Structural Heart Disease Research Articles

Preventing unnecessary echocardiograms in de novo patients referred to the cardiology outpatient clinic using electrocardiogram-based deep learning

Abstract Introduction The growing demand on European echocardiography labs, driven by the rise in structural heart disease (SHD), is further complicated by a shortage of skilled sonographers, necessitating resource optimisation strategies. Electrocardiogram (ECG)-based deep learning models may assist in streamlining the echocardiography workflow. Purpose This study sought to develop a deep learning model capable of identifying patients at very low risk of SHD in a population of de novo patients referred to the cardiology outpatient clinic. Methods We identified all adult patients who underwent a 12-lead ECG and echocardiogram at a Dutch academic teaching hospital between 2011 and August 2023. Echocardiogram outcomes were extracted from reports, including left ventricular systolic dysfunction (LVSD), left ventricular dilatation (LVD), aortic stenosis (AS), aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR), from which a composite outcome label was derived. A cohort of patients newly referred to our cardiology outpatient clinic with a primary complaint of chest pain, dyspnea, palpitations, dizziness, a murmur, or an abnormal ECG was held out as a test set, while the remaining dataset was split patient-wise into training (90%) and validation (10%) sets. A convolutional neural network was trained using only the ECG tracing as input and the composite label as outcome. Results We included 92,210 ECG-echo pairs from 44,785 patients (19,717 female) with 25,543 (27.7%) abnormal ECG-echo pairs. Among 2724 newly referred patients in the test set, 210/1389 males (15.1%) and 201/1335 females (15.1%) were diagnosed with SHD. In the test set, the model for predicting composite outcome demonstrated an area-under-the-curve, negative predictive value, and specificity of 0.74 (95% confidence interval [CI] 0.71-0.79), 0.94 (95% CI 0.92-0.95), and 0.47 (95% CI 0.45-0.49), respectively. Conclusion This study demonstrates the feasibility of employing deep learning models based solely on electrocardiogram (ECG) data to identify patients at very low risk of structural heart disease (SHD). Further validation and prospective studies are warranted to confirm the generalizability and clinical utility of our findings in diverse patient populations and healthcare settings.

Sex-specific association of NT-proBNP with clinically inapparent structural heart disease in the general population: results from the STAAB study

Abstract Background Guidelines recommend echocardiography in subjects beyond defined levels of natriuretic peptides. The ACC/AHA guidelines on heart failure (HF) state echocardiographic signs of structural heart disease (SHD) that define the precursor stage B of heart failure. Purpose To study the age- and sex-specific association between echocardiographically assessed structural heart disease (echoSHD) and NT-proBNP levels in the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Study participants were recruited between 12/2013 and 10/2017 from the source population without preceding HF diagnosis, stratified for sex and age (30-79 years). For this analysis, we excluded participants with previously diagnosed coronary artery disease. EchoSHD was accepted if one of the following criteria, diagnosed according to current echo guidelines, was detectable at echocardiography: left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction, moderate-to-severe LV valve disease, and LV diastolic dysfunction. Results Of 4,649 subjects analysed (93.6% of STAAB participants, age 30-79 years, 53.5% women), 863 (18.6%) had echoSHD. NT-proBNP depended strongly on age and sex (figure). Frequencies of echoSHD varied between women (23.0%) and men (13.5%; P<0.001). EchoSHD was associated with increased NT-proBNP levels in both women (geometric mean ratio 1.18, 95%CI 1.09–1.27, P<0.001; figure) and men (ratio 1.62, 1.46–1.79, P<0.001); P<0.001 for different ratios in both sexes. Of note, age did not influence these ratios as well as their difference (P=0.34 and P=0.95, resp.). Conclusion Clinically inapparent echoSHD was associated with higher levels of NT-proBNP, of a magnitude that was relevant in men. The sex difference in the strength of this relationship might be due to different pathophysiological processes leading to SHD and ultimately HF in women and men. It might also indicate the need for adopted definitions of echoSHD in women. Our results further point towards the need of age- and sex-specific NT-proBNP thresholds.NTproBNP according to sex, age, and SHD

Normal values and reference ranges for quantitative assessment of myocardial first-pass perfusion by spectral computed tomography. From the Cadami-Spectral study

Abstract Background Spectral computed tomography (SCT) can generate iodine concentration maps according to the tissue iodine uptake, serving as a surrogate marker of organ perfusion. Thus, assessment of the iodine distribution maps derived from SCT allows to detect deviations in normal myocardial perfusion. As of present, reference ranges for the iodine concentration in each myocardial segment of the left ventricle (LV) derived from the first-pass perfusion have not been published. Purpose To provide normal values of first pass perfusion in individuals without coronary artery disease (CAD). Additionally, we explored whether these values could vary according to gender, contrast dosing or the cardiac cycle phase assessed. Methods From October 2021 to January 2024, we retrospectively identified patients who underwent a CT Cardiac Angiography (CTCA) and had no evidence of CAD or structural heart disease. Subjects were scanned using a dual-layer SCT, following a standard local protocol which included a weight-based contrast medium dosing of 0.8 mL/Kg. Iodine density maps were reconstructed using the MCA filter at a phase of 78%. An additional sample of 18 subjects who received a dosing of contrast of 1 mL/Kg and 16 cases scanned using a systolic acquisition and reconstructed at phase of 35% were also included. Spectral reconstructions were combined with tissue segmentation to obtain the spatial distribution of iodine along the myocardium. Mean, median and standard deviations values of density of iodine (mg/ml) were quantified for each segment following the AHA-17 segment model. Results Perfusion data from 80 woman (median age: 60 [IQR: 54-65.6] years) and 47 males (median age: 47 [IQR: 43 – 54] years) were analysed. Despite receiving higher dose of contrast (67.9 vs 59.8 mL; p < 0.05), male subjects exhibited lower iodine density values in the myocardium compared to females (median concentration per segment 1.58 vs 2.01 mg/dL, p<0.001; figure 1). Notably, the volume of the LV myocardium was higher in male than in women (143 mL vs 92 mL, p<0.001). These differences could be partially explained in a mixed model considering the ratio contrast dose/myocardium volume (b = 1.500, p < 0.001). Higher contrast dosing (1 mL/Kg vs 0.8 mL/kg) correlated with higher iodine density values in the myocardium (2.03 vs 1.83 mg/dL, respectively; p = 0.023). No differences were noted when comparing reconstructions at systole vs diastole (1.86 vs 1.80 mg/dL, respectively; p = 0.484). Reference range values of each myocardial segment are listed in table 1. Conclusions Significant gender discrepancies are detected in the analysis of first-pass myocardial perfusion. These variations can be partially explained by differences in the LV myocardium volume. Our findings provide applicable reference ranges of the iodine concentration in myocardium at first pass perfusion in controls without coronary or structural heart disease.

Insights into the aetiology and temporal trends in cardiac mortality in the young: a 21-year review of national and registry data in the united kingdom

Abstract Background An accurate representation of the incidence and aetiology of cardiac and sudden cardiac death (SCD) is vital for healthcare policymakers to effectively allocate resources for preventative strategies. Purpose We aimed to report on the incidence and causes of cardiac and SCD among individuals under 35-years-old in England and Wales for 21 years (2001-2021), with a focus on identifying any temporal trends. Methods Annual mortality data from the Office for National Statistics (ONS) pertaining to cardiovascular (CV) and possible CV deaths in individuals under 35-years-old were analyzed using International Classification of Diseases-10 codes. Deaths were categorized into four-classes: A1- definitive cardiac deaths without identifiable structural heart disease (consistent with sudden arrhythmic death syndrome, SADS); A2- definitive cardiac deaths with identified structural heart disease; A3- definitive cardiac deaths with indeterminate cause; and B- potential cardiac deaths. Incidence rates were computed based on annual ONS census data. Additionally, insights were gleaned from the Cardiac Risk in the Young Centre for Cardiac Pathology (CRYCCP) nationwide registry. Results The mean annual number of definitive cardiac deaths (classes A1+A2+A3) was 414 (SD 27.4), resulting in an incidence of young cardiac and SCD of 1.68/100,000 individuals/year. Ischaemic heart disease (28.4%), cardiomyopathies (25.9%), and SADS (21.8%) were the most prevalent cardiac conditions. Cardiomyopathies and SADS related mortality peaked in the 10-to-19 age group, while ischaemic heart disease peaked in the 30-to-35 age group. A mean of 573 (SD 76.6) possible cardiac deaths (class B) occurred, these primarily included ill-defined causes (33.5%), epilepsy (32.4%), sudden infant death syndrome (24.2%), and drowning (7%). Definitive and possible cardiac deaths showed a male preponderance (male to female ratios: 2.3:1 and 1.6:1, respectively). A declining trend in cardiac mortality was observed with a 1.3% (95%CI: 1.0%-1.7%) incidence rate reduction/year (p<0.001). This was associated with a 2.5% annual incidence rate reduction for deaths attributed to structural heart disease (p<0.001), but an 8.5% annual incidence rate increase for deaths attributed to SADS (p<0.001). These trends corelated with increasing numbers of deaths referred to the CRYCCP where an expert cardiac pathologist diagnosed SADS in over 52% of cases. Conclusions Over 21 years in England and Wales, national datasets suggest the incidence of young cardiac and SCD is 1.68/100,000/year, with a small but appreciable declining mortality trend. The rise in SADS rates and contemporaneous decline in deaths attributed to structural heart disease may signify increased awareness and accessibility to expert cardiac pathologists. Ensuring accurate mortality coding is crucial for thoroughly assessing first-degree family members in cases of suspected inherited cardiac conditions.

Cardiac motion in patients with ventricular tachycardia: potential implications for the treatment of patients candidates to stereotactic arrhythmia radio-ablation (STAR)

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has proven to be a valid alternative treatment for refractory ventricular tachycardia (VT) in patients who are unsuitable to undergo standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. There is increased research activity on better understanding the complex and fast motion of the heart and on reducing radiation toxicity. Purpose In the context of an in silico study to evaluate the feasibility of STAR with protons in patients with VT, the initial findings related to cardiac motion on the first 10 patients are here presented. Methods Prior to CA, each patient underwent ECG gated CT scans in expiratory breath-hold, with and without contrast and reconstructed at 30% (systole) and 80% (diastole) of the cardiac R-R cycle. Contouring of the ablation target as a clinical target volume (CTV) for proton treatment planning was performed based on a standard electrophysiological study with 3D eletroanatomical mapping. Two different treatment plans were created: the first with only the diastolic CTV as target (gated treatment), the second including both diastolic and systolic CTVs to create an Internal Target Volume (ITV) in the hypothesis of non-gated treatment. Robust optimization was used to create the Planning Target Volume (PTV). Results The target volumes used for treatment planning are given in Table 1. The median CTV was 10.90 (2.93-36.94) cm3 for diastole and 14.26 (1.73-36.31) cm3 for systole. These volumes are somewhat smaller than those reported in patients treated previously with STAR: this difference may be due to the fact that no respiratory motion was included in the target contour and that the study population includes many patients referred for ventricular ectopic beats without structural heart disease, where the ablation target is expected to be smaller as compared to patients with VT in structural heart disease. Despite a small median difference between the diastolic and systolic CTV of 0.53 (0.03-9.61) cm3, the ITV approach resulted in a median increase in volume compared to the largest of the two CTVs of 29 % (1%-44%). When considering the proton range uncertainty and potential errors in patient positioning (PTV), the target is this time enlarged by a factor 2.9 (1.9-3.9). This data indicates that both cardiac motion and uncertainties in patient positioning before treatment will have a large impact on the treatment volume thus affecting the amount of surrounding tissue exposed to radiation. Conclusion The ablation target contour at systole and diastole are of similar magnitude but their non-overlap results in a large increase in treated volume when radiation delivery is not gated for cardiac motion. Further analysis shall investigate on a case-by-case basis the potential reduction in risk of healthy tissue toxicity with cardiac-gated proton delivery.Table 1

The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy.

The SCN5A gene encodes the alpha subunit of the cardiac sodium channel, which plays a fundamental role in the generation and propagation of the action potential in the heart muscle. During the past years our knowledge concerning the function of the cardiac sodium channel and the diseases caused by mutations of the SCN5A gene has grown. Although initially SCN5A pathogenic variants were mainly associated with channelopathies, increasing recent evidence suggests an association with structural heart disease in the form of heart muscle disease. The pathways leading to a cardiomyopathic phenotype remain unclear and require further elucidation. The aim of the present review is to provide a concise summary regarding the mechanisms through which SCN5A pathogenic variants result in heart disease, focusing in cardiomyopathy, highlighting along the way the complex role of the SCN5A gene at the intersection of cardiac excitability and contraction networks.

Ablation of tachyarrhythmias with zero fluoroscopy technique in patients under 18 years of age. 4-year follow-up

Abstract Introduction Arrhythmias occur in 5% of preschool patients, with an increased incidence in adolescence. Treatment of rapid arrhythmias or tachyarrhythmias may include ablation of the cardiac structures. Catheter ablation is the possibility of producing an injury to the endocardium by administering energy through the catheter in a limited and controlled way to those parts of the cardiac tissue where tachycardias are initiated and/or maintained, it is performed through a catheter connected to an energy source, which is introduced through arterial or venous lines. to the chambers of the heart. In recent years, different technological innovations have emerged aimed at better understanding and identifying the substrate of arrhythmia, thus facilitating catheter navigation and reducing the need for fluoroscopy. Different studies have shown that ablation without fluoroscopy is feasible, especially in the context of supraventricular tachycardia. Objective To describe the clinical characteristics of pediatric patients undergoing ablation with zero fluoroscopy in a pediatric hospital of the National Medical Center of the West (CMNO). Material and Methods descriptive and retrospective study, the clinical characteristics of 42 patients who were taken to arrhythmia ablation by zero fluoroscopy technique at the CMNO IMSS pediatric hospital for 4 years in the period from June 2019 to May 2023 were analyzed. Results A total of 42 patients, of which 55% were male, with a median age of 13 years with a range of 4 to 17 years, the median weight was 49 kg with a standard deviation of +- 19.5 kg. Of the arrhythmias treated, supraventricular tachycardia accounted for 97.6% of cases and ventricular arrhythmias for 2.4%. Of the supraventricular tachycardias, atrioventricular reentrant tachycardia accounted for 68.35%. 25 cases with a diagnosis of Wolff Parkinson White with 28% of the right lateral location, followed by the right postoseptal 24%. Structural heart disease was present in 31% of the cases, the most frequent being Ebstein's anomaly (41.7%). Immediate success rate was 97.3%, with recurrence in the first three months of follow-up of 5.4%. A Kaplan-Meier curve was performed, showing a success rate of 77.3% at 12 months of follow-up. No statistical significance was found in patients with congenital heart disease and recurrence, p=0.698 and with Fisher's exact test, p=0.530. Conclusion Ablation of cardiac arrhythmias in children under 18 years of age without the use of fluoroscopy is an effective procedure, obtaining an immediate success rate of 97.3% of patients, 77.3% of patients are free of recurrence one year after treatment. There was no statistical significance for patients with congenital heart disease who might have recurrence.

Machine-learning models to predict the risk of recurrent VT following catheter ablation in patients with structural heart disease

Abstract Background Ventricular tachycardia (VT) is a life-threatening arrhythmia that can complicate structural heart disease. While catheter ablation is effective in treating this condition, the recurrence of VT after the procedure continues to be a concern. Consequently, there is a need for a reliable system to evaluate the likelihood of arrhythmia recurrence following an ablation. Objective To predict recurrence or repeat ablation after a VT catheter ablation procedure using machine learning (ML) models. Methods We conducted a single-center, retrospective study of all patients undergoing catheter ablation for scar-related VT between 2012 and 2022. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, echocardiograms, detailed procedural characteristics, and outcomes. Python version 3.8.5 for exploratory data analysis (EDA) and visualization. Using six different ML models from the training set (90:10 split), we used 34 variables to predict the primary outcome, including VT recurrence or repeat catheter ablation. The accuracy of these models was compared using ROC curves based on their performance on the test set. Results Out of 508 VT ablation procedures, 261 experienced a recurrence. Support Vector Classifier (SVM) performed the best, having an AUC of 0.73, followed by logistic regression at 0.69 (Figure A). SVM yielded sensitivity, specificity, positive and negative predictive values of 0.73, 0.73, 0.79, and 0.67, respectively. The F1 score was 0.70. Among the factors with the highest feature importance in the model, the most influential variable was the proceduralist’s experience level, followed by QRS width at baseline, LVEF, and patient’s age (Figure B). Conclusion Our model can predict recurrent VT after ablation with reasonable accuracy, outperforming the existing clinical risk scores significantly. Larger training sample sizes will help achieve more robust ML models and improve predictive accuracy further.Figure A: ROC curve depicting the AUROCB. Feature importance graph

Right atrial strain: the hidden proof of bi-atrial cardiomyopathy in AF patients?

Abstract Background Although assessment of left atrium (LA) abnormalities has been extensively studied in atrial fibrillation (AF), structural and functional changes in the right atrium (RA) have remained almost unexplored in this context. Purpose We investigated the role of bi-atrial strain in patients with AF undergoing catheter ablation (CA). Methods Fifty-six consecutive patients undergoing catheter ablation of AF were prospectively studied with speckle-tracking echocardiography and electrophysiological study, before and after CA (median follow-up: 7±3 months). A group of 32 subjects undergoing CA of paroxysmal atrioventricular node-reentrant tachycardia, without structural heart disease, served as control group. Results Patients with AF had worse LA, but also RA strain indexes compared to controls [RA strain parameters: peak RAS reservoir (pRASr): 22.1±12.6 vs 29.8±12.7%, p=0.009; RA dispersion: SD-regional-RA-time-to-peak (SD-regional-RA-TTP): 0.048±0.015 vs 0.038±0.009, p=0.020)]. Patients with persistent AF showed similar LA strain values, but worse RA strain indexes, compared to patients with paroxysmal AF (pRASr: 24.8±12.1 vs 15.9±11.7%,p=0.017; SD-regional-RA-TTP:0.043±0.023 vs 0.062±0.030, p=0.016). RA function showed a significant relation with both LA strain and volume indexes and with abnormal LA electroanatomical substrate (pRASr and pLASr, Pearson correlation: r 0.594, p< 0.001; pRASr and low-voltage LA area: -0.316, p=0.018). RA, but not LA, parameters were found significantly reduced in patients with AF recurrence post-CA compared to those who maintain sinus rhythm (pRASr: 14.1±11.7 vs 24.6±13.5, p=0.039; SD-regional-RA-TTP: 0.054±0.031 vs 0.032±0.010, p=0.002), while the only independent clinical predictor of AF recurrence remained cardiovascular risk profile (CHA2DS2 VASc Score: HR 1.47,CI 1.003-2.158, p= 0.048). Conclusion RA function, as assessed by strain imaging, resulted progressively impaired in worse subtypes of AF, showing a strong correlation with bi-atrial mechanical and electroanatomical parameters, and associated with AF recurrences post-ablation.Graphical Abstract

ACE inhibitor and angiotensin receptor blocker use during pregnancy: data from the ESC Registry of pregnancy and cardiac disease (ROPAC)

Abstract Background and Aims Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester due to the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and to evaluate the impact on perinatal outcomes. Methods The Registry of Pregnancy and Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. In addition, the perinatal outcomes of patients who stopped ACE-Is and/or ARBs before pregnancy were assessed. Results ACE-I (n=35) and/or ARB (n=8) were used in 42 (0.7%) of the 5739 ROPAC pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p=0.021), had chronic hypertension (31% vs 6%, p<0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p<0.001). No pregnancy terminations due to fetal anomaly were reported. ACE-I use during the first trimester was independently associated with an increased risk of congenital anomaly (OR 3.1; 95% CI 1.0-9.3). No adverse fetal or neonatal effects were seen when ACE-I and/or ARB were discontinued prior to pregnancy. Conclusions ACE-Is and ARBs are seldom used during pregnancy and based on our data, ACE-Is should also be avoided in the first trimester due to a higher risk of congenital anomalies. Preconception counseling is crucial to discuss the potential risks of these medications, and to evaluate the clinical condition and, if possible, the woman can be switched to an alternative medication.

3D target definition and initial results from the electroanatomic substrate-guided stereotactic ablative radiotherapy for refractory ventricular tachycardia (ELSTAR-VT)

Abstract Background/introduction Noninvasive stereotactic radiotherapy (STAR) is an emerging transmural ablative therapy for refractory ventricular tachycardia (VT). Delineation of the arrhythmogenic gross target volume (GTV) relies on electrical (exit and isthmus) VT characteristics and anatomical scar detailing. 17-AHA segmental approaches or eyeballing techniques are adopted to transfer the GTV to the treatment planning CT. An individualized 3D GTV delineated with ADAS3D based on the areas of interest of each modality could lead to a smaller GTV compared to 17-AHA segmental approaches. Purpose We investigated whether our workflow using ADAS3D for the delineating of the GTV renders smaller GTV compared to 17-AHA segmental approaches whilst remaining effective for VT treatment during follow-up. Methods We targeted 3D-personalized GTV with STAR in patients with refractory VT in structural heart disease. Electroanatomical detailing was achieved by combining high-resolution invasive and noninvasive (ECG imaging during noninvasive programmed stimulation) mapping, combined with wall thickness analyses by cardiac CT. After coregistration in ADAS3D, a 3D DICOM-radiation therapy file including the delineated target volume was generated and transferred into the free-breathing and respiration-corrected 4D CT scan. Standard STAR using a single-fraction of 20-25 Gy was applied. We compared conventional (17-AHA segmental approaches) versus 3D-based GTV demarcation, and assessed VT burden and procedural safety. Results From January 2023 to February 2024 STAR was successfully performed in three patients (all male, mean age 73±1 years, two ischemic cardiomyopathy, one laminopathy) with persistent VT despite ≥2 catheter-based (endocardial/epicardial) ablation procedures. The 3D-derived GTVs showed a statistical trend towards smaller volumes compared to conventional segmental delineation (11±4 versus 21±3 cm3, p=0.07). VT burden and ICD therapy was reduced by 100% over 9 patients-months (8-week blanking period). No acute or subacute adverse events occurred. One patient died of progressive heart failure. Conclusion 3D-individualized target volume annotation may hold promise for effective and safe STAR employment.ELSTAR workflow

Monocytic mitochondrial dysfunction and impaired monocytic bioenergetic profile in patients with heart failure symptoms in post-COVID syndrome

Abstract Introduction/Purpose Approximately 35% of COVD-19 patients have persistent symptoms similar to congestive heart failure. The so called post-Covid syndrome, which includes symptoms such as dyspnea and angina pectoris, is presumably associated to cellular metabolism and oxidative stress, yet whether mitochondrial function is impaired in post-COVID patients is still unclear. We thus investigated the mitochondrial function in monocytes of symptomatic post-COVID patients compared to matched controls. Methods Patients with persisting cardiac symptoms in their daily activities and diagnosed with post-COVID syndrome (n=14) were recruited and matched with unaffected controls (n=10) for age, sex and cardiovascular risk factors. Structural heart disease was excluded through cardiac work-up (echocardiography, functional stress testing and when necessary coronary angiography). Primary monocytes were isolated using negative selection method. The bioenergetic status of the monocytes was assessed using the Agilent Seahorse XF Cell Mito Stress Test without and after modulation of reactive oxygen species (ROS) by buthionine sulfoximine (BSO). Results CD14++ monocytes isolated from post-COVID patients showed non-significantly increased basal proton leak (p=0.57), reduced maximal respiration, and reserved respiratory capacity (p=0.19) compared to controls. Induction of additional oxidative stress by ROS modulation revealed a significantly impaired bioenergetic profile of monocytes in terms of reduction of basal respiration (3-fold, p=0.0005), maximal respiration (4-fold, p=0.004) and spare respiratory capacity (5-fold, p=0.008). Conclusions We demonstrated an impaired bioenergetic profile of CD14++ monocytic mitochondria in patients suffering from heart failure symptoms following COVID-19 infection. Whether the findings provide a novel biomarker for measuring systemic oxidative stress conditions or whether there is a direct link between symptoms of post-COVID disease and monocytic function needs to be addressed in further studies.

Accuracy of a non-invasive mapping system for the localisation of re-entrant VT site of origin and its relationship to myocardial scar on cross-sectional imaging

Abstract Introduction View in ventricular onset (VIVO) is a non-invasive mapping system used for localising the site of earliest activation in ventricular arrhythmia, utilising a mathematical algorithm, patient specific cardiac model (constructed using cross-sectional imaging data), 3D images of the patient’s torso (for localising surface electrodes), and a 12-lead electrocardiogram (ECG).(1, 2) Several publications have examined its role in the localisation of premature ventricular contractions (PVCs), and a 5 patient case series assessed its role in scar related re-entrant VT.(1-4) However, its validity in a larger cohort and of the relationship to the relevant myocardial scar has not been investigated. Objective Assess the accuracy of the VIVO mapping system in localising the VT-SoO for patients with scar related re-entrant VT and its relationship to the relevant myocardial scar on cross-sectional imaging. Methods 20 patients with structural heart disease (18 ischaemic cardiomyopathy (ICM), 1 dilated cardiomyopathy (DCM), 1 hypertrophic cardiomyopathy (HCM)) (Male n=18, 63±14 years) and recent cross-sectional cardiac imaging, were recruited over a 16-month period (table 1). All patients had a clinical indication for VT ablation and were on optimal medical therapy, 19 had an implantable cardiac defibrillator. Invasive electro-anatomical mapping (EAM) was performed with the Advisor HD Grid multipolar catheter and maps were generated using Omnipolar electrograms (EGMs). The VT-SoO was identified using an activation- or pace-map by an experienced operator and the location defined using the American heart association’s 17 segment model of the left ventricle during the procedure.(5) VIVO maps were reviewed by a second independent operator and a segment allocated, scar segments were obtained from cross-sectional imaging. A "complete match" was defined as exact segment concordance between allocated segments, "partial match" as adjacent segments, and "no match" if it does not satisfy either of those requirements. Results Mean left ventricular ejection fraction was 35.5 ± 10.6%. Mean procedure time was 242 ± 70 minutes, with a mean ablation time of 20 ± 11.1 minutes. A total of 32 re-entrant VTs were mapped. The VT exit site was identified in all cases (11 activation-map; 21 pace-map). A complete match between the EAM and VIVO map was seen in 75% of VTs and partial match in a further 15% (table 2). The VT-SoO was located withing the myocardial scar (or directly adjacent to is) in 83% of accurately mapped VTs. Procedural success (defined as freedom from device treated episodes) was seen in 90% of patients at mean follow up of 7.3 ± 4.7 months. Conclusion VIVO non-invasive mapping system was able to accurately map the VT-SoO in scar dependent VT, and identify the relevant myocardial scar as seen on cross sectional imaging. Further research assessing its ability to accurately identify relevant ablation targets is ongoing.

The association between exercise-induced ventricular premature contractions and long-term mortality in patients without coronary artery disease

Abstract Background/Introduction The treadmill exercise test is widely used clinical test to determine cardiovascular risk and mortality, regardless of clinical risk factors (1). ST-segment changes detected in the exercise test are shown to predict myocardial ischemia (2) and premature ventricular complexes (PVCs) are frequently observed during exercise stress testing (3). Exercise-related PVC is observed in 14% to 23% of healthy individuals without significant heart disease (4,5). The literature on the role of PVCs observed during treadmill exercise testing in predicting prognosis is controversial. Purpose Therefore, we aimed to evaluate the clinical results of PVCs seen during exercise testing in patients who had been diagnosed with non-obstructive coronary artery disease after coronary angiography. Methods The study population consisted of 1624 consecutive patients who were considered high risk according to the Duke treadmill risk score and had no significant stenosis on coronary angiogram from January 2016 to April 2021. Patients with previous history of coronary revascularization, previous myocardial infraction, heart failure, moderate or severe heart valve disease, congenital heart disease, cardiomyopathy, bundle branch block, and left ventricular hypertrophy were excluded from the study. The primary endpoints of the study were long-term all-cause mortality of patients who had PVCs during the exercise test or during the resting phase. Results The long-term mortality was observed in 53 patients out of 1624 patients in the mean follow-up of 47 months. PVCs was observed in 293 (18.7%) patients without long-term mortality, while PVCs was observed in 24 (45.3%) patients with long-term mortality (p<0.001). The model adjusted for all covariates showed that the presence of PVCs in the recovery phase (p<0.007, HR (95% CI) 2.244 (1.244 – 4.047)) and advanced age (p<0.001, HR (95% CI) 1.194 (1.143 – 1.247)) were associated with long-term all-cause mortality (Figure 1). Considering Kaplan-Meier curve, individuals with PVCs in recovery had significantly higher risk of long-term mortality compared with those with without PVCs (log-rank statistic: 22.47, p<0.001) (Figure 2). Conclusion(s) The study highlights that PVCs monitored in the recovery phase of the treadmill exercise test were associated with long -term mortality in patients without structural heart disease and coronary artery disease.Figure 2Figure 1

Ablation of right ventricular endocavitary arrhythmias

Abstract Background The right ventricular moderator band-papillary muscle (RV MB-PM) complex has a rich subendocardial network of purkinje fibers which can lead to ventricular arrhythmias (VA)1. Catheter ablation of such arrhythmias is procedurally challenging and there remains limited studies on long-term procedural success. Purpose We aimed to systematically study RV MB-PM complex VA. Methods A single center retrospective study from January 2013 to December 2023 identified 3249 patients who underwent VA ablation. The RV MB-PM complex was targeted in 47 patients. Acute success was defined as suppression of the targeted VA >=30 minutes post ablation. Long-term success was defined as the absence of symptoms, total PVC burden <5% or improvement in EF in patients presenting with isolated PVCs and as freedom from appropriate ICD therapy in patients presenting with malignant PVCs inducing VF, sustained VT or VT storm. Results Mean age was 51.9 ± 16.7 years and 64% were male. 40 (85%) patients had VA targeted from the MB and 7 (15%) from the PM complex (2 anterior, 2 inferior and 3 septal PM). 34 (72%) had no underlying structural heart disease, 3 (6%) ischemic cardiomyopathy and 10 (21%) non-ischemic cardiomyopathy. No patient had delayed gadolinium enhancement in the RV MB-PM complex. VA were inducible in 42 (89%) of patients and activation mapping was used in 9 (19%), pace mapping in 5 (11%) and a combination of activation and pace mapping used in 33 (70%) patients. Intracardiac echocardiography was used in all cases. Pre-QRS duration was 34.0 ± 10.4 ms. Radiofrequency ablation was used in 37 (78.7%) cases, cryotherapy in 4 (8.51%) cases and a combination of the 2 energy sources in 6 (12.8%) cases. In all cases, acute peri-procedural success was achieved. 24 (51.1%) patients presented with isolated PVCs and were followed up for 4.72 ± 3.55 years after their index procedure. 3 patients underwent repeat catheter ablation targeting the same PVC focus but all patients had long term success with a PVC burden of 16.1 ± 12.5% prior to ablation and 2.40 ± 2.44% at last follow-up. 16 patients underwent ablation for recurrent ICD shocks after initially presenting with PVC induced VF. Patients were followed up for 3.22 ± 2.09 years and 14 (88%) patients remained free from ICD therapy. 7 patients had MB ablation for sustained VT and were followed up for 4.06 ± 3.77 years. 5 (71%) patients remained free from ICD therapy. A purkinje potential was seen in 8% (2/24) cases of isolated PVCs and in 39% (9/23) cases of PVC induced VF or VT (p=0.13). Conclusions RV MB-PM VA commonly present with malignant VF and a purkinje potential is more likely to be seen in these cases suggesting different VA mechanisms to isolated PVCs and catheter ablation is an effective long-term strategy.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Longitudinal changes in the prevalence of indicators for the precursor stage B of heart failure: results of the STAAB study

Abstract Background The ACC/AHA guidelines on heart failure (HF) use selected echocardiographic signs of structural heart disease (SHD) as well as NT-proBNP levels to define the precursor stage B of heart failure in asymptomatic individuals. Purpose To study the change in prevalence over time of echocardiographic signs of SHD or elevated NT-proBNP levels in clinically inapparent individuals of the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Participants, stratified for sex and age (30-79 years), were recruited between 12/2013 and 10/2017 from the source population if they had no preceding HF diagnosis and were followed for 2-4 years. Echocardiographic signs of SHD were (for exact definitions see table): left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction. Subjects with history of myocardial infarction, significant LV valve disease or symptomatic HF (Framingham criteria) were excluded. Results Of 4,965 subjects included at baseline, 3,684 (74.2%; mean age 55.2 years, 52.7% women) with at least one paired measurement were analysed. The changes observed over time in the prevalence of echocardiographic signs of SHD and elevated NT-proBNP levels are displayed in the table. Prevalences of echocardiographic signs of SHD increased (significantly for LVEF and LV dilation, trend for LV hypertrophy). Addition of NT-proBNP increased the cross-sectional prevalences, but not the change in prevalence of potential HF precursor stages. Conclusion The net incidence of clinically inapparent echocardiographic signs of SHD increased over time at a rate consistent with the prevalence observed for clinically apparent HF in the general population. Of note, not all echocardiographic findings will eventually result in symptomatic HF, and the classification is influenced by measurement errors. However, our data support the concept of HF precursor stages.

Atrial and ventricular arrhythmias in young, lifelong and retired elite endurance athletes

Abstract Background Whilst endurance athletes are known to have an overall higher prevalence of atrial fibrillation (AF), the prevalence of other non-sustained and sustained atrial arrhythmias (AAs) and ventricular arrhythmias (VAs) remains poorly defined. Purpose We aimed to define the prevalence of non-sustained and sustained AAs (including AF) and VAs in a healthy cohort of young, lifelong and retired elite endurance athletes. We also sought to assess associations between arrhythmias, fitness and measures of cardiac structure. Methods Holter monitors in healthy endurance athletes (n=288) from an international cohort of elite endurance athletes (the Pro@Heart consortium) were analysed for the presence of sustained and non-sustained AAs and VAs. Athletes were sub-divided into young elite athletes (n=176) and former elite athletes (n=112) of which 60 were lifelong (≥2.5 hours/week) and 52 retired (<2.5 hours/week) athletes (determined by current high-intensity exercise activity). Each athlete underwent cardio-pulmonary exercise testing, echocardiography and contrast-enhanced cardiac MRI. Participants with known structural or electrical cardiac disease were excluded. Independent T-test / One-Way ANOVA (parametric data) or Mann-Whitney U / Kruskal-Wallis Tests (non-parametric data) assessed for differences between the groups. Results Young athletes (n=176, 70.5% male) were significantly fitter with a greater degree of cardiac remodelling as compared with lifelong (n=60, 63.3% male) and retired (n=52, 82.7% male) athletes (Figure 1). The prevalence of non-sustained AAs (young: 4.0% vs lifelong: 66.7% vs retired: 61.5%, p<0.001), sustained AAs (young: 0.6% vs lifelong: 8.3% vs retired: 15.4%, p<0.001) and non-sustained VAs (young: 1.7% vs lifelong: 18.3% vs retired: 23.1%, p<0.001) was higher in lifelong and retired athletes compared with young athletes (Figure 2). Non-sustained VAs were predominately monomorphic (85%), short and moderate rate (median duration 2.8 seconds and heart rate 154 beats per minute). No athletes developed sustained VAs and/or sudden cardiac arrest. Young athletes had less VAs that were multifocal in origin compared with lifelong and retired athletes (young: 29.5%, lifelong: 37.3%, retired: 53.5%, p=0.027). There was no difference in prevalence of any arrhythmia between lifelong and retired athletes. There were no significant correlations between arrhythmias and fitness or cardiac imaging parameters. Conclusion Healthy athletes have a significant prevalence of non-sustained atrial and ventricular arrhythmias and sustained atrial arrhythmias that is more prevalent in older athletes. In older athletes, the prevalence of arrhythmias is similar regardless of whether athletes are actively engaged in training or retired suggesting that pro-arrhythmic remodelling in athletes is sustained, not immediately reversible and may be minimally responsive to detraining.Arrhythmias and cardiac imagingArrhythmias amongst athlete groups

Utility of mobile phone app-assisted screening for heart failure and heart stress in primary care

Abstract Background As heart failure (HF) still has a similar prognosis to some of the most common cancers, a timely diagnosis of HF is of paramount importance. We sought to determine whether a mobile phone app can facilitate screening for HF in primary care. Material and methods The national echocardiographic society conducted a multicenter screening programme for HF in which general practitioners from 13 primary care centres used a mobile phone app to decide whether patients without a prior HF diagnosis should be referred to one of the 6 university hospitals for transthoracic echocardiography (TTE) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing. The app would recommend further testing (TTE and NT-proBNP) to patients with symptoms potentially associated with HF, atrial fibrillation, pathologic electrocardiogram (ECG), previous myocardial infarction or exposure to cardiotoxic cancer therapies, or at least two other risk factors listed in Figure (left panel). Patients with signs of HF were not eligible for the programme. The algorithms proposed in the 2021 ESC guidelines were used to diagnose HF across the entire spectrum of left ventricular ejection fraction (EF). Results Of the 930 screened outpatients (mean age 66±11 years, age range 21-91 years, 61% female), 318 symptomatic patients (34.2%) were diagnosed with new HF (Figure). HF with preserved (HFpEF) was diagnosed more frequently than HF with mildy reduced (HFmrEF) and reduced EF (HFrEF). Heart stress, defined as elevated plasma NT-proBNP in asymptomatic individuals with risk factors irrespective of the presence or absence of structural heart disease or cardiac dysfunction, was found in 22.3% (Figure, right panel). In multivariate regression analysis, advanced age, atrial fibrillation, pathological ECG, long-standing history of arterial hypertension and chronic kidney disease were independently associated with HF, while other risk factors were not (Figure, middle panel). Conclusions Screening in primary care based on symptoms and risk factors, facilitated by a mobile phone app, resulted in a new HF diagnosis in approximately one third of screened patients, with the majority of them having HFpEF. Recalibration of the referral criteria might further improve the performance of the app for screening purposes.

Natriuretic peptides, kidney function and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction: pooled data from the I-PRESERVE, TOPCAT, PARAGON and DELIVER trials

Abstract Background The prognostic utility of N-terminal pro-B-type (NT-proBNP) in patients with heart failure and chronic kidney disease (CKD) is incompletely understood since elevations in NT-proBNP could be related either to decreased clearance by the kidney or to increased severity of structural heart disease. Purpose We sought to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. Methods We conducted a pooled analysis of individual participants with NT-proBNP and estimated glomerular filtration rate (eGFR) measured at baseline in the I-PRESERVE, TOPCAT (Americas region), PARAGON and DELIVER trials. We evaluated the relationship between NT-proBNP and kidney function using piecewise linear regression. Using multivariable Cox and Poisson regression models, we assessed the association of NT-proBNP with clinical outcomes across different levels of eGFR (≥60, 45-<60 and <45 mL/min/1.73m2). The primary outcome was hospitalisation for heart failure or cardiovascular death. Results Among 14,831 participants (mean age 72.1 years, 50.3% female, mean eGFR 63.3 mL/min/1.73m2 and median NT-proBNP 840 pg/mL) followed for a median 33.5 months, there were 3,092 primary outcomes, 2,184 heart failure hospitalisations, 1,465 cardiovascular and 1,049 non-cardiovascular deaths. Participants in lower eGFR categories were more likely to be older, female, and have atrial fibrillation and diabetes (all p<0.001). NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73m2 lower eGFR in patients with baseline eGFR ≥60, 45-60, and <45 mL/min/1.73m2, respectively (P for non-linearity <0.001). For any given NT-proBNP concentration, participants with eGFR <45 mL/min/1.73m2 were at highest risk (Figure 1). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR 1.37, 95% CI 1.34-1.41), consistent across different eGFR categories (P-interaction=0.42). Association between NT-proBNP and other clinical outcomes were also consistent across different levels of kidney function (all P-interaction>0.3; Figure 1). Equivalent risk for the primary outcome was apparent at NT-proBNP levels approximately 2.5- to 3.5-fold lower in patients eGFR <45 mL/min/1.73m2, compared to those with eGFR ≥60 mL/min/1.73m2. (Figure 2). Conclusion NTproBNP is a potent predictor of risk in patients with heart failure with mildly reduced or preserved ejection fraction across the spectrum of kidney function. However, in patients with reduced kidney function, lower NT-proBNP levels confer absolute risk of cardiovascular outcomes similar to substantially higher NT-proBNP levels in patients with normal kidney function. Accordingly, interpretation of NTproBNP levels should vary according to kidney function, particularly in those with eGFR <45 mL/min/1.73m2.