Citations

Background: Bariatric surgery (BS) has been shown to be beneficial in improving co-morbid conditions in morbidly obese patients. Long-term cardiovascular complications remain undefined and warrant further investigation. We examined the prevalence and risk of atrial fibrillation (AF) in obese patients who underwent BS. Methods: PUBMED/Medline, SCOPUS, EMBASE databases were systematically reviewed using relevant keywords to search prospective and retrospective studies reporting AF with long-term (at least >1-year follow-up) follow-up in patients who had undergone BS. Random effects models were used for meta-analysis and subgroup analysis. I 2 statistics was used to identify substantial (>75%) heterogeneity. Results: Nine studies (3 USA, 2 UK, 4 Sweden) including 24,164 patients who had undergone BS (mean BMI cut off: 35, mean age 42 years) with 29,330 controls were included in the analysis with a median follow-up of 8 years. Pooled prevalence of AF was lower in BS arm (3.0%, 95%CI: 1.4%-5%) as compared to non-BS arm (3.8%, 95% CI: 1.8%-5.0%). The Forest Plot (Fig. 1) depicts significantly reduced odds of having AF in patients who have undergone BS vs controls (OR: 0.74, 95%CI: 0.60-0.91, I 2 =70.2%, p<0.01). Sensitivity analysis using the leave-one-out method did confirm equivalent results. On subgroup analysis, AF prevalence in the BS group was slightly higher in studies with a mean age of ≥50 years (4.8%, 0-12%) as compared to cohorts with mean age <50 (2.0%, 1.4-5.0%). The pooled rate of AF was low on short-term follow-up compared to long-term follow-up after BS: 1.5% (0.9-2.5%) in 1-5 years, 1.9% (0.2-4.5%) in 6-10 years, 5.4% (0-13.9%) ≥10 years of BS. Conclusions: Obese patients undergoing BS had nearly 25% lower risk and lower pooled rate of AF when compared to controls over 8 years of follow-up. The protective effect of BS on reduced risk of AF was seen to gradually wane over longer follow-up which warrants continued efforts to effectively control CVD risk factors.

Background: Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy Syndrome (TS) with severe QT prolongation, cardiac hypertrophy, syndactyly, facial dysmorphisms, developmental delay, and sudden death by impaired channel inactivation and increase peak current. Recently, a small number of patients with CACNA1C mutations with only long QT syndrome (LQTS) have been described. Objective: To explore whether CACNA1C mutations associated with TS were mechanistically and clinically distinct from CACNA1C-mediated LQTS. Methods/Results: Illumina HiSeq 2000 platform-based whole exome sequencing with variant alignment using HGSC Mercury analysis and Atlas2 revealed a novel variant CACNA1C-L762F that co-segregated with affected patients of a large, multi-generational family with LQTS and sudden death. The proband presented at 3 years of age with out-of-hospital cardiac arrest and demonstrated QTc of 530. The mutation localized to the DII/DIII intracellular linker domain of the channel in a highly conserved region in close proximity to the 6th DI transmembrane domain. Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased late current indicating its gain-of-function cellular electrophysiological phenotype. Comprehensive review and topological mapping of all described CACNA1C mutations associated with TS or LQTS revealed disease-specific hotspots. TS-associated mutations localized to cytoplasmic aspects of transmembrane domains while LQTS-associated mutations localized to cytoplasmic N- and C-terminal domains and linker regions. Probands hosting TS mutations demonstrated markedly prolonged QTc values compared to LQTS (618 vs 486 ms, p<0.001) and were younger at presentation (2.7 vs 20.1 years, p<0.002). Supporting these associations, the L762F mutation localized closer to the CACNA1C transmembrane domain than any other LQTS mutation and are associated with a QTc and age of diagnosis reflective of TS-associated mutations. Conclusions: The CACNA1C-L762F mutation is associated with biochemical and clinical features which highlight a molecular and clinical distinction between TS- and LQTS-associated CACNA1C mutations.

Introduction: Cardiac rehabilitation (CR) is recommended for secondary prevention following a coronary artery disease (CAD) event. The association between CR attendance and long-term major cardiovascular events (MACE)in the community has not been previously reported . Hypothesis: We tested the hypothesis that higher CR participation would be related to a lower risk of MACE,in residents of Olmsted county, Minnesota. Methods: We performed a community-based retrospective longitudinal study on patients referred to CR for CAD events or procedures between the years 2002 and 2012. Follow-up was performed using a record linkage system from the Rochester Epidemiology Project. CR participation was assessed as the number of CR sessions attended, and was analyzed as a continuous variable, as quintiles and also as a binomial variable using 12 sessions as the cutoff. The composite outcome MACE was defined as having an acute coronary syndrome (myocardial infarction (MI) or unstable angina), revascularization (CABG or PCI), ventricular arrhythmias requiring hospitalization, stroke or death from any cause. Multivariate models were adjusted for age and gender and also for factors associated with MACE in the univariate analysis. Results: Our cohort included 2273 patients, 69% males, mean age (SEM) 64 (0.26) years. After a mean follow-up of 6 (0.07) years, 827 patients had an event: MI (73), unstable angina (113), CABG(53), PCI (260), ventricular arrhythmia (13), stroke (72) and death (243). Participation in 12 or more sessions (vs <12 sessions) had a lower rate of MACE (HR 0.81, 95% CI 0.70-0.93, p=0.003, see Figure1 . After adjusting for smoking, hypertension, diabetes and history of MI the association remained significant HR 0.85, 95% CI 0.74-0.98, p=0.03. Conclusions: A higher participation in CR was associated with a lower risk of MACE. These results provide additional evidence of important CR health advantages and expand on previous evidence of a dose-response benefit of CR.

Introduction: Congenital long QT syndrome (LQTS) is a sudden cardiac death-predisposing genetic disorder that has a characteristic electrocardiographic signature. Specific LQTS genotypes have been associated classically with different qualitative electrocardiographic ST - T wave patterns; however, clinical recognition of these patterns could be improved by an automated and quantitative method. We therefore aimed to use a novel, quantitative T wave morphological analysis technique from 12-lead surface ECGs to identify genotype specific LQTS ECG patterns. Methods: We analyzed a genotyped cohort of 420 patients (22 ± 15.7years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using a custom T wave program to automatically detect subtle changes in T wave morphology across all 12 Leads. Classification was performed using the top three T wave features in a linear discriminant classifier by 10x10 cross-validation. Results: The top three discriminant features were (1) a steeper T wave left slope for LQT1 in lead II (2950 vs 1700 mV/ms, p < 0.0001), (2) a greater center of gravity in 1st segment of T wave in lead aVR in LQT1 (0.248 vs 0.209, p<0.0001) and (3) a smaller Tpeak - Tend/QT ratio in lead aVR in LQT1 (0.20 vs 0.24, p<0.0001). Using these top three features, we were able to successfully differentiate LQT1 and LQT2 in 79% of cases (figure 1). Conclusions: An automated morphological T wave analysis was able to discriminate between the two most common LQTS genotypes. This novel method enhances phenotypic characterization of LQT and could have a significant clinical impact on the diagnosis and management of patients with suspected LQTS.

Introduction: Long QT syndrome (LQTS) is the most common, autosomal dominant, sudden death predisposing cardiac channelopathy. Although 17 LQTS genes have been discovered, 20% of LQTS remains genetically elusive. Whole exome sequencing (WES) followed by a strategic, knowledge-based variant filtration approach may elucidate novel LQTS-susceptibility genes. Methods: A LQTS family with multiple sudden deaths was referred for genetic evaluation. The index case was a 21-year-old male who died suddenly but had a pre-mortem ECG with marked QT prolongation. The decedent’s mother also showed QT prolongation. Only paraffin embedded tissue (PET) was available from the decedent, so the mother’s DNA was analyzed by WES. Following WES, variants were filtered using Ingenuity Variant Analysis (IVA) software. Only non-synonymous variants with a quality score >20, read-depth >10, and absent in ExAC were considered. Further filtration was performed using IVA’s biological context pathway analysis set to capture genes most likely related to LQTS. Electrophysiological studies were performed on the variant with highest probability of pathogenicity. Results: Following WES and variant filtration, only a CALR frame-shift variant (R376fs/10) remained as a probable LQTS mutation. No radical CALR variants reside in ExAC’s 60,000+ exomes. The mutation was confirmed in the decedent’s PET-derived DNA. CALR-encoded calreticulin (CRT) is a Ca2+ binding chaperone of the endoplasmic reticulum. Both knockout and over-expression of CRT exert extreme effects on the murine cardiac system, including sudden death. Recently, CRT has been linked with altered L-type calcium (LTCC) ion channel activity. Wild-type (WT)-CALR reduced Cav1.2 peak current density by 43.1%. In contrast, CALR-R376fs/10 mutation reversed this Cav1.2 inhibition and caused a net gain-of-function of Cav1.2 channel current compared with CALR-WT co-expression (64.2% increase). No pathogenic variants in CALR were identified in 25 additional, unrelated, genetically elusive LQTS cases. Conclusion: Mutations in CALR-encoded calreticulin may be a rare cause of autosomal dominant LQTS precipitated in part by an accentuation of the LTCC, thereby potentially mimicking CACNA1C-mediated LQTS.

AbstractTo compare pulse oximetry (PO) levels during swallowing in healthy adults and adults with severe chronic obstructive pulmonary disease (COPD). Participants included two groups of 60 healthy adults, balanced for gender. The young group ranged from 18 to 38 years, and the older group from 60 to 87 years. In addition, there were 11 participants with COPD aged 43 to 82 years. PO levels were collected as each participant swallowed 10 mL of water, 10 mL of applesauce, and a piece of diced pear (three trials each). Analyses for the healthy groups revealed neither statistically significant main effects for bolus type nor interactions between gender and age. For between-subject effects, there was no main effect for gender, but there was a large main effect for age, and a gender and age interaction. In the group with COPD, there were no significant differences across bolus types; however, PO measures were consistently lower than the healthy groups for all bolus types. Healthy adults exhibited stable PO levels across bolus types. Adults with COPD, although exhibiting significantly lower PO levels, also remained stable. For clinicians who monitor PO measures, these results offer a more comprehensive understanding of the nature of these measures during swallowing in these groups.

Abstract Background: The etiology of colorectal cancer is not fully understood. Methods: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 &gt; 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis. Results: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini–Hochberg FDR (BH-FDR) &lt; 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10−8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR &lt; 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60−2.36, P = 2.6 × 10−11; OREUR: 1.01, 95% CI, 0.99−1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het &lt; 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer. Conclusions: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data. Impact: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.

Abstract Introduction: Hepatopulmonary syndrome (HPS) is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting and manifests as dyspnea. The portal hypertension may be a result of cirrhosis or non-cirrhotic causes such as nodular regenerative hyperplasia of the liver that is associated with drug therapy. Progressive hypoxemia often occurs despite stable liver function. Ado-trastuzumab emtansine (T-DM1; KADCYLA) is an antibody-drug conjugate comprised of a humanized monoclonal antibody trastuzumab covalently linked to the cytotoxic agent maytansine. T-DM1 is prescribed in the postneoadjuvant setting in persons with residual invasive HER2-positive (HER2+) breast cancer (BC) as well as in persons with metastatic HER2+ BC who were previously treated with trastuzumab and a taxane. Liver toxicities including an asymptomatic, transient increase in transaminases and nodular regenerative hyperplasia that results in portal hypertension have been described; however, HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not been reported. We have identified patients (pts) with this infrequent, yet serious complication, and we aim to better characterize their clinical course to guide earlier detection and hopefully prevent irreversible hypoxic respiratory failure. Methods: Institutional search tools were utilized to identify pts at Mayo Clinic with HER2+ BC treated with T-DM1 in either the postneoadjuvant or metastatic setting. Electronic health records were manually reviewed for HPS criteria including 1) hypoxemia 2) portal hypertension and 3) intrapulmonary shunt/vasodilation confirmed by contrast echocardiogram or macroaggregated albumin lung perfusion scan. For pts meeting criteria for HPS, imaging was independently reviewed by a hepatologist to determine whether there was preexisting liver disease or if changes occurred after initiation of T-DM1. Results: We identified 259 pts with HER2+ BC treated with T-DM1 in the postneoadjuvant (n=70) or metastatic setting (n=185). Four pts met criteria for HPS (1.5%) while receiving T-DM1 for metastatic disease (Table 1; listed in chronological order of onset of HPS). Median age was 43 (range 35 - 53 years), median prior lines of treatment was 1.5 (range 0 - 7), and the median number of cycles of T-DM1 prior to discontinuation was 68.5 (range 51 - 90). All pts had evidence of left atrial enlargement on echocardiogram, and evidence of portal hypertension as determined by the presence of varices, and splenomegaly. Three pts had documented telangiectasias as well as Grade 1-2 elevations in serum transaminases and bilirubin. Elevations in hemoglobin were noted in 2 pts during treatment with T-DM1. All pts had a confirmed intrapulmonary shunt via contrast echocardiogram and a lung perfusion scan. Three pts discontinued T-DM1 after diagnosis of HPS and experienced some clinical improvement in hypoxia. One pt died two months after stopping T-DM1 due to progression of BC. Conclusion: HPS may occur in the setting of prolonged exposure to T-DM1 and can be associated with severe hypoxic respiratory failure. Further data are required to characterize the spectrum of liver injury that occurs with long-term use of T-DM1 to provide further guidance to clinicians as regards monitoring for these adverse effects. Patients who developed hepatopulmonary syndrome while on T-DM1Age, yrsSites of metastases# lines of prior txCycles of T-DM1Presenting sign or symptomsNon-contrast ECHO findingsSupplemental oxygenTransaminitis; hyperbilirubinemiaEvidence of portal hypertensionTelangiectasiasHgb prior to T-DM1Hgb end of txLung perfusion studyContrast ECHOPt 153LN, bone090DOE, hypoxemia, clubbingleft atrial enlargement (62 mg/m2)YesNovarices, splenomegalyNot documented12.9 g/dL10.7 g/dL13.5%Yes, small shuntPt 235LN, bone, liver751DOEleft atrial enlargement (54 mg/m2)YesGrade 1; Grade 2varices, splenomegaly; thrombocytopeniaYes, face and handsn/a11.9 g/dL24%Yes, large shuntPt 338LN, bone251Hyperbilirubinemiaborderline left atrial enlargementYesGrade 1; Grade 2varices, splenomegalyYes, trunk, extremities, face11.7 g/dL16.2 g/dL17.8%Yes, moderate shuntPt 448LN, liver186DOEleft atrial enlargement (49 mg/m2)NoGrade 1; Grade 2varices, splenomegalyYes, trunk12.5 g/dL16.1 g/dL7.9%Yes, large shunt Citation Format: Ally Higgins, Adham K Alkurashi, Patrick S Kamath, Vivek N Iyer, Ciara O'Sullivan, Tufia C Haddad. Hepatopulmonary syndrome with long term use of ado-trastuzumab emtansine (T-DM1) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-03.

Background: Clinically significant outcomes (CSOs) connect patient-reported outcome measures data to patient-perceived benefit. Although investigators have established threshold values for various CSOs, the timeline to achieve these outcomes after isolated biceps tenodesis (BT) has yet to be defined. Purpose: To define the time-dependent nature of minimal clinically important difference (MCID), substantial clinical benefit (SCB), and Patient Acceptable Symptom State (PASS) achievement after isolated BT. Study Design: Case series; Level of evidence, 4. Methods: The American Shoulder and Elbow Surgeons score (ASES), the Single Assessment Numeric Evaluation, and the Constant-Murley score (CMS) were administered preoperatively and at 6 and 12 months postoperatively to patients undergoing isolated BT between 2014 and 2018 at our institution. Cumulative probabilities for achieving MCID, SCB, and PASS were calculated using Kaplan-Meier survival analysis. Weibull parametric regression evaluated the hazard ratios (HRs) of achieving earlier MCID, SCB, and PASS. Results: Overall cohort (N = 190) achievement rates ranged between 77.8% and 83.2% for MCID, between 42.2% and 80.2% for SCB, and between 59.7% and 62.9% for PASS. Median achievement time was 5.3 to 6.1 months for MCID, 5.9 to 6.4 months for SCB, and 6.07 to 6.1 months for PASS. Multivariate Weibull parametric regression identified older age, male sex, higher body mass index, preoperative thyroid disease, smoking history, and higher preoperative CMS as predictors of delayed CSO achievement (HR, 1.01-6.41), whereas normal tendon on arthroscopy, defined as absence of tenosynovitis or tendon tear on arthroscopy, predicted earlier CSO achievement (HR, 0.19-0.46). Location of tenodesis and worker compensation status did not significantly predict the time to achieve CSOs on multivariate analysis. Conclusion: After isolated BT, patients can expect to attain CSO by 13 months postoperatively, with most patients achieving this between 5 and 8 months. Patients tend to take longer to achieve PASS than MCID and SCB.