Compared to control group, hypertensive patients experienced significantly impaired global longitudinal STE at rest (-18.08±1.63% versus 20.50±1.52% respectively; P<0.001) and at low-dose dobutamine (-19.11±1.75% versus 22.61±1.88% respectively; P<0.008). Conclusion: Speckle tracking echocardiography increases the sensitivity in detecting subclinical cardiac involvement in early stages of hypertension compared to conventional 2-D echocardiography.