Citations

Abstract Purpose: To evaluate the impact of trimodality treatment versus monotherapy or dual therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment. Experimental Design: With Institutional Review Board approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included (i) taxane induction, (ii) concurrent taxane/radiation, and then (iii) surgical resection with wide margins. Results: A total of 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 monotherapy/dual therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared with 48% of monotherapy/dual therapy patients (P < 0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the monotherapy/dual therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year recurrence-free survival [RFS; 93.8% vs. 42.9%; P = 0.004; HR, 7.6 (95% confidence interval, CI: 1.3–44.2)]. Combining all patients with RAASB regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR, 9.0; P = 0.002); distant recurrence developed in 3 of 28 (11%) patients without local recurrence compared with 6 of 10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing. Conclusions: Trimodality therapy for RAASB was more toxic but is promising, with a high rate of pCR, durable local control, and improved RFS.

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Idiopathic ventricular fibrillation (IVF) is responsible for 5-7% of sudden cardiac arrests in the absence of substrate for ventricular arrhythmia, structural diseases, or primary arrhythmic syndromes. The characteristics, management, and prognosis of these patients are unclear. Purpose To investigate the clinical features, management, and prognosis of IVF in our hospital healthcare system Methods Mayo Database Explorer software was used to identify IVF patients from our hospital electronic medical records between 1990 to 2022 in 5 states. The medical records were manually reviewed. Results A total of 132 patients were initially diagnosed with IVF. During the 9.2±6.8 years mean follow-up, 36 [27.3%] patients were later diagnosed with structural diseases or primary arrhythmic syndromes (dilated cardiomyopathy [41.7%], Long QT syndrome [27.8%], catecholaminergic polymorphic ventricular tachycardia [8.3%], Brugada syndrome [5.6%], mitral valve-related arrhythmia [5.6%], and short QT syndrome [2.8%]). Among the rest of the 96 patients with true IVF (mean age 38.4±15.7 years, male 59.4%, Caucasian 80.2%, hypertension 28.1%, diabetes 8.3%), 91 (94.8%) patients presented with out-of-hospital cardiac arrest and 88 (91.7%) patients had a history of syncope. Early repolarization and fragmented QRS were noted in 32 (33.3%) and 28 (29.1%) patients, respectively. Defibrillators were implanted in 92 (95.8%) patients. Genetic testing was performed in 35 (36.5%) patients, and possible associated mutations were found in 13 (37.1%) patients. An Electrophysiology study was conducted in 55 (57.3%) patients, and ventricular fibrillation was induced in 17 (30.9%) patients. The medical management with antiarrhythmic drugs was selected in 60 (62.5%) patients, and the catheter ablation ± anti-arrhythmic drugs was selected in 36 (37.5%) patients. The recurrence of ventricular fibrillation during 9.2±6.8 years of mean follow-up was significantly higher in the ablation strategy group (p=0.0003) (Figure 1). Conclusions We reported the largest cohort of IVF patients from a single healthcare system. Early repolarization and fragmented QRS were common in IVF. The possible associated mutations were found in one-third of IVF who underwent genetic testing. The ventricular fibrillation recurrences were significantly higher in the catheter ablation strategy group.

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic Background/Introduction Syncope is a common presentation in heart failure (HF) patients. However, the associations between syncope and prognosis in HF patients with the cardiac implantable electronic device (CIED) have not been demonstrated. It is unclear whether syncope increases all-cause mortality in HF patients with CIED. Purpose We aimed to examine the association between syncope and all-cause mortality in the largest cohort of HF with reduced ejection fraction (HFrEF), mid-ranged ejection fraction (HFmEF), and preserved ejection fraction (HFpEF) patients with and without CIED. Methods A retrospective cohort of patients with HF and syncope at our hospital between 2010 and 2015 were identified, and 1:1 propensity was matched with a control group of HF patients without syncope. A chart review was conducted. The multivariate Cox regression model was applied to estimate the association between syncope and the all-cause mortality endpoint. Results 3,449 HF patients were diagnosed with syncope (mean age, 72.8±14.5 years; 41.5% women), and the propensity-matched control HF patients without syncope (n=3,449) aged 72.8±14.3 years, and 42.5% women were selected. Cardiac implantable electronic devices were implanted more in HF patients with syncope (32.5% versus 13.7%, p<0.001). Implantable cardioverter defibrillators were implanted more in HF patients with syncope (15.6% versus 8.3%, p<0.001) as well as pacemakers (16.9% versus 7.5%, p<0.001) and cardiac resynchronization therapy devices (6.9% versus 4.8%, p=0.015). Among HF patients with CIED, syncope significantly increased the risk of all-cause mortality in HFrEF patients (hazard ratio [HR]=1.479, 95% confidence interval [CI]: 1.197-1.828, p<0.001) but not in HFpEF (HR=0.980, 95%CI: 0.793-1.210, p=0.849)(Figure 1). Syncope also tended to increase the risk of all-cause mortality in HFmEF patients with CIED but was not significant (HR=1.193, 95%CI: 0.762-1.865, p=0.762)(Figure 1). Among HF patients without CIED, syncope did not increase the risk of all-cause mortality in HFrEF (HR=0.923, 95%CI: 0.806-1.057, p=0.247), HFmEF (HR=1.074, 95%CI: 0.848-1.360, p=0.554), or HFpEF (HR=0.964, 95%CI: 0.883-1.052, p=0.406). Conclusions Syncope significantly increased the risk of all-cause mortality in HFrEF patients but not in HFmEF or HFpEF patients with CIED. The association of syncope and increased mortality in HFrEF patients with CIED suggests that syncope may be a marker and a factor of mortality and warrants further investigation.

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Immune checkpoint inhibitor (ICI) myocarditis is a life-threatening condition characterized by lymphocytic myocardial infiltration[1]. Complete heart block (CHB) occurs in 15% of cases and is often fatal[2-4]. The nature and optimal management of this often-malignant condition is poorly understood[5]. Purpose This case series assesses prognostic factors associated with survival at 90 days among people with ICI myocarditis and CHB. Methods The electronic patient record system was used to identify patients admitted with ICI myocarditis. A two-physician review was used to assess the presence of ICI-associated CHB. Wilcoxon rank sum and Spearman’s rank correlation were used for categorical and quantitative variables respectively. Data was analysed using STATA/IC 16.1. The primary outcome was person-day survival 90 days after presenting symptom onset. Results Six patients were included in the final analysis. Mean survival was 47 person days. All had metastatic disease and presented 15 to 32 days after the first ICI infusion. All had muscle weakness. Other common self-symptoms were shortness of breath (4), blurred vision (4), double vision (3), collapse (3), and leg swelling (1). Proximal myopathy (2), fatigable myopathy (1), ptosis (3), and peripheral oedema (1) were present on examination. Raised troponin T and white blood cell count (WBC) were associated with 90-day survival (see Table 1). Nt-pro BNP, AST, and CK levels were raised in all patients. Two patients were tested for anti-striated muscle antibody titres, and both were strongly positive. Increase in QRS duration compared to baseline ECG was associated with lower survival at 90 days. Only one patient had CHB on admission. Steroid dose, IVIG, and plasmapheresis weren’t associated with survival. One patient declined device therapy. One declined permanent pacemaker (PPM) after insertion of transvenous pacemaker (TVP). Both died within 2 weeks. Three people underwent insertion of a transvenous pacemaker (TVP) followed by PPM insertion (table 2). All three eventually died within 100 days. One person received isoproterenol and immunosuppression as a bridge to PPM and survived. One patient was managed initially with TVP but subsequently declined PPM insertion. TVP removal resulted in CHB recurrence, and they died shortly after discharge. One person declined device therapy and died while receiving comfort care. Lead malfunction was frequent. One patient experienced bradycardia arrest with failure of a TVP lead to capture, while another experienced lead dislodgement. Conclusion CHB secondary to ICI is often fatal. It should be considered in patients presenting with symptoms of myositis, raised troponin and increased QRS duration. Despite a small sample size, this study identifies several prognostic factors which can guide both patients and physicians with decision-making. Larger studies are needed to better understand the role of device therapy in this population.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research St George's, University of London Background SCN5A-E1784K (c.5350G>A) is the most common variant associated with the LQT3 long QT syndrome (LQTS) and Brugada syndrome (BrS). It exhibits incomplete penetrance and can manifest variably as a mixed clinical phenotype of LQTS, BrS and/or conduction disorders (1-4). This presents a challenge for risk stratification and optimal management. We aimed to describe the clinical characteristics and risk markers in a large, well characterised international cohort of SCN5A-E1784K subjects and identify demographic and/or ECG parameters associated with event free survival. Methods Comprehensive clinical data, including initial presentation and follow-up data, were collected from SCN5A-E1784K subjects. Outcome ‘events’ included sudden death, aborted cardiac arrest, and documented VF or VT or arrhythmic syncope. ‘Lethal events’ included sudden death, aborted cardiac arrest or documented VF or VT. Associations between clinical characteristics and event free survival were investigated using Cox proportional hazard regression models. Results SCN5A-E1784K subjects (n=231) were recruited from 16 centres. Median follow up was 24.9 years (15.2 - 43.3) and 45 individuals (19%) experienced an event. Lethal events were observed in 14 subjects (6%). Figure 1 shows event (A) and lethal event (B) free survival in SCN5A-E1784K subjects. Higher QRS duration (corrected for age) was associated with shorter event-free interval. QRS duration was the only characteristic associated with increased risk with a hazard ratio (HR) of 1.04 or 1.05 per ms for events and lethal events, respectively. The observed survival for events and lethal events for QRS tertiles are shown in Figure 2. Discussion Ventricular myocardial conduction, as evidenced by QRS duration, appears to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. Corrected QT interval and BrS phenotype were, however, not associated with risk. This provides an important opportunity for the personalisation of risk stratification of these patients, whose management can otherwise be very challenging. Figures

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the ZonMW Priority Medicines for Rare Diseases and Orphan Drugs (grant 113304045 to Dr Van der Werf) and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (PREDICT2 to Dr. Wilde). Background In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), β-blocker may be insufficiently protective. A randomized clinical trial showed that flecainide reduces ventricular arrhythmias (VAs) in CPVT and small retrospective cohort studies suggest that this translates into a reduction of arrhythmic events. Objective To evaluate the efficacy of flecainide when added to β-blockers for the prevention of arrhythmic events (AE) in a large cohort of patients with CPVT using paired analysis. Methods From two international registries, this multicentre retrospective cohort study included patients with a clinical and/or genetic diagnosis of CPVT using flecainide as an adjunct to β-blockers. The study period, which comprised a pre- and on-flecianide period, was defined as the period in which background therapy, i.e. β-blocker type (β1-selective or nonselective), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillator (ICD) treatment status, remained unchanged within individual patients. The primary endpoint was AEs, defined as SCD, sudden cardiac arrest (SCA), appropriate ICD shock, and arrhythmic syncope. The effect of flecainide on AE rates was assessed using a generalized linear mixed model assuming Poisson distribution and random effects for patients. Results Two-hundred forty-seven patients (median age at start of flecainide 18 years [IQR 14-29], 123 [50%] female, median flecainide dose 2.2 mg/kg/day [IQR 1.7-3.1]) were included. At baseline, 70 (28%) patients had an ICD and 21 (9%) had a LCSD performed. Nonselective β-blockers were used by 133 (54%) patients. During a median pre-flecainide follow-up of 2.1 years (IQR 0.4-7.2), 41 patients experienced 58 AEs. During a median on-flecainide follow-up of 2.9 years (IQR 1.0-6.0), 23 patients experienced 38 AEs. There was a significant reduction in AEs after initiation of flecainide (OR 0.55 [0.38-0.83]; p=0.007). Among patients who were symptomatic before diagnosis or before the initiation of flecainide (n=167), flecainide was associated with a significant reduction in AEs (OR 0.49 [0.31-0.77]; p=0.002). Among patients with ≥1 AE on β-blocker therapy (n=41), adding flecainide was associated with a significant reduction in AEs (OR 0.25 [0.14-0.45]; p<0.001). Conclusion Flecainide was associated with a reduction in AEs when added to β-blockers in patients with CPVT in the overall cohort, symptomatic patients, and particularly in patients with breakthrough AEs on β-blocker therapy.

Background Although endothelial function is a marker for cardiovascular risk, endothelial dysfunction assessment is not routinely used in daily clinical practice. A growing challenge has emerged in identifying patients prone to cardiovascular events. We aim to investigate whether abnormal endothelial function may be associated with adverse 5-year outcomes in patients presenting to a chest pain unit (CPU). Methods Following endothelial function testing using EndoPAT 2000 in 300 consecutive patients without a history of coronary artery disease, patients underwent coronary computerized tomographic angiography (CCTA) or single-photon emission computed tomography according to availability. Results Mean 10-year Framingham risk score (FRS) was 6.6 ± 5.9%; mean 10-year atherosclerotic cardiovascular disease (ASCVD) risk was 7.1 ± 7.2%; median reactive hyperemia index (RHI) as a measure of an endothelial function 2.0 and mean was 2.0 ± 0.4. During a 5-year follow-up, the 30 patients who developed major adverse cardiovascular events (MACE), including all-cause mortality, nonfatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous coronary interventions, had higher 10-year FRS (9.6 ± 7.8 vs. 6.3 ± 5.6%; P = 0.032), higher 10-year ASCVD risk (10.4 ± 9.2 vs. 6.7 ± 6.9%; P = 0.042), lower baseline RHI (1.6 ± 0.5 vs. 2.1 ± 0.4; P < 0.001) and a greater degree of coronary atherosclerotic lesions (53 vs. 3%, P < 0.001) on CCTA compared with patients without MACE. Multivariate analysis demonstrated that RHI below the median was an independent predictor of 5-year MACE (odds ratio 5.567, 95% confidence interval 1.955–15.853; P = 0.001). Conclusion Our findings suggest that noninvasive endothelial function testing may contribute to clinical efficacy in triaging patients in the CPU and in predicting 5-year MACE. Clinical Trials.gov Identifier NCT01618123

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Pfizer Background Type 1 long QT syndrome (LQT1) is a genetic channelopathy characterized by both haploinsufficient and dominant-negative loss-of-function pathogenic variants in the KCNQ1-encoded Kv7.1 K+ channels conducting IKs. Patients with LQT1 may manifest QT prolongation and ventricular arrhythmias that can culminate in sudden cardiac death. Purpose With this project, we aim to investigate whether our mutation independent, KCNQ1-specific suppression-replacement (SupRep) gene therapy can restore the deficient K+-channel and thereby restore the healthy phenotype. Methods Our proprietary dual component SupRep gene therapy was created by combining a custom-designed KCNQ1 shRNA and a shRNA-immune (shIMM) KCNQ1 cDNA into AAV9. In vivo AAV9-mediated KCNQ1SupRep gene therapy was performed by targeted intra-aortic root construct injection (1E12 vg/kg body weight) during balloon occlusion using a Swan Ganz catheter. 2 weeks after in vivo gene therapy, 12-lead ECGs were assessed in adult transgenic LQT1 (KCNQ1-Y315S, loss-of IKs) and wild-type (WT) rabbits to determine the effect of SupRep therapy on the rabbit’s QTc. Patch-clamp and calcium transient measurements were performed in isolated ventricular cardiomyocytes to evaluate the effect of SupRep on the cardiomyocyte’s action potential duration (APD90) and Ca2+ transient duration (Ca2+90) both, in vitro – after plasmid transfection, and in vivo – after AAV9-mediated gene therapy. AAV9-KCNQ1-construct expression was verified with immunohistochemistry targeting the GFP-tag. Results After injection of 3 LQT1 rabbits so far, no significant changes were observed in the LQT1 rabbits’ QTc before and after in vivo AAV9-mediated gene therapy. However, at the cellular level, LQT1 cardiomyocytes transfected in vitro with the SupRep-plasmid demonstrated a significant reduction of APD90 (ms, 1Hz stimulation at 37°) compared to LQT1 control cells (SupRep-in-vitro, 358±21 vs. control 447±22, p&lt;0.05). No differences were observed between sham-plasmid transfected cardiomyocytes and LQT1 control cells after one day of culturing. Similarly, cardiomyocytes isolated from the 3 LQT1 rabbits that underwent in vivo SupRep gene therapy demonstrated pronounced shortening of both APD90 and Ca2+90 compared to LQT1 controls, leading to levels similar to WT controls (APD90, 1Hz, 37°: LQT1: 530±18, WT: 445±18, LQT1-SupRep: 375±25, p&lt;0.0001 LQT1 vs. LQT1-SupRep, p=ns LQT1-SupRep vs. WT) (Ca2+90: LQT1: 487±23, WT: 346±16, LQT1-SupRep: 393±19, p&lt;0.0001 LQT1 vs. LQT1-SupRep, p=ns LQT1-SupRep vs. WT). Conclusion In vivo KCNQ1-suppression-replacement gene therapy normalizes cellular action potential and calcium transient duration in transgenic LQT1 rabbits. Further in vivo experiments will be conducted to evaluate whether this therapeutic correction at the cardiomyocyte level will translate into normalization of the LQT1 rabbits’ QTc both at rest and during stress testing.

Abstract Funding Acknowledgements Type of funding sources: None. Background Falls are the leading cause of injury-related morbidity and mortality among older adults in the United States, including those with cardiovascular disease. Cardiac rehabilitation (CR) helps to optimize functional capacity, strength, and balance in patients with cardiovascular disease and, in theory, may reduce the risk of falls. However, little evidence has been published in this regard. Purpose The purpose of this study was to assess the association between CR participation and risk of falls in a community-based sample of individuals 65 years of age and older with cardiovascular disease who were eligible for CR participation. Methods Individuals from Southeastern MN and Western WI, USA, 65 years of age and older who had experienced a cardiovascular event that qualified them for CR (MI, PCI, CABG, Valve Surgery, Transplant) between January 1, 2000, and December 31, 2018, were included in this study. Participation in CR (≥1 sessions, CR-group) and subsequent falls (moderate or severe, using the Campbell classification system) were ascertained using the Rochester Epidemiology Project records-linkage system. Logistic model to create propensity weighting were used to test the association between CR participation and falls after adjustment for potentially confounding factors. Results A total of 5004 individuals met inclusion criteria for the study, with 2183 (44%) included in the CR group and 2821 (56%) in the non-CR group (CR was indicated, but the individual did not participate). Overall, 1122 patients experienced a fall within the first 5 years (16% of those in the CR-group, 23% of those in the non-CR group). After adjustment, CR participation was not associated with falls, but older individuals, females, and those with a history of falls were more likely to have had a fall, compared to young individuals, males, and those without a history of a fall. Conclusions While CR is beneficial for patients with cardiovascular disease, our study did not find evidence of an association between CR participation and fall risk in individuals 65 years of age and older who have cardiovascular disease. Additional research is needed to evaluate the role of CR components that may potentially reduce modifiable risk factors for falls and thereby reduce the risk of falls.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UiT The Arctic University of Norway, Northern Norway Regional Health Authority. Background/Introduction Machine learning models have been applied to magnetic resonance images of the brain to estimate brain age gap as a biomarker of biological aging. Because of its association with cognitive performance and neurological disorders, brain age gap has become an indicator of general brain health. Among others, cardiovascular risk factors are associated with brain health. Recently a novel non-invasive biomarker of vascular ageing has been proposed based on the application of a deep-learning algorithm to digitised 12-lead electrocardiograms. The difference between electrocardiogram predicted age and chronological age is defined as vascular age gap and has been shown to be associated with an adverse cardiovascular profile. However, the association of vascular age gap with cognitive health and dementias has not yet been examined. Purpose We apply a causal mediation framework to vascular age gap, brain age gap and cognitive function data obtained in the same individuals who took part in a population-based study in Norway. We hypothesise that cardiovascular risk factors encapsulated in vascular age gap can indirectly affect cognitive function by increasing the brain age gap. Methods We applied a deep learning algorithm (1) to electrocardiograms (N=7779, age 40-85 years) collected from the population-based sample in Norway (mean age 63.8 years, 45.3% men) to obtain a vascular age gap. For a subsample (N=1693) magnetic resonance images of the brain were also available and another deep neural network algorithm (2) was applied to obtain a biomarker of brain age. For 1678 participants with both vascular age gap and brain age gap available we used mediation analysis to test whether brain age gap mediates the effects of vascular age gap on cognitive function (as measured by mini mental status test, word memory test, digit–symbol coding test, tapping test) by estimating total, direct and indirect effects. Results We found a weak correlation (Pearson’s r = 0.12) between vascular age gap and brain age gap. Both age gaps were associated with cognitive scores capturing psychomotor speed, attention and mental flexibility. For a 1 standard deviation (7.3 years) increase in vascular age gap digit-symbol coding test score decreased by 0.63 (95%CI: -0.89, -0.36; p&lt;0.001) points, and tapping test decreased by 0.36 (95%CI: -0.56, -0.14; p=0.001). Only 13% of effect of vascular age gap on cognitive test results was mediated by brain age gap. Conclusion(s) Vascular age gap was weakly associated with poorer cognitive functioning, and only 13% of this association was mediated by brain age gap. This suggests that cognitive decline linked to accumulated damage of the vascular system is not fully captured by structural changes in the brain. Further investigations of novel measures of biological aging in relation to cognitive decline are warranted as these may hold promise for improved understanding of mechanisms and clinical prediction.