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Background The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. Hypothesis We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. Methods We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age 35 years (group B, n = 68). Echocardiographic indices were measured before head‐up tilt test (HUTT). Results A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2, p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p 3 recurrences (82.0% vs. 50.1%, p

Objective: Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optimal medical therapies. This study aimed to identify evolutionarily conserved lesion-based regulatory signaling networks in diabetic versus nondiabetic conditions during the development of atherosclerosis in an initial translational effort to provide insights for targets. Approach and Results: Serial 3-mm coronary artery segments of hypercholesterolemic Yorkshire swine and diabetic-hypercholesterolemic swine were characterized as mild, moderate, or severe phenotypic manifestations of coronary atherosclerosis based on histopathologic examination. Lesional RNA sequencing was performed (n=3–8 lesions per group) corresponding to increasing phenotypic severity. Differentially expressed genes, transcription factors, upstream regulators, and hubs were validated using the NanoString technology and a human atherosclerotic specimen cohort. Despite similar stage histopathologic characterization of lesions, genome-wide transcriptomics revealed gene sets and nodal signaling pathways uniquely expressed in diabetic lesions including signaling pathways for Th17, IL (interleukin)-17F, TWEAK (TNF [tumor necrosis factor]-related weak inducer of apoptosis), CD27, and PI3K/Akt. In contrast, pathways of nondiabetic lesions involved TREM-1 and Th1 and Th2 responses during the initiation stage, whereas networks for mitochondrial dysfunction, oxidative phosphorylation, and lipid metabolism emerged with progression. RNA sequencing data were validated in a human atherosclerosis specimen cohort using machine learning algorithms. F8 , MAPKAPK3 , and ITGB1 emerged as powerful genes for clustering diabetic versus nondiabetic lesions and for separating different degrees of atherosclerosis progression. Conclusions: This study identifies evolutionarily conserved gene signatures and signaling pathways in a stage-specific manner that successfully distinguishes diabetes- and non–diabetes-associated atherosclerosis. These findings establish new molecular insights and therapeutic opportunities to address accelerated atherosclerotic lesion formation in diabetes.

In syncopal patients without underlying structural disease, we sought to investigate the association of Adenosine Plasma Levels (ADP) with the clinical presentation of neurally mediated syncope (NMS) and the outcomes of Head-Up Tilt Table Test (HUTT) and Adenosine test (ADT).We studied 124 patients with different clinical types of NMS, i.e., Vasovagal (VVS, n=58), non-prodromes (NPS, n=18), or situational syncope (SS, n=48), using a standard protocol including HUTT and ADT. During HUTT, ADP was measured in the supine position, at table tilting and in syncope.Baseline ADP did not differ among groups. ADP at syncope were higher in NPS (n=5) compared to VVS (n=20): 0.23 vs. 0.12 μΜ, p=0.03, and SS (n=22): 0.04 μΜ, p=0.02. In NPS, ADP increased from supine to syncope (n=5): 0.15 vs. 0.23 μΜ, p=0.04. In VVS, ADP increased only from supine to tilt position: 0.11 vs. 0.14 μΜ, p=0.02. In SS, ADP did not change during HUTT. In positive vasodepressor HUTT, ADP increased from supine to tilt position (p=0.002) and at syncope (p=0.01). In SS, 20.0% exhibited cardioinhibitory HUTT vs. 6.8% in other forms of syncope (p=0.04). In SS, 22.9% manifested positive ADT vs 6.6% in other types of syncope (p=0.012).The subset of NPS patients with positive HUTT, show excessive ADP release at the time of syncope. This may explain the lack of prodromes in this form of syncope. Such observations contribute to the understanding of distinct profiles of clinical forms of syncope and may differentiate the management approach accordingly.

Background and aims: Clinical atherosclerosis manifestations are different in women compared to men. Since endothelial shear stress (ESS) is known to play a critical role in coronary atherosclerosis development, we investigated differences in anatomical characteristics and endothelial shear stress (ESS)–related plaque growth in human coronary arteries in men compared to women. Methods: 1183 coronary arteries (male/female: 944/239) from the PREDICTION study were studied for differences in artery/plaque and ESS characteristics, and ESS-related plaque progression (6–10 months follow-up) among men and women and after stratification for age. All characteristics were derived from IVUS-based vascular profiling and reported per 3 mm-segments (13,030 3-mm-segments (male/female: 10,465/2,565)). Results: Coronary arteries and plaques were significantly smaller in females compared to males; but no important differences were observed in plaque burden, ESS and rate of plaque progression. Change in plaque burden was inversely related to ESS (p

Background There is no consensus on the most efficient catheter ablation (CA) strategy for patients with atrial fibrillation (AF). The objective of this study was to compare the efficacy and safety of different CA strategies for AF ablation through network meta-analysis (NMA). Methods A systematic search of PubMed, Web of Science, and CENTRAL was performed up to October 5th, 2020. Randomized controlled trials (RCT) comparing different CA approaches were included. Efficacy was defined as arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of 6 months. Results In total, 67 RCTs (n = 9871) comparing 19 different CA strategies were included. The risk of recurrence was significantly decreased compared to pulmonary vein isolation (PVI) alone for PVI with renal denervation (RR: 0.60, CI: 0.38–0.94), PVI with ganglia-plexi ablation (RR: 0.62, CI: 0.41–0.94), PVI with additional ablation lines (RR: 0.8, CI: 0.68–0.95) and PVI in combination with bi-atrial modification (RR: 0.32, CI: 0.11–0.88). Strategies including PVI appeared superior to non-PVI strategies such as electrogram-based approaches. No significant differences in safety were observed. Conclusions This NMA showed that PVI in combination with additional CA strategies, such as autonomic modulation and additional lines, seem to increase the efficacy of PVI alone. These strategies can be considered in treating patients with AF, since, additionally, no differences in safety were observed. This study provides decision-makers with comprehensive and comparative evidence about the efficacy and safety of different CA strategies. Systematic review registration PROSPERO registry number: CRD42020169494.

Background Heart failure with reduced ejection fraction (HFrEF) is a disease that confers significant morbidity and mortality to patients. Patients suffer from increased arrhythmia burden; lethal ventricular arrhythmias are frequent. Iron deficiency (ID) is increasingly recognized as a common comorbidity that constitutes a further detriment to patients' cardiorespiratory capacity and an independent prognosticator of mortality. ID treatment with intravenous ferric carboxymaltose (IV FCM) has proven beneficial, improving QoL and exercise capacity in HFrEF patients with ID. Iron depletion is linked to disturbed myocyte electromechanical balance, especially in HF. However, the role of IV FCM arrhythmic burden in HFrEF patients with ID has not been examined. Purpose Investigate the effect of IV FCM treatment on the functional capacity, QoL and arrhythmic burden of in HFrEF patients with ID and cardiac implantable electronic devices (CIED). Methods HFrEF patients with ID and CIEDs were recruited from our outpatient HF clinic. CIED telemetry revealed their arrhythmic burden for the 6 months preceding IV FCM administration. Patients underwent physical examination, blood testing, 6-minute walk testing, 24-hour Holter monitoring, QoL quantification with the KCCQ and EQ-5D-5L questionnaires and repeat CIED telemetry at study baseline (IV FCM administration) and 6-months. Microvolt T-wave alternans (MTWA) and heart rate turbulence (HRT) slope and onset were quantified through the 24-hour ECG recordings. HRT results are reported as HRT0, HRT1 or HRT2 based on the number of abnormal HRT parameters. Results So far, 83 (aged 68.3±8.7 years, 82% male) out of a total of 96 recruited patients have completed the 6-month follow-up (3 of 83 died before the 6-month mark). Picture 1 contains patients' baseline characteristics and 6-month results. Patients received a mean of 1.43±0.61g of IV FCM during the follow-up period, which significantly ameliorated iron status (Picture 1). The 6MWD increased by 32.4m (95% CI: 14.7–47.2, P Conclusions After 6 months of IV FCM treatment, HFrEF patients with ID had significantly better exercise capacity and quality of life. Regarding arrhythmias, a tentative improvement in CIED- and Holter-derived arrhythmic markers was observed. Extended follow-up of a larger sample size will provide further insight for the effect of IV FCM in these patients' arrhythmic burden. Funding Acknowledgement Type of funding sources: None. Baseline and 6-month resultsHospitalization curves pre-post IV FCM

Background/Introduction The neurohumoral profile underlying the manifestation of reflex syncope remains incompletely understood. Adenosine plasma (ADP) and adenosine receptor (ADR) levels may differentiate the outcomes of head-up tilt table test (HUTT) and adenosine test (ADT) but their role in the diagnostic evaluation of patients with syncope has yet to be determined. Purpose We sought to assess the ADP and ADR levels in patients without structural heart disease who underwent HUTT and ADT tests as part of the diagnostic workup of syncope. We specifically investigated differences in the outcomes of the HUTT and ADT tests as well as to the ADP levels during HUTT. Methods HUTT and ADT were performed as per the standard protocols. ADT was considered positive in the event of asystole >6 seconds or heart block for >10 seconds after intravenous Adenosine 0.15 mg/kg administration in the supine position. ADP levels were assessed at three timepoints during the HUTT: at baseline (supine), immediately after bed tilt and, in cases of a positive HUTT, at the time of syncope. Patients were categorized in quintiles of very low, low, intermediate, high and very high baseline ADP levels. We also assessed the A2A ADR levels of monocytes. Results We prospectively analyzed 124 patients (71 women, age 46.78±21.01 years). ADT was positive in 12.9% of patients and HUTT in 44.4% of patients. Patients with very low baseline ADP levels (lowest quintile) more frequently presented with a positive ADT (odds ratio [OR] 4.08, 95% Confidence Interval [CI] 1.40 to 13.13, p20 min) had lower ADR levels (80.88±238.98 vs 89.43±96.08 MFI, p Conclusion(s) Baseline ADP levels are related to the outcome of ADT while an ADP increase immediately after bed tilt and in syncope is evident in vasodepressor response to HUTT. Higher ADR levels are related to positive ADT and negative HUTT. Lower ADR levels are associated with more delayed onset of syncope during HUTT. ADP and ADR levels warrant further investigation as they may characterize a subset of patients with specific responses to ADT and HUTT and may be implicated in the pathophysiology of reflex syncope. Funding Acknowledgement Type of funding sources: None.

Background Diastolic function assessment in patients with hypertrophic hearts and preserved ejection fraction (EF) is a rather challenging task. Combined plotting of deformation parameters against other indices, especially left ventricular (LV) volume, may reflect diastolic function components of the hypertrophic myocardium. Purpose Aim of this study was i) to apply strain-volume loops (SVLs) in hypertrophic cardiomyopathy (HCM) patients based on simultaneous frame-by-frame strain and volume changes' recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to investigate potential correlations between these loops, traditional diastolic function indices and phenotypic features of HCM (thickness, obstruction and fibrosis) that may also reflect myocardial “stiffness”. Methods We included 40 HCM patients (54.1±14.3 years, 82.5% male, maximum wall thickness 19.3±4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build an SVL. Peak of radial, longitudinal and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), strain to end-diastolic volume (EDV) ratios (Rs/V, Ls/V, Cs/V) as well as the extent of systolic-diastolic uncoupling (difference between systolic and diastolic strain for the same volume) (panel A) were computed for the analysis. Left atrial volume index (LAVI), E/E' and tricuspid regurgitation velocity (TRvel) were measured to define diastolic dysfunction (DD) stage. Burden of fibrosis was evaluated by LGE extent in CMR slices. Results All HCM patients had preserved EF (60.5±5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO>30 mm Hg at rest). Mean LV mass index was 78.9±14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2±4.5% of LV mass. Concerning SVLs the following values were recorded for radial (Rsp 30.8±9.8%, RsSl 0.4±0.13 and Rs/V 0.25±0.09), longitudinal (Lsp −9.4±3.7%, LsSl 0.12±0.06 and Ls/V 0.08±0.04) and circumferential deformation (Csp −14.2±3.5%, CsSl 0.18±0.05 and Cs/V 0.11±0.03). Traditional isolated diastolic indices (E/E', LAVI, TRvel and DD stage) did not present significant correlations with SVL parameters or HCM phenotypic features. However, potentially “stiffer” hearts (combination of increased LVMI and fibrosis) presented a leftward transition of longitudinal SVLs, which also became wider (greater uncoupling) (panel B). Conclusions Traditional diastolic indices show modest only correlations with SVLs or HCM phenotypic characteristics, necessitating new approaches to DD of HCM patients. SVLs seem to be a promising-innovative tool for indirect assessment of myocardial “stiffness” and diastolic function. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Atrial fibrillation (AF) is the most common arrhythmia and is associated with high risk of morbidity and mortality. In many patients, AF is of episodic character (paroxysmal AF – PAF), which makes the identification of these patients during sinus rhythm (SR) challenging. Purpose The aim of the present study is to compare the performance of beat-to-beat P-wave analysis with P-wave indices used as predictors of PAF, such as P-wave duration, area, voltage, axis, terminal force in V1, inter-atrial block or orthogonal type, in identifying patients with history of PAF during sinus rhythm. Methods Standard 12-lead ECG and 10-minute orthogonal ECG recordings were obtained from 40 consecutive patients with short history of PAF under no antiarrhythmic medication and 60 age- and sex- matched healthy controls. The P-waves on the 10-minute recordings were analyzed on a beat-to-beat basis and classified as belonging to a primary or secondary morphology according to previous study. Wavelet transform used to further analyze P-wave orthogonal signals of main morphology on a beat-to-beat basis. Results 38 out of 327 studied features were found to differ significantly among the two groups. These features were tested for their diagnostic ability and receiver operating characteristic curves were ploted. Only 3 of them performed adequetly, with an area under curve (AUC) above 0.65; Two of them came from morphology analysis (percentage of beats following main morphology in axis X and Y) and one from wavelet analysis (max energy in high frequency zone -Y axis). Among standard P-wave indices, P-wave area in lead II was the one with the highest AUC (0.64). Conclusion Novel indices derived from beat-to-beat analysis outperform stadard P-wave markers in identifying patients with PAF history during sinus rhythm. Funding Acknowledgement Type of funding sources: None. ROC curves of most significant featuresAUC characteristics of P-wave indices

Early identification of patients at risk for paroxysmal atrial fibrillation (PAF) is essential to attain optimal treatment and a favorable prognosis. We compared the performance of a beat-to-beat (B2B) P-wave analysis with that of standard P-wave indices (SPWIs) in identifying patients prone to PAF. To this end, 12-lead ECG and 10 min vectorcardiogram (VCG) recordings were obtained from 33 consecutive, antiarrhythmic therapy naïve patients, with a short history of low burden PAF, and from 56 age- and sex-matched individuals with no AF history. For both groups, SPWIs were calculated, while the VCG recordings were analyzed on a B2B basis, and the P-waves were classified to a primary or secondary morphology. Wavelet transform was used to further analyze P-wave signals of main morphology. Univariate analysis revealed that none of the SPWIs performed acceptably in PAF detection, while five B2B features reached an AUC above 0.7. Moreover, multivariate logistic regression analysis was used to develop two classifiers—one based on B2B analysis derived features and one using only SPWIs. The B2B classifier was found to be superior to SPWIs classifier, B2B AUC: 0.849 (0.754–0.917) vs. SPWIs AUC: 0.721 (0.613–0.813), p value: 0.041. Therefore, in the studied population, the proposed B2B P-wave analysis outperforms SPWIs in detecting patients with PAF while in sinus rhythm. This can be used in further clinical trials regarding the prognosis of such patients.

Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) - the most common sustained cardiac arrhythmia - while not a life-threatening condition itself, leads to an increased risk of stroke and high rates of mortality. Early detection and diagnosis of AF is a critical issue for all health stakeholders. Purpose The aim of this study is to compare the performance of standard P-wave indices with beat-to-beat P-wave morphological variability parameters in identifying patients with history of Paroxysmal Atrial Fibrillation (PAF). Methods Three-dimensional 1000Hz ECG digital recordings of 10 minutes duration were obtained from a total of 39 PAF patients and 60 healthy individuals. Following artifacts and ectopic beats removal, P‑wave morphology analysis was performed based on the dynamic application of the k‑means clustering process and main and secondary P-wave morphologies were identified. The percentage of P-waves following the main or the secondary morphology in each lead was calculated, as well as established indices such as Advanced Interatrial Block, P-wave duration, axis and area, P-wave Terminal Force in lead V1 and Orthogonal Leads Type 1, 2 or 3. Results 9 out of 24 parameters studied, were found to be significantly different between the two groups. 7 of these indices were derived from morphology analysis and 2 from P-wave area. Logistic regression revealed that the percentage of P-waves allocated to main morphology in X axis performed better than all other indices in identifying patients with PAF history from healthy volunteers in terms of total accuracy and F1 measure. Conclusion P-wave beat-to-beat morphology analysis can identify PAF patients during normal sinus rhythm more efficiently than standard P-wave indices. Abstract Figure.

Funding Acknowledgements Type of funding sources: None. Background The emergence of digital health has revolutionized most aspects of healthcare. Meanwhile, atrial fibrillation (AF) remains the most common sustained arrhythmia associated with high morbidity and impaired quality of life. Patient-perceived treatment burden can be further optimized by digital health interventions utilizing smartphone technology. The MyAlgos platform is an integrated software system designed to enhance the remote management and communication between the patient and the healthcare practitioner. The mobile application encourages patient self-management through educational modules and tools to improve medication adherence. The web-based platform allows the health care practitioner to receive live updates on patient status and design personalized self-care management plans. Purpose To investigate whether the use of the MyAlgos platform by AF patients is safe and improves the quality of self-care, quality of life (QoL), and hospitalization rate. Methods We designed a single-center, randomized, controlled, prospective, open-label, pilot study to compare the effect of the use of the full-feature MyAlgos platform version versus a stripped-down control version of the platform on the QoL, medication adherence and hospitalization rate in patients with paroxysmal AF. The full version of the e-medicine platform includes active patient education, communication with the medical team, medication reminders as well as the full record of clinically significant data such as heart rate and blood pressure. Specialized algorithms monitor patient data and alert physicians for potential AF episodes. The control version only allows the recording of patient’s heart rate. Results A total of 80 patients with paroxysmal AF were randomized in a 1:1 ratio to receive either the full or the control version of the MyAlgos Platform. The mean age of all patients, 53 (66%) male, was 58.1 ± 9.1 years. Hypertension and diabetes were present in 47 (59%) and 7 (9%) respectively. At baseline, the majority of patients had AF-related symptoms classified as European Heart Rhythm Association (EHRA) I (45%) or EHRA II (24%), while the mean Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) score was 70.1 ± 17.0. Between the two groups, there were no statistically significant differences in the baseline characteristics of the participants. Conclusion The emPOWERD trial will provide data on the impact of a novel e-medicine platform on the QoL, medication adherence and hospitalizations of patients with paroxysmal AF. We anticipate better outcomes for the subjects receiving the full version of the MyAlgos platform, allowing it to positively affect the further management of paroxysmal AF. Abstract Figure. The MyAlgos e-medicine Platform

Introduction: Plaque natural history is related to local shear stress, and shear stress has been shown to be heterogeneously distributed along the length of individual plaques. We investigated the longitudinal spatial heterogeneity of plaque progression/regression/quiescence in human coronary arteries. Methods: 591 coronary arteries from 302 patients with coronary disease who presented with an acute coronary syndrome from the PREDICTION study were investigated for local plaque progression/regression/quiescence patterns in non-culprit plaques after 6-10 month FU. Arterial geometry was derived from angiography/IVUS-based vascular profiling and reported in 3 mm segments. Plaques were defined as >3 consecutive segments with maximal wall thickness>0.5 mm. Plaque progression was defined as >5% increase, regression as Results: 5658 3mm-segments of 661 plaques were analyzed. Plaque burden changes ranged from -22% to +20%. Among all plaques, 56% showed segments with plaque progression, 60% with regression and 96% with quiescence. On average, 17% of the plaque length displayed plaque progression, 20% regression and 63% quiescence. The presence and number of natural history features (progression, regression, quiescence) within the individual plaques were significantly related to plaque length using logistic mixed model regression analysis (figure). Conclusions: Coronary plaque natural history is extremely heterogeneous along the length of an individual plaque. These observations may explain why revascularization of a focal severe obstruction in the ISCHEMIA trial did not affect clinical outcomes, since remaining high-risk plaque up- or down-stream from the revascularization may have led to future cardiac events.

Background/Introduction The effects of the left atrial and ventricular function in the pathophysiology of reflex syncope remain elusive. Head-up tilt table test (HUTT) is frequently used in the diagnostic workup of patients with syncope, but the outcomes of HUTT have not been attributed to any anatomical or functional cardiac characteristics. Purpose We sought to assess the effects of anatomical and functional echocardiographic features of the left atrium and the left ventricle at rest in the clinical presentation of syncope and the outcomes of HUTT. Methods We investigated patients with a history of syncope and symptoms suggestive of reflex syncope who underwent HUTT. Specific echocardiographic indices of left cardiac morphology and function were assessed at rest. The patients were divided into two groups, those who presented with syncopal episodes at age 35 years (group B). Results In 119 patients (age 46.75±21.17 years, 69 women), patients in group A exhibited a higher chance for numerous (>3) syncopal episodes (odds ratio [OR] 3.4, 95% Confidence Interval [CI] 1.41 to 7.93, p Conclusion(s) Patients with a younger age of onset and recurrent syncopal episodes manifest smaller dimensions of the left atrium with distinct patterns of diastolic performance and better reservoir and booster function. These findings may indicate a more pronounced susceptibility of this group of patients to preload reduction, thereby triggering the mechanism of reflex syncope. Funding Acknowledgement Type of funding source: None

Background Atherosclerosis manifests itself differently in women compared to men. Since the pathophysiology of atherosclerotic plaques is known to be related to endothelial shear stress (ESS), it was hypothesized that female compared to male coronary arteries demonstrate a different i) ESS and ii) ESS related plaque progression. Methods 1183 coronary arteries (male/female:944/239) from the PREDICTION trial were studied for differences in vessel geometry (plaque area (PA) and lumen area (LA)), hemodynamic parameters (flow, minimal ESS over 90 degree arc (minESS) and maximal ESS over 90 degree arc (maxESS)) and ESS related plaque progression (1 year follow up) measured as change in maximal plaque thickness and plaque burden comparing female to male arteries. Arterial geometry and ESS measures were derived from IVUS-based vascular profiling and reported per 3 mm segments. For plaque progression studies minESS was subdivided into low, mid and high (1.7 Pa). To test statistical differences univariate anova or linear mixed models were used. Results 13030 3mm-segments (m/f: 10.465/2565) were analyzed. Female compared to male coronary arteries were smaller and presented with less plaque area (Table I). No differences in average ESS, minESS and maxESS were found for male versus female coronary arteries, partly explained by the lower flows in female arteries (Table I). The ESS-related plaque growth showed for both sexes an significant inverse relationship between maximal wall thickness (Figure, left) and plaque burden (Figure, right) and the three minESS categories. However, ESS-related plaque growth was not different for male vs females. Conclusion Our data demonstrated that vessel and plaque size are smaller in female compared to male coronary arteries. However, ESS and ESS related plaque progression were not different. Shear stress related plaque progression Funding Acknowledgement Type of funding source: None

Background Combined plotting of deformation parameters against other indices [e.g. arterial pressure, left ventricular (LV) volume] might offer additional information about different diseases. Especially in hypertrophic cardiomyopathy (HCM) this approach might offer new insights into the various phenotypic and pathophysiologic features of this entity. Purpose Aim of this study was i) to apply strain-volume loops in HCM based on simultaneous frame-by-frame strain and volume changes' recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to investigate potential correlations between these loops and phenotypic features of HCM (including thickness, obstruction and fibrosis). Methods We included 40 HCM patients (54.1±14.3 years, 82.5% male, maximum wall thickness 19.3±4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build a strain–volume loop. Peak of radial, longitudinal, and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), and strain to end-diastolic volume (EDV) ratio (Rs/V, Ls/V, Cs/V) were computed for the analysis (panel A). Additionally, burden of fibrosis (percentage of LV mass) was defined by LGE extent (>5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60.5±5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO>30 mm Hg at rest). Mean LV mass index was 78.9±14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2±4.5% of LV mass. Concerning strain-volume loops the following values were recorded for radial (Rsp 30.8±9.8%, RsSl 0.4±0.13 and Rs/V 0.25±0.09), longitudinal (Lsp −9.4±3.7%, LsSl 0.12±0.06 and Ls/V 0.08±0.04) and circumferential deformation (Csp −14.2±3.5%, CsSl 0.18±0.05 and Cs/V 0.11±0.03). Among typical HCM characteristics tested (LV mass, LVOTO and LGE), only LV mass presented significant correlations with LsSl (r=−0.41, p Conclusions Strain-volume loop is an innovative application of 3D deformation imaging in HCM. According to this new non-invasive method, increase of LVMI in HCM is accompanied by less longitudinal contribution to stroke volume, whereas better systolic-diastolic coupling may exclude the presence of underlying fibrosis. Funding Acknowledgement Type of funding source: None

Background/Introduction Head-up tilt table test (HUTT) and Adenosine test (ADT) can be useful in the diagnostic evaluation of syncope. Adenosine plasma (ADP) and Adenosine receptor (ADR) levels may differentiate the outcomes of HUTT and ADT but their precise role in the risk stratification of patients with syncope remains elusive. Purpose We sought to assess the ADP and ADR levels in patients without structural heart disease who underwent HUTT and ADT tests as part of the diagnostic workup of syncope. We specifically investigated differences in the outcomes of the HUTT and ADT tests as well as to the ADP levels during HUTT according to the baseline ADP levels. Methods HUTT and ADT were performed as per the standard protocols. ADT was considered positive in the event of asystole >6 seconds or heart block for >10 seconds after intravenous Adenosine 0.15 mg/kg administration in the supine position. ADP levels (ppm/Um/L) were assessed at three timepoints during the HUTT: at baseline (supine), immediately after bed tilt and, in cases of a positive HUTT, at the time of syncope. Patients were categorized in terciles of low, intermediate and high baseline ADP levels. We also assessed the A2A ADR levels of monocytes. Results We prospectively analyzed 106 patients (62 women, age 46.87±20.63 years). ADT was positive in 14.2% of patients and HUTT in 47.2% of patients. Females were more likely to have low ADP levels (odds ratio [OR] 2.70, 95% Confidence Interval [CI] 1.04 to 6.94, p Conclusion(s) Baseline ADP levels may be related to the outcome of ADT and HUTT. ADP increases during HUTT except for patients with high baseline ADP. ADP and ADR levels warrant further investigation as they may characterize a subset of patients with specific responses to HUTT and may be implicated in the pathophysiology of reflex syncope. Funding Acknowledgement Type of funding source: None

Background A manually beat-to-beat P-wave analysis has previously revealed the existence of multiple P-wave morphologies in patients with paroxysmal Atrial Fibrillation (AF) while on sinus rhythm, distinguishing them from healthy, AF free patients. Purpose The aim of this study was to investigate the effectiveness of an Automated Beat Exclusion algorithm (ABE) that excludes noisy or ectopic beats, replacing manual beat evaluation during beat-to-beat P-wave analysis, by assessing its effect on inter-rater variability and reproducibility. Methods Beat-to-beat P-wave morphology analysis was performed on 34 ten-minute ECG recordings of patients with a history of AF. Each recording was analyzed independently by two clinical experts for a total of four analysis runs; once with ABE and once again with the manual exclusion of ineligible beats. The inter-rater variability and reproducibility of the analysis with and without ABE were assessed by comparing the agreement of analysis runs with respect to secondary morphology detection, primary morphology ECG template and the percentage of both, as these aspects have been previously used to discriminate PAF patients from controls. Results Comparing ABE to manual exclusion in detecting secondary P-wave morphologies displayed substantial (Cohen"s k = 0.69) to almost perfect (k = 0.82) agreement. Area difference among auto and manually calculated main morphology templates was in every case 0.99 (p Conclusion The use of the ABE algorithm does not diminish inter-rater variability and reproducibility of the analysis. The primary and secondary P-wave morphologies produced by all analyses were similar, both in terms of their template and their frequency. Based on the results of this study, the ABE algorithm incorporated in the beat-to-beat P-wave morphology analysis drastically reduces operator workload without influencing the quality of the analysis. Abstract Figure.

Background Atrial fibrillation (AF) - the most common sustained cardiac arrhythmia - while not a life-threatening condition itself, leads to an increased risk of stroke and high rates of mortality. Early detection and diagnosis of AF is a critical issue for all health stakeholders. Purpose The aim of this study is to identify P-wave morphology patterns encountered in patients with Paroxysmal AF (PAF) and to develop a classifier discriminating PAF patients from healthy volunteers. Methods Three-dimensional 1000Hz ECG signals of 5 minutes duration were obtained through the use of a Galix GBI-3S Holter monitor from a total of 68 PAF patients and 52 healthy individuals. Signal pre-processing, consisting of denoising, QRS auto-detection, and ectopic beats removal was performed and a signal window of 250ms prior to the Q-wave (Pseg) was considered for every single beat. P‑wave morphology analysis based on the dynamic application of the k‑means clustering process was performed. For those Pseg that were assigned in the largest cluster, the mean P-wave was computed. The correlation of every P-wave with the mean P-wave of the main cluster was calculated. In case that it exceeded a prespecified threshold, the P-wave was allocated to the main morphology. For the remaining P‑waves, the same approach was followed once again, and the secondary morphology was extracted (picture). The P-waves of the dominant morphology were further analyzed using wavelet transform, whereas time-domain characteristics were also extracted. A Support Vector Machine (SVM) model was created using the Gaussian Radial Basis Function kernel and the forward feature selection wrapper approach was followed. ECGs were allocated to the training, internal validation, and testing datasets in a 3:1:1 ratio. Results The percentage of P-waves following the main morphology in all three leads was lower in PAF patients (91.2 ±7.3%) than in healthy subjects (96.1 ±3.5%, p = 0.02). Classification between the two groups highlighted 7 features, while the SVM classifier resulted in a balanced accuracy of 91.4 ± 0.2% (sensitivity 94.2 ± 0.3%, specificity 88.6 ± 0.1%) Conclusion An Artificial Intelligence based ECG Classifier can efficiently identify PAF patients during normal sinus rhythm. Abstract Figure.

Purpose of Review: Excessive supraventricular ectopic activity (ESVEA), in the form of frequent premature atrial contractions (PACs) and runs of PACs, is commonly observed in clinical practice and is frequently considered to be benign. Yet, recent studies have demonstrated a link between ESVEA and adverse cardiovascular outcomes. The aim of this meta-analysis was to examine the association between ESVEA and the risk of atrial fibrillation (AF), stroke, and mortality. Recent Findings: A systematic search was performed in PubMed, EMBASE, and the Cochrane Library up to December 2017 to identify studies assessing adverse cardiovascular outcomes in patients with ESVEA, recorded on ambulatory electrocardiography. ESVEA was defined as a burden of PACs > 30 PACs/h or any runs of ≥20 PACs. The risk estimates for EVSEA and each clinical endpoint were pooled and analyzed separately. Results: Five studies comprising 7545 participants were included in this meta-analysis. The pooled analysis showed that ESVEA doubled the risk of AF (HR 2.19, 95% CI 1.70–2.82). ESVEA was also associated with a higher incidence of stroke (HR 2.23, 95% CI 1.24–4.02). Finally, ESVEA was associated with higher all-cause mortality (HR 1.61, 95% CI 1.25–2.07). Summary: Our meta-analysis found that ESVEA is closely associated with AF, stroke, and all-cause mortality. Further studies are required to examine the implication of therapeutic strategies in patients with ESVEA, in order to prevent potential subsequent adverse cardiovascular outcomes.

PURPOSE OF REVIEW Anatomic and morphologic features of high-risk coronary plaque have been identified by novel imaging modalities, but it has been less clear which ostensibly high-risk plaques will actually destabilize and cause a new cardiac event. Different plaques with different morphologies coexist within the same artery, but the impact of this heterogeneity on the natural history of coronary artery disease has not been extensively investigated. RECENT FINDINGS Coronary plaques exhibit remarkable heterogeneity of local morphological and blood-flow patterns, including endothelial shear stress (ESS), along their longitudinal axis, with important implications for the heterogeneous natural history of coronary disease. The natural history of individual plaques is considerably divergent, with most plaques, even ostensibly high-risk plaques, becoming quiescent and only a minority progressing to destabilize and precipitate a new clinical event. Local areas of proinflammatory low ESS appear to be an important condition for plaque destabilization. SUMMARY Characterization of an individual atherosclerotic plaque based on a snapshot of morphological features at a specific location, such as the minimal lumen diameter, may not be sufficiently comprehensive to accurately reflect the risk associated with that plaque. A detailed assessment of both anatomical and functional pathobiologic characteristics in the longitudinal plaque dimension may enhance our understanding of atherosclerosis progression and improve the management of individual patients with coronary artery disease.

Background The natural history of plaque growth is, among other systemic risk factors, related to the blood flow induced local shear stress. Especially at regions of low shear stress plaques are initiated. Upon plaque encroachment into the lumen, plaques will be exposed to high shear stress. Interestingly, it has been observed that individual plaques are very heterogeneous regarding the local shear stress exposure and remodeling patterns along the plaque length. However no information is available on the spatial heterogeneity of temporal changes in plaques burden. We studied the longitudinal spatial heterogeneity of plaque burden progression, regression, quiescence in human coronary plaques. Methods 591 coronary arteries from 302 patients with coronary artery disease who presented with an acute coronary syndrome from the PREDICTION study were investigated for local plaque progression, regression, quiescence patterns after 6–10 months follow up. Arterial geometry was derived from angiography/IVUS-based vascular profiling and reported in 3 mm segments. Plaques were defined as >3 consecutive segments with maximal wall thickness>0.5 mm. Plaque progression was defined as >5% increase, regression as Results 5658 3mm-segments of 661 plaques were analyzed. Plaque burden changes over time ranged from −22% to +20%, with an average of −0.4%±4% which was not significant different from 0. Among all plaques, 56% showed segments with plaque progression of more than 5%, 60% with plaque regression ( Conclusion Plaques are very heterogeneous in plaque progression patterns. Most of the plaques show within the plaque length simultaneously more than one plaque progression feature (segments that do not change in plaque burden, segments that regress or progress). The number of observed plaque progression features was related to the plaque length. Funding Acknowledgement Type of funding source: None

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality of patients with left ventricular (LV) systolic dysfunction and intra-ventricular conduction delay. However, its clinical outcomes are heterogeneous and not all patients show a beneficial response. Multisite pacing (MSP), by stimulating the myocardium from more than one locations, is a potential therapeutic option in patients requiring CRT. This article provides a current update in the methods and outcomes of MSP, as well as in challenges in this field and opportunities for further research and development. MSP can be delivered either with multiple leads or with quadripolar LV leads which can stimulate the LV from two separate sites. Initial results are promising but not always consistent across studies. Larger patient subgroups and longer follow-up duration are required for more conclusive evaluation of MSP. Routine use of MSP in clinical practice cannot be advocated at present. In selected patient subgroups, however, MSP could be considered. Newer devices and expanding knowledge are expected to facilitate the more widespread implementation of MSP and the assessment of its effects in the clinical outcomes of CRT.

Intracoronary hemodynamics play a pivotal role in the initiation and progression of the atherosclerotic process. Low pro-inflammatory endothelial shear stress impacts vascular physiology and leads to the occurrence of coronary artery disease and its implications.

Background/Introduction Head-up tilt table test (HUTT) and Adenosine test (ADT) are tools frequently used in the diagnostic workup of syncope. It has been suggested that patient responses to HUTT and ADT can be related to the plasma levels of Adenosine (ADPL) and Adenosine receptors (ADR). However, the exact type of association and the role of (ADPL) and ADR levels in the risk stratification and management of patients with syncope has not yet been clarified. Purpose We sought to assess the ADPL and ADR levels in patients without structural heart disease who underwent HUTT and ADT tests as part of the diagnostic workup of syncope. We specifically investigated differences with regards to the presence of a history of prodromal symptoms. Methods HUTT and ADT were performed as per the standard protocols. ADT was considered positive in the event of asystole >6 seconds or heart block for >10 seconds after intravenous Adenosine administration in a supine position at a dose of 0.15 mg/kg. ADPL were assessed at three timepoints during the HUTT: in the supine position, immediately after bed tilt and, in cases of a positive test, at the time of syncope. Furthermore, we assessed the A2A ADR of monocytes in the study patients. Results We prospectively analyzed 77 patients (48 women, age 47.05±21.10 years). ADT was positive in 16.7% of patients and HUTT in 49.4% of patients. ADPL in the supine position did not differ between patients with negative vs. positive ADT but showed a significant correlation with the body mass index (p=0.002). There was a trend for reduced ADPL at the tilt phase in patients with positive HUTT (0.32±0.89 vs. 0.42±0.77 ppm/Um/L, p=0.09). Of all patients, 60 (77.9%, 41 women, age 46.80±21.83 years) had reported a history of prodromal symptoms at syncope. In the subset of patients with prodromal symptoms, the ADL at the tilt phase were lower in patients with positive vs. negative HUTT (0.15±0.23 vs. 0.51±0.89, p Conclusion(s) Patients with prodromal symptoms and a positive HUTT demonstrate reduced ADPL at the tilt phase of HUTT preceding syncope. In these patients, ADPL in syncope correlate with the ADR. Adenosine plasma levels and receptors warrant further investigation and may predict the response to HUTT thereby contributing to the diagnostic evaluation and risk stratification of patients with syncope.

Objectives This study sought to determine whether indocyanine green (ICG)–enhanced near-infrared fluorescence (NIRF) imaging can illuminate high-risk histologic plaque features of human carotid atherosclerosis, and in coronary atheroma of living swine, using intravascular NIRF-optical coherence tomography (OCT) imaging. Background New translatable imaging approaches are needed to identify high-risk biological signatures of atheroma. ICG is a U.S. Food and Drug Administration–approved NIRF imaging agent that experimentally targets plaque macrophages and lipid in areas of enhanced endothelial permeability. However, it is unknown whether ICG can target atheroma in patients. Methods Eight patients were enrolled in the BRIGHT-CEA (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque) trial. Five patients were injected intravenously with ICG 99 ± 25 min before clinically indicated carotid endarterectomy. Three saline-injected endarterectomy patients served as control subjects. Excised plaques underwent analysis by intravascular NIRF-OCT, reflectance imaging, microscopy, and histopathology. Next, following ICG intravenous injection, in vivo intracoronary NIRF-OCT and intravascular ultrasound imaged 3 atheroma-bearing coronary arteries of a diabetic, cholesterol-fed swine. Results ICG was well tolerated; no adverse clinical events occurred up to 30 days post-injection. Multimodal NIRF imaging including intravascular NIRF-OCT revealed that ICG accumulated in all endarterectomy specimens. Plaques from saline-injected control patients exhibited minimal NIRF signal. In the swine experiment, intracoronary NIRF-OCT identified ICG uptake in all intravascular ultrasound–identified plaques in vivo. On detailed microscopic evaluation, ICG localized to plaque areas exhibiting impaired endothelial integrity, including disrupted fibrous caps, and within areas of neovascularization. Within human plaque areas of endothelial abnormality, ICG was spatially related to localized zones of plaque macrophages and lipid, and, notably, intraplaque hemorrhage. Conclusions This study demonstrates that ICG targets human plaques exhibiting endothelial abnormalities and provides new insights into its targeting mechanisms in clinical and experimental atheroma. Intracoronary NIRF-OCT of ICG may offer a novel, clinically translatable approach to image pathobiological aspects of coronary atherosclerosis. (Indocyanine Green Fluorescence Uptake in Human Carotid Artery Plaque [BRIGHT-CEA]; NCT01873716)

Aims The association of low endothelial shear stress (ESS) with high-risk plaque (HRP) has not been thoroughly investigated in humans. We investigated the local ESS and lumen remodelling patterns in HRPs using optical coherence tomography (OCT), developed the shear stress score , and explored its association with the prevalence of HRPs and clinical outcomes. Methods and results A total of 35 coronary arteries from 30 patients with stable angina or acute coronary syndrome (ACS) were reconstructed with three dimensional (3D) OCT. ESS was calculated using computational fluid dynamics and classified into low, moderate, and high in 3-mm-long subsegments. In each subsegment, (i) fibroatheromas (FAs) were classified into HRPs and non-HRPs based on fibrous cap (FC) thickness and lipid pool size, and (ii) lumen remodelling was classified into constrictive, compensatory, and expansive. In each artery the shear stress score was calculated as metric of the extent and severity of low ESS. FAs in low ESS subsegments had thinner FC compared with high ESS (89 ± 84 vs.138 ± 83 µm, P < 0.05). Low ESS subsegments predominantly co-localized with HRPs vs. non-HRPs (29 vs. 9%, P < 0.05) and high ESS subsegments predominantly with non-HRPs (9 vs. 24%, P < 0.05). Compensatory and expansive lumen remodelling were the predominant responses within subsegments with low ESS and HRPs. In non-stenotic FAs, low ESS was associated with HRPs vs. non-HRPs (29 vs. 3%, P < 0.05). Arteries with increased shear stress score had increased frequency of HRPs and were associated with ACS vs. stable angina. Conclusion Local low ESS and expansive lumen remodelling are associated with HRP. Arteries with increased shear stress score have increased frequency of HRPs and propensity to present with ACS.

BackgroundIf undetected, infrarenal Abdominal Aortic Aneurysm (AAA) growth can lead to rupture, a high-mortality complication. Some AAA patients exhibit inhomogeneous luminal contrast attenuation at first-pass CT angiography (CTA). This study assesses the association between this observation and aneurysm growth.MethodsSixty-seven consecutive pre-repair AAA CTAs were included in this retrospective study. The "Gravitational Gradient" (GG), defined as the ratio of the mean attenuation in a region-of-interest placed posteriorly to that in a region-of-interest placed anteriorly within the lumen of the aortic aneurysm on a single axial slice, and the maximum aneurysm diameter were measured from each CT data set. "AAA Contrast Inhomogeneity" was defined as the absolute value of the difference between the GG and 1.0. Univariate and multivariate logistic regression was used to assess the association of aneurysm growth >0.4 and>1.0cm/year to AAA Contrast Inhomogeneity, aneurysm diameter, patient characteristics and cardiovascular co-morbidities.ResultsAAA Contrast Inhomogeneity was not correlated to aneurysm diameter (p=0.325). In multivariable analysis that included initial aneurysm diameter and AAA Contrast Inhomogeneity, both factors were significantly associated with rapid aneurysm growth (initial diameter: p=0.029 and 0.011, and, AAA Contrast Inhomogeneity: p=0.045 and 0.048 for growth >0.4cm/year and >1cm/year respectively).ConclusionsAAA Contrast Inhomogeneity is a common observation in first-pass CTA. It is associated with rapid aneurysm growth, independent of aneurysm diameter.

Coronary atherosclerosis manifests differently in females (f) compared to males (m). Since plaque progression is related to endothelial shear stress (ESS), we hypothesized that female compared to male coronary arteries demonstrate differences in ESS pattern and ESS related plaque progression. 1164

Objective. This study aims to (i) translate, culturally adapt, and preliminarily validate the arrhythmia-specific Umea22 (U22) questionnaire and (ii) assess the impact of radiofrequency (RF) ablation and medical treatment on the quality of life of patients with supraventricular tachycardias (SVTs). Methods. A total of 140 patients with atrioventricular nodal re-entry tachycardia (AVNRT) and atrioventricular re-entry tachycardia (AVRT) were enrolled in the study. Of these, 100 patients underwent RF ablation (group A) and 40 patients were managed with antiarrhythmic medications (group B). Health-related quality of life (HRQoL) was assessed for both groups using the Short Form-36 Health Survey (SF-36) and the arrhythmia-specific Umea22 (U22) questionnaire at baseline and 3-month follow-up. Exploratory and confirmatory factor analyses were performed to assess the validity of the U22 questionnaire. Univariate comparisons of HRQoL scores between study timepoints and multivariate regression analyses adjusting for baseline confounders were conducted. Results. The factor analysis of the U22 questionnaire yielded a six-factor model (“burden of spells”; “heart contractility”; “character of spells”; “general/non-specific feeling”; “other specific somatic symptoms”; “fear”) with acceptable fit results. Patients of group A showed significant improvement in all SF-36 and U22 scores at 3 months’ follow-up compared to baseline (all p Conclusion. The Greek version of the U22 questionnaire is a valid tool to assess SVT-related symptoms. RF ablation appears to exert more pronounced beneficial outcomes on HRQoL of patients with SVTs compared to medical treatment. Prompt referral of patients with SVTs to specialist centers may favorably affect their quality of life and should be encouraged.

Treatment of coronary bifurcation lesions remains an ongoing challenge for interventional cardiologists. Stenting of coronary bifurcations carries higher risk for in-stent restenosis, stent thrombosis, and recurrent clinical events. This review summarizes the current evidence regarding application and use of biomechanical modeling in the study of stent properties, local flow dynamics, and outcomes after percutaneous coronary interventions in bifurcation lesions. Biomechanical modeling of bifurcation stenting involves computational simulations and in vitro bench testing using subject-specific arterial geometries obtained from in vivo imaging. Biomechanical modeling has the potential to optimize stenting strategies and stent design, thereby reducing adverse outcomes. Large-scale clinical studies are needed to establish the translation of pre-clinical findings to the clinical arena.