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Abstract Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for malignant ventricular arrhythmias during exercise and emotions which may lead to sudden cardiac death. Beta-blockers (BB) are the mainstay of therapy in patients with CPVT, but studies comparing the efficacy of different types of BB are scarce. Our objective was to determine the efficacy of different types of BB in reducing the ventricular arrhythmia (VA) severity on exercise stress test (EST) in patients with CPVT. Data was derived from the International CPVT Registry, a large retrospective cohort study. We included patients who had an EST before (pre-EST) and after start of BB (post-EST). We divided the cohort into five groups based on the first prescribed BB and compared pre-EST and post-EST. We included 428 patients (median age 18.5 [11.7–39.6] years, 240 (56.%) female), 155 (36.2%) probands) of whom 38 (8.9%) used atenolol, 131 (30.6%) bisoprolol, 82 (19.2%) metoprolol, 124 (29.0%) nadolol and 53 (12.4%) propranolol. Sex and history of aborted cardiac arrest were similar in all groups. The age at start of BB differed (p<0,001): patients using bisoprolol were oldest (35.0 [15.7–35.3]) while patients using propranolol were youngest (12.3 [8.8–24.9]). Median daily BB dose in mg/kg was: 1.0 [0.8–2.3] for atenolol, 0.06 [0.05–0.10] for bisoprolol, 0.9 [0.6–1.5] for metoprolol, 1.1 [0.9–1.6] for nadolol and 1.5 [1.1–2.8] for propranolol. Resting heart rate on pre-EST and post-EST was similar in all groups. Patients using metoprolol had a significantly higher maximum heart rate post-EST compared to nadolol and propranolol (161±18 vs 136±19 and 130±22 bpm, p=0,002 and p=0,001, respectively). The VA severity decreased significantly after BB (147 (37.9%) (non-sustained) ventricular tachycardia ((NS)VT) and 120 (30.9%) no or isolated ventricular premature beat (iVPB) pre-EST vs 46 (11.4%) (NS)VT and 184 (45.7%) iVPB post-EST, p<0,001). Examining the different groups, the VA severity decreased significantly after BB in all but atenolol (13 (40.6%) (NS)VT and 8 (25.0%) iVPB pre-EST vs 9 (25.0%) (NS)VT and 15 (41.7%) iVPB post-EST, p=0,103). Based on these results we conclude that all beta-blockers except atenolol are effective in reducing the VA severity on EST in patients with CPVT. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science”

Abstract Background Orthotopic heart transplantation is the most effective long-term therapy for end-stage heart disease. Denervation of transplanted heart with the loss of autonomic modulation, vasculopathy, utilization of immunosuppressant drugs, and risk of allograft rejection may result in change in the prevalence of arrhythmias in transplanted hearts. Purpose To describe the trends, distribution and the clinical impact of arrhythmias in transplanted hearts in a large nationwide population. Methods We queried the National Inpatient Sample with administrative codes. Cardiac transplant patients were identified using procedure ICD-9-CM codes 37.5 and 33.6. Common arrhythmias were extracted using appropriate validated ICD-9-CM codes. Statistical Analysis System (SAS) version 9.4 was used for analysis of data. Results There was a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States and 16342 (54.4%) of these had arrhythmias. The prevalence of total arrhythmias increased from 53.6% (n=1,158) in 1999 to 67.3% (n=1,575) in 2014. The most common arrhythmia was atrial fibrillation (26.83%) followed by ventricular tachycardia (22.86%) and the prevalence of individual arrhythmias is as shown in Figure 1. Cardiogenic shock was higher in transplanted hearts with arrhythmias when compared with patients without arrhythmias (25.96% vs 18.18%; p<0.001). Transplant recipients with arrhythmias were also associated with an increased use of mechanical circulatory device (18.22% vs 12.67%, p<0.001). The use of implantable cardiac defibrillators and permanent pacemaker was also higher in the arrhythmia group (2.19% vs 0.63% and 40.43% vs 30.24% respectively, p<0.0001). However, there was no significant difference in inpatient mortality between transplant recipients with arrhythmias and without arrhythmias (7.72% vs 6.90%, p=0.225). Further, there was no significant difference in frequency of strokes between the groups (4.98% vs 5.08%; p=0.857). The total hospital cost when adjusted for inflation was significantly higher in the arrhythmic patients, with an average cost of about $570,415±9,590 vs $439,707±8362 in patients without arrhythmias (p<0.0001). The mean length of hospitalization was 44.2±0.8 days in patients with arrhythmias compared to 33.9±0.8 days in patients without arrhythmias (p<0.0001). Conclusion A significant proportion of patients with heart transplant have cardiac arrhythmias and are associated with worse in-hospital outcomes of cardiogenic shock, increased length of stay, and cost of hospitalization. However, they are not associated with worse inpatient mortality. Funding Acknowledgement Type of funding source: None

Abstract Background Optimization of mechanical ventilation (MV) in patients with cardiac arrest (CA) may help improve outcomes in these patients. We sought to investigate the association between hyperoxia, PCO2, and positive end-expiratory pressure (PEEP) with mortality in patients with CA. Methods Patients admitted to our medical center CICU from 2001 through 2012 (MIMIC-III database) who received MV with available information on MV parameters and had arterial blood gases sampling were included. Hyperoxia was defined as time-weighted mean of PaO2 >120 mmHg and non-hyperoxia as PaO2 ≤120 mmHg, while Hypercarbia was defined as PCO2 >35 mmHg during CICU admission. The primary outcome was in-hospital mortality. Multivariable logistic regression was used to assess the association between hyperoxia and in-hospital mortality adjusted for age, female sex, Oxford Acute Severity of Illness Score, creatinine, lactate, pH, PaO2/FiO2 ratio, PCO2, PEEP, and time spent on PEEP. Results Among 136 patients, PaO2 = 139±55 mmHg, PCO2 = 39±10 mmHg, and PEEP = 6.4±2.2cmH2O. Unadjusted mortality was higher in the hyperoxic group (51.4%) compared to the non-hyperoxic group (29.0%) (long rank test p=0.0034, figure). In multivariable analysis, hyperoxia was independently associated with higher in-hospital mortality (OR 4.046, 95% CI: 1.501–10.907, p=0.0057). Additionally, there was no association between the presence of hypercarbia and in-hospital mortality (OR 0.896, 95% CI: 0.319 to 2.521, p=0.836) nor when PCO2 was analyzed as a continuous variable (OR 1.063 per 1 mmHg increase in CO2, 95% CI: 0.111–10.145, p=0.957). Similarly, there was no assocation between PEEP and in-hospital mortality (OR 1.012 per 1cmH2O increase, 95% CI: 0.807 to 1.270, p=0.917). Post-hoc analysis with PaO2 as a continuous variable was consistent with the primary analysis (OR 1.214 per 10 mmHg increase in PaO2, 95% CI: 1.059–1.391, p=0.005). Conclusions In patients with CA, hyperoxia was associated with increased mortality, while PCO2 and PEEP levels were not. Optimal MV parameters are important in the management of patients with CA. Further research is warranted to confirm this association and explore the mechanisms behind these observations. These studies can help establish the best MV strategies for patients with CA. Funding Acknowledgement Type of funding source: None

Abstract Introduction Cardiopulmonary exercise testing (CPET) has an established role in the clinical evaluation of exercise intolerance and in the risk stratification of patients with heart failure. There is limited data assessing its prognostic utility in the evaluation of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The predisposition of patients with ARVC for ventricular arrhythmias and sudden cardiac death has led to recommendations for exercise restrictions and limits our understanding of how the impairment in oxygen extraction and cardiac output impact disease progression and outcomes in these patients. Purpose We examined the association between CPET indices and event free survival (time to mortality or cardiac transplantation) in patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Methods Patients with definite ARVC based on 2010 task force criteria and genetically positive were enrolled into our institutional ARVC registry. 43 patients underwent CPET and have been included in our analyses. Indications for testing included: Evaluation of exercise-induced palpitations/arrhythmias or syncope (37%), pharmacotherapy optimization (28%), heart failure evaluation (19%), and ARVC management decisions (16%). CPET data (peak oxygen consumption (pVO2), respiratory exchange ratio (RER), and ventilatory efficiency (VE/VCO2) were assessed in patients at time of initial evaluation. Median follow-up time was 4.9 years (IQR 9 years). Results 126 patients were studied (age 43.7+ 15 yrs; 41% women; LVEF 57+ 11%; 15% with LVEF <50%) and 43 underwent CPET evaluation. 41 patients (95%) performed at near maximal effort (RER >1) and no fatal events were reported during testing. During the follow up period, the outcome (death or cardiac transplantation) occurred in 31 patients. On Kaplan Meier analysis, pVO2 ≤14 mL/kg/min was associated with worse outcomes (unadjusted p<0.001). Peak oxygen consumption (pVO2) ≤14 mL/kg/min and ventilatory efficiency (VE/VCO2) >34 were associated with shorter event free survival (HR 5.58, p=0.002 and HR 5.56 p=0.005, respectively). After adjusting for age, sex, and right ventricular function, the association between peak oxygen consumption (pVO2) and event free survival remained significant (p=0.02). Conclusions In patients with ARVC, peak oxygen consumption (pVO2) was a prognostic indicator of worse outcomes. Our findings suggest a potential role for pVO2 in disease surveillance and early assessment for advanced heart failure therapies. Figure 1. KM plot pVO2 & event free survival Funding Acknowledgement Type of funding source: Other. Main funding source(s): Mayo Clinic

Abstract Background The management of patients with severe but asymptomatic aortic stenosis (AS) is a challenge of daily practice. Evidence on early aortic valve replacement (AVR) versus symptom-driven approach is controversial. Methods Electronic databases were searched and articles comparing early-AVR with conservative management for severe asymptomatic AS were identified. The pooled unadjusted odds ratio (OR) was computed using a random-effects model. Results A total of 10 studies (observational=9, and randomized clinical trials=1) consisting of 5,291 patients were included. On a mean follow up duration of 4 years, the odds of early-AVR vs conservative management were in favour for early intervention in terms of cardiovascular mortality (OR 0.26, 95% CI 0.13–0.53, p=0.0002, figure-1) and all-cause mortality (OR 0.27, 95% CI: 0.17–0.41, p≤00001). The number needed to treat (NNT) by performing early AVR (either SAVR or TAVR) to prevent one death secondary to either cardiovascular or all-cause was 8 (95% CI: 6–10), and 5 (95% CI, 4.2–5.4) respectively. The odds of all-cause mortality in a selected patient population undergoing surgical AVR (SAVR) (OR 0.17, 95% CI 0.10–0.29, p≤0.00001) or transcatheter AVR (TAVR) (OR 0.45, 95% CI 0.31–0.64, p≤0.0001) were significantly lower compared to patients who were managed conservatively. A subgroup sensitivity analysis based on severe vs. very severe AS and early vs. symptom based AVR also mirrored the findings of overall results. Conclusions Patients with asymptomatic aortic valve stenosis have lower odds of all-cause and cardiovascular mortality when managed with early-AVR compared to conservative management. Figure 1 Funding Acknowledgement Type of funding source: None

AbstractIntroductionLittle is known on continued response following completion of therapy in light chain (AL) amyloidosis.MethodsWe studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first‐line therapy.ResultsBy end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10‐year OS 87% vs 71% vs 56%, P < .001).ConclusionsThis study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.

Introduction: Obstructive sleep apnea (OSA) is associated with increased rates of atrial fibrillation (AF). Recent randomized data suggest that traditional scoring of OSA needs to evolve to improve cardiovascular outcomes. Traditional scoring of OSA does not fully reflect pathophysiological links between OSA and AF, particularly regarding OSA-induced prolongation of p-wave duration (PWD), which is the most powerful predictor of AF occurrence. Hypothesis: We hypothesized that OSA episodes that closely follow each other (serially stacked apneas, ssOSA) exert greater effect on PWD compared to isolated OSA (iOSA) episodes. Methods: Sleeping patients (adults with mild-moderate OSA and presence of both iOSA and ssOSA, but without other cardiovascular comorbidities) undergoing diagnostic polysomnography were recorded by continuous 8-lead ECG. iOSA was defined as OSA episodes with no other episode within 30 seconds. ssOSA consisted of ≥3 consecutive apneas with inter-OSA intervals <30 seconds. PWD was defined from onset of p-wave in any ECG lead to termination in any lead (measured by digital calipers, averaged over 3 beats from first half of OSA and 3 beats from second half of OSA). Wilcoxon rank-sum test was used. Results: We analyzed 208 OSA episodes (51.0% iOSA, 49.0% ssOSA) which occurred in 12 patients (7 women; age 63.1±11.5 years; apnea hypopnea index 16.8±5.4). PWD was longer during ssOSA compared to iOSA (median 117.7ms vs 109.6ms; p<0.0001). The following variables did not differ between ssOSA and iOSA: PR interval (p=0.3139), RR interval (p=0.7531), peripheral oxygen saturation (p=0.7776). Conclusions: The impact of OSA on atrial conduction delay is exacerbated by the phenomenon of OSA stacking, which seems independent of oxygen desaturation and heart rate. Stacking of OSA episodes may be an underused and cost-efficient variable in evaluating the severity of OSA and the effectiveness of OSA treatments with the ultimate goal of reducing occurrence of AF.

AbstractBackgroundThe prognostic importance of intraparotid lymph node metastasis (P+) in patients with primary parotid gland carcinoma is unclear.MethodsNineteen retrospective and noncomparative cohort studies, published between 1992 and 2020, met the inclusion criteria and included 2202 patients for this systematic review.ResultsThe pooled prevalence of the P in adult patients in the unselected studies was 24.10% (95% confidence interval = 17.95‐30.25). The number of P+ lymph nodes per patient was counted in only three studies and ranged from 1 to 11. The 5‐year recurrence‐free survival rate based on Kaplan‐Meier analysis varied from 83% to 88% in P− patients compared to 36% to 54% in P+ patients. The average hazard ratio for tumor recurrence in patients with P+ compared to P− was 2.67 ± 0.58.ConclusionsP+ is an independent negative prognostic factor in primary parotid gland cancer and should be included into the treatment planning.

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P =0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.