Significant Cardiac Disease Research Articles

Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma

Background: Autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy with an immunomodulatory agent or a proteasome inhibitor remains an important strategy for upfront treatment in multiple myeloma (MM) with progression-free survival (PFS) and overall survival (OS) advantage. We designed a two-arm, open-label prospective study to examine the safety and tolerability of two different dosing schedules of an oral pan-histone deacetylase inhibitor, panobinostat (pano) as an alternative maintenance therapy option in patients with MM (NCT02722941). Methods: A total of 30 MM patients who underwent autologous HCT within the preceding 90 to 180 days were enrolled at Moffitt Cancer Center using a sequential alternating allocation to starting dose of either Cohort A: 20 mg PO 3/week, q 2 weeks on a 28-day cycle, or Cohort B: 10 mg PO daily for 7 days, q 2 weeks on a 28-day cycle, for 12 cycles. Dose level -1 was cohort A: 15 mg 3/week; and cohort B: 10 mg 4/week. Patients with clinically significant cardiac diseases, bradycardia, QTc > 470 msec, bifascicular block were ineligible. EKG was performed on pre- and post-dose on day 1 & 5 of cycle 1, and pre-dose on day 1 of cycles 2-4. Relative dose intensity (RDI), a ratio of amount of drug actually delivered in mg over the amount of planned dose in mg, was calculated to evaluate the treatment feasibility as a surrogate measure. Results: The median age of the entire cohort was 60 (range, 40-73) years with a male/female = 18/12. Disease characteristics are summarized in the Table. Patients initiated pano maintenance at a median of 131 (range 91 - 178) days after autologous HCT. As of 8/1/2019, 16 patients (8 in each cohort) completed full 12 cycles of pano. The RDI for the entire cohort, cohort A, and cohort B was 94.1% (33,750mg/35,860, 98% (16,350mg/16,680mg), and 90.7% (17,400mg/19,180mg), respectively. One patient in cohort A had dose reduction, and 6 patients in cohort B had dose reductions with cytopenias (43%) and GI toxicities (43%) being the most common reasons. No patients required dose modifications due to QT prolongation thus far. There were 3 possibly treatment-associated serious adverse events (pneumonia=2; colitis=1) but all patients successfully resumed pano. Three patients progressed while on pano maintenance. No mortality has been observed thus far. Ten patients are still on pano treatment. The median follow-up is 11 (range, 1-29) months. Conclusions: RDI is 90% overall and panobinostat as a single oral maintenance agent either at 20 mg three times per week or 10 mg po daily for 7 days on alternating weeks appears to be overall well tolerated. There were more dose reductions required in the 10 mg starting dose (cohort B). Panobinostat is a safe alternative for maintenance therapy after autologous HCT. Longer follow-up is needed to confirm the utility of this approach and updated results will be presented at the meeting. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Baz:Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Panobinostat single agent maintenance therapy after autologous hematopoietic cell transplantation for multiple myeloma

Abstract CT083: A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors

Abstract Background: LY3295668 erbumine (AK-01) is a selective, reversible, ATP-competitive small molecule inhibitor of aurora kinase A (AurA). LY3295668 erbumine treatment in xenograft and patient-derived xenograft models resulted in tumor growth arrest or regression of several tumor types with an acceptable safety profile. This study evaluated dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of LY3295668 erbumine monotherapy in patients with locally advanced or metastatic solid tumors. Methods: This ongoing phase I/II, open-label, multicenter study enrolled patients with locally advanced or metastatic solid tumors, ECOG PS 0-1, estimated life expectancy ≥ 12 weeks, adequate organ function, disease progression after 1 - 4 regimens for locally advanced or metastatic disease and no history of clinically significant cardiac disease. The primary objective was to determine MTD; secondary objectives included evaluation of tolerability and overall safety profile of LY3295668 erbumine. All patients received oral, twice daily (BID) doses of LY3295668 erbumine in cycles of 21 days in a multiple ascending dose schedule. Adverse events (AEs) were graded per NCI CTCAE v4.03. Results: Twelve patients median age of 60 (range 39-74, 5 male and 7 female) were enrolled in the phase I study at the following dose levels: 25 mg (n=8); 50 mg (n=2); 75 mg (n=2). One patient in the 25 mg cohort experienced a DLT of grade (G) 3 mucositis. One patient in the 50 mg cohort experienced a DLT of G3 mucositis and G3 diarrhea. Both patients in the 75 mg cohort experienced DLTs (1=G3 mucositis, 1=G4 mucositis and G3 corneal deposits). The treatment-related AEs (TRAEs) observed in each cohort were as follows: in the 25 mg treatment group, six patients experienced various G1/2 TRAEs with only mucositis reported in > one patient (n=2); G3 TRAEs were anemia (n=1) and mucositis (n=1). In the two patients receiving 50 mg, G3 TRAEs were: mucositis (n=1), diarrhea (n=1), and upper chest rash (n=1). In the two patients receiving 75 mg, G3/4 TRAEs were: mucositis (n=2), corneal deposits (n=1), neutropenia (n=1) and diarrhea (n=1). There were no treatment-related deaths. During this study, three patients died due to disease progression: one patient died < 30 days and two patients died > 30 days after the last treatment dose. At the time of data lock, two of the eight patients in the 25 mg BID phase I cohort remained on treatment for ≥ 8 months. In addition to the 12 patients in phase I, one patient was enrolled in phase II after the MTD was determined, totaling 13 patients who received treatment in the entire study. Conclusion: The MTD of LY3295668 erbumine was determined to be 25 mg BID and found to be well tolerated in patients with locally advanced or metastatic solid tumors. Trial Registration: NCT03092934 Citation Format: Quincy Chu, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, John R. Stille, Jill D. Kremer, Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Andrew Lithio, Patricia S. Smith, Gerald Batist. A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT083.

High dose testosterone in men with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD).

TPS5095 Background: mCRPC progresses via adaptive mechanisms that allow ongoing androgen receptor (AR) signalling despite castrate levels of androgens. Bipolar androgen therapy (BAT), cycling between supraphysiologic and subphysiologic serum testosterone levels, aims to exploit these adaptations to induce tumor regression. Extensive clinical data demonstrate the safety and efficacy of BAT in men with asymptomatic mCRPC. However, de novo resistance is still common and predictive biomarkers to refine patient selection are lacking. Pre-clinical data suggest that the induction of double-stranded DNA (dsDNA) breaks by BAT may be crucial to its mechanism of action. DNA repair defects, such as HRD, are particularly relevant in CRPC patients. We hypothesize that CRPC patients with DNA repair deficits such as HRD, may be particularly responsive to BAT. Methods: This is a phase II prospective single arm interventional trial (NCT03522064). Up to 30 patients will be recruited based on a Simon two-stage design with a power of 90% to detect an increase in response rate from 20% to 40%. Key inclusion criteria include i) asymptomatic or minimally symptomatic mCRPC, ii) rising PSA despite a castrate serum testosterone and iii) HRD on germline, tumor and/or circulating tumor DNA (ctDNA) analysis. Key exclusion criteria include i) ADT < 1 year, ii) disease extent/sites that would cause significant risk if tumor flare occurs (e.g.: brain) and iii) significant cardiac disease. Previous PARP inhibitor therapy will be permitted in a subset. Participants will receive IM testosterone enanthate 500mg q4w in combination with ongoing LHRH antagonist/agonist or orchidectomy. The primary endpoint is PSA response rate defined as PSA reduction ≥50% from baseline. Secondary endpoints include time to PSA progression, quality of life, radiologic response and safety and tolerability. Exploratory endpoints include changes in ctDNA and tumoral DNA alterations from baseline to progression. Accrual is ongoing. Clinical trial information: NCT03522064.

Abstract OT1-03-01: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET)

Abstract Background: Although ET remains the basis of therapy for ER+, HER2– ABC, treatment resistance frequently occurs. Novel strategies to target the receptor and/or alternative pathways to overcome therapeutic resistance are under investigation. LSZ102 is a novel, orally bioavailable, nonsteroidal SERD. Preclinically, LSZ102 inhibits ER gene transcription, induces receptor degradation, blocks ER-dependent cell growth, and has synergistic activity with the phosphoinositide 3-kinase (PI3K)-alpha inhibitor alpelisib (BYL719). The present study is evaluating the safety and tolerability of LSZ102 plus alpelisib in patients with ER+, HER2– ABC with progression on ET. Trial Design: This phase 1/1b, open-label study is enrolling ˜18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Enrollment in Arm C started after identification of a safe and tolerable single-agent dose for LSZ102. Alpelisib dosing began at 200 mg/day and will not be escalated beyond the maximum tolerated dose (MTD) determined in the alpelisib single-agent arm of study CBYL719X2101 (400 mg/day). Dose escalation of alpelisib in combination with LSZ102 is guided by BLRM and integrates Cycle 1 DLT rates, lower grade and later cycle AE, PK, PD and preliminary activity to identify a recommended dose for expansion (RDE). Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent. For inclusion in the study, patients must have histologically confirmed ER+, HER2– ABC and disease progression after ET for ABC or recurrence on/within 12 months of completion of adjuvant ET. In the escalation part of the study, patients are eligible regardless of PIK3CA status. Premenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligible patients must have adequate bone marrow and organ function, Eastern Cooperative Oncology Group performance status of 0 or 1, and have completed and recovered from acute toxicities of radiotherapy and/or prior anticancer therapy. Exclusion criteria include symptomatic central nervous system metastases, clinically significant cardiac disease or impaired cardiac function (including a QT interval corrected for heart rate using Fridericia's formula [QTcF] >460 ms in women or >450 ms in men), uncontrolled diabetes mellitus type II (or type I), and prior treatment with a PI3K inhibitor. The primary objectives are characterization of safety and tolerability for the combination and identification of a recommended dose. Secondary objectives include characterization of pharmacokinetic properties and pharmacodynamic effects. Recruitment for Arm C is ongoing. NCT02734615 Citation Format: Curigliano G, Cresta S, Yap Y-S, Juric D, Duhoux FP, Terret C, Takahashi S, Layman RM, Kundamal N, Baldoni D, Liao S, Crystal A, Jhaveri K. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-03-01.

A Population‐wide study of electrocardiographic (ECG) norms and the effect of demographic and anthropometric factors on selected ECG characteristics in young, Southeast Asian males—results from the Singapore Armed Forces ECG (SAFE) study

Routine use of pre-participation electrocardiograms (ECGs) has been used by the Singapore Armed Forces, targeting early detection of significant cardiac diseases. We aim to describe the impact of demographic and anthropometric factors on ECG variables and establish a set of electrocardiographic reference ranges specific to a young male multiethnic Southeast Asian cohort. Between November 1, 2009, and December 31, 2014, 144,346 young male conscripts underwent pre-participation screening that included a 12-lead ECG, demographic and anthropometric measurements. The Chinese population had the longest PR interval (146.7±19.7 vs. 145.21±19.2 in Malays vs. 141.2±18.8ms in Indians), QRS duration (94.5±9.8 vs. 92.6±9.7 in Malays vs. 92.5±9.4ms in Indians) and QTcB interval (408.3±21.3 vs. 403.5±21.6 in Malays vs. 401.2±21.4ms in Indians) (all p<0.001). Body mass index (BMI) >25kg/m2 and body fat >25% were independently associated with lower prevalence of increased QRS voltage on ECG. Systolic blood pressure of >140mmHg or diastolic blood pressure of >90mmHg independently increased the prevalence of increased QRS voltage on ECG. Electrocardiographic parameters vary across different ethnicities and in comparison with international norms. In our population, diagnosis of increased QRS voltage by ECG is less prevalent with obesity and increased body fat. Further analysis of gold standard measurements for the diagnosis of LVH in our population is ongoing, to improve the accuracy of the ECG screening process.

Management of Pediatric Chest Pain, Palpitations, Syncope, and Murmur Presenting to the Emergency Department

Chest pain, palpitations and syncope are amongst the most common symptoms presenting to the emergency department (ED). A finding of a murmur, although rare to present as primary cause for ED visit, can often be an associated finding noted during the evaluation. Although these symptoms can be very alarming to patients and parents, they are infrequently associated with significant cardiac disease. Although the cardiac etiologies for these common symptoms are rare, these cardiac conditions can sometimes be life threatening. This review examines these presenting symptoms of chest pain, syncope and palpitations or the finding of murmur for possible differential diagnoses.

The impact of continuous positive airway pressure treatment on the recurrence of atrial fibrillation post cardioversion: A randomized controlled trial

BackgroundObservational data suggest that positive airway pressure (PAP) treatment of obstructive sleep apnea (OSA) can reduce the risk of recurrent atrial fibrillation (AF) post-direct current cardioversion (DCCV) or catheter ablation. MethodsWe conducted a study of adult patients with AF and sleep apnea, stratified by age and gender, who underwent successful DCCV to sinus rhythm, and who were randomized to receive PAP or usual care. Those with sleepiness, significant cardiac or respiratory disease were excluded. Patients were followed for ≤1 year. Primary outcome assessed was time to AF recurrence. Secondary outcomes included sleepiness and quality of life measured using the Epworth Sleepiness Scale (ESS) and Functional Outcome of Sleep Questionnaire (FOSQ) respectively. ResultsOf 1757 patients that were screened, 34 underwent polysomnography for this study, 25 of whom had an apnea-hypopnea index (AHI) >5/h. Twelve were randomized to PAP therapy and 13 to usual care. All eligible patients were found to have OSA. There were no differences in body mass index, blood pressure, ejection fraction, AHI, or nocturnal oxygen parameters between intervention and control groups (all p > 0.05). AF recurred in 25% of patients in the PAP and control groups, at 129.0 ± 166.5 versus 109.3 ± 73.2 days respectively, p = 0.98; there were no differences in ESS (5.8 ± 2.6 versus 5.7 ± 2.3; p = 0.17) or FOSQ (18.3 ± 1.5 versus 17.5 ± 1.9; p = 0.26) at follow-up. ConclusionsThis is the first randomized controlled trial assessing the impact of treatment of OSA on recurrence of AF post-DCCV, and did not detect a difference between those treated with PAP versus usual care. Clinical trial registrationClinicaltrials.gov, identifier number: NCT00263757.

Ultrasound Assessment of the Change in Carotid Corrected Flow Time in Fluid Responsiveness in Undifferentiated Shock.

Adequate assessment of fluid responsiveness in shock necessitates correct interpretation of hemodynamic changes induced by preload challenge. This study evaluates the accuracy of point-of-care Doppler ultrasound assessment of the change in carotid corrected flow time induced by a passive leg raise maneuver as a predictor of fluid responsiveness. Noninvasive cardiac output monitoring (NICOM, Cheetah Medical, Newton Center, MA) system based on a bioreactance method was used. Prospective, noninterventional study. ICU at a large academic center. Patients with new, undifferentiated shock, and vasopressor requirements despite fluid resuscitation were included. Patients with significant cardiac disease and conditions that precluded adequate passive leg raising were excluded. Carotid corrected flow time was measured via ultrasound before and after a passive leg raise maneuver. Predicted fluid responsiveness was defined as greater than 10% increase in stroke volume on noninvasive cardiac output monitoring following passive leg raise. Images and measurements were reanalyzed by a second, blinded physician. The accuracy of change in carotid corrected flow time to predict fluid responsiveness was evaluated using receiver operating characteristic analysis. Seventy-seven subjects were enrolled with 54 (70.1%) classified as fluid responders by noninvasive cardiac output monitoring. The average change in carotid corrected flow time after passive leg raise for fluid responders was 14.1 ± 18.7 ms versus -4.0 ± 8 ms for nonresponders (p < 0.001). Receiver operating characteristic analysis demonstrated that change in carotid corrected flow time is an accurate predictor of fluid responsiveness status (area under the curve, 0.88; 95% CI, 0.80-0.96) and a 7 ms increase in carotid corrected flow time post passive leg raise was shown to have a 97% positive predictive value and 82% accuracy in detecting fluid responsiveness using noninvasive cardiac output monitoring as a reference standard. Mechanical ventilation, respiratory rate, and high positive end-expiratory pressure had no significant impact on test performance. Post hoc blinded evaluation of bedside acquired measurements demonstrated agreement between evaluators. Change in carotid corrected flow time can predict fluid responsiveness status after a passive leg raise maneuver. Using point-of-care ultrasound to assess change in carotid corrected flow time is an acceptable and reproducible method for noninvasive identification of fluid responsiveness in critically ill patients with undifferentiated shock.

Evidence Basis for a Point-of-Care Ultrasound Examination to Refine Referral for Outpatient Echocardiography

Few data exist on the potential utility of a cardiac point-of-care ultrasound (POCUS) examination in the outpatient setting to assist diagnosis of significant cardiac disease. Using a retrospective sequential cohort design, we sought to derive and then validate a POCUS examination for cardiac application and model its potential use for prognostication and cost-effective echo referral. For POCUS examination derivation, we reviewed 233 consecutive outpatient echo studies for 4 specific POCUS "signs" contained therein representing left ventricular systolic dysfunction, left atrial enlargement, inferior vena cava plethora, and lung apical B-lines. The corresponding formal echo reports were then queried for any significant abnormality. The optimal POCUS examination for identifying an abnormal echo was determined. We then reviewed 244 consecutive outpatient echo studies from another institution for associations between the optimal POCUS examination, clinical variables, and referral source with major adverse cardiac events and all-cause mortality in univariate and multivariate models. Assuming a referral model where the absence of POCUS signs or variables would negate initial echo referral, theoretical cost savings were expressed as a percentage in reduction of echo studies. In the derivation cohort, the combination of two signs, denoting left atrial enlargement and inferior vena cava plethora resulted in the highest accuracy of 72% [95% CI: 65%, 78%] in detecting an abnormal echocardiogram. In the validation cohort, mortality at 5.5 years was 14.6% overall, 23% in patients with the left atrial enlargement sign (OR 3.5 [1.6, 7.6]), 25% with inferior vena cava plethora sign (OR 2.2 [0.8, 6.0]), and 8.0% (OR 0.3 [0.2, 0.7]) in those lacking both signs. After adjusting for age, both diabetes (OR 4.8 [2.0, 11.6]), and the left atrial enlargement sign (OR 2.4 [1.1, 5.4]) remained independently associated with mortality (p<0.05). In the referral model, patients younger than 65 years of age without diabetes and without the left atrial enlargement sign would not have received echo referral, resulting in a 33% reduction in total echo cost and would have constituted a low-risk group with a 1.2% 5.5-year mortality. A quick-look sign for left atrial enlargement is associated with 5-year mortality and could function as an easily obtained outpatient POCUS examination to help in identifying patients in need of echo referral.

Distinct monocyte subset phenotypes in patients with different clinical forms of chronic Chagas disease and seronegative dilated cardiomyopathy.

BackgroundChronic infection with Trypanosoma cruzi leads to a constant stimulation of the host immune system. Monocytes, which are recruited in response to inflammatory signals, are divided into classical CD14hiCD16—, non-classical CD14loCD16+ and intermediate CD14hiCD16+ subsets. In this study, we evaluated the frequencies of monocyte subsets in the different clinical stages of chronic Chagas disease in comparison with the monocyte profile of seronegative heart failure subjects and seronegative healthy controls. The effect of the anti-parasite drug therapy benznidazole on monocyte subsets was also explored.Methodology/Principal findingsThe frequencies of the different monocyte subsets and their phenotypes were measured by flow cytometry. Trypanosoma cruzi-specific antibodies were quantified by conventional serological tests. T. cruzi-infected subjects with mild or no signs of cardiac disease and patients suffering from dilated cardiomyopathy unrelated to T. cruzi infection showed increased levels of non-classical CD14loCD16+ monocytes compared with healthy controls. In contrast, the monocyte profile in T. cruzi-infected subjects with severe cardiomyopathy was skewed towards the classical and intermediate subsets. After benznidazole treatment, non-classical monocytes CD14loCD16+ decreased while classical monocytes CD14hiCD16—increased.Conclusions/SignificanceThe different clinical stages of chronic Chagas disease display distinct monocyte profiles that are restored after anti-parasite drug therapy. T. cruzi-infected subjects with severe cardiac disease displayed a profile of monocytes subsets suggestive of a more pronounced inflammatory environment compared with subjects suffering from heart failure not related to T. cruzi infection, supporting that parasite persistence might also alter cell components of the innate immune system.

Lamotrigine pharmacokinetics following oral and stable-labeled intravenous administration in young and elderly adult epilepsy patients: Effect of age.

The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability. Patients (>18years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3). Twenty-eight patients representing 16 young (18-48years old) and 12 elderly (63-87years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80L/h for a 70-kg patient). Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.

Abstract 265: TGF Beta Signaling and Fibrosis in cMyBP-C-dependent Cardiac Disease

Background: Mutations in cardiac myosin binding protein C ( MYBPC3 ) account for more than one third of identified hypertrophic cardiomyopathy (HCM). Data from both human patients and mouse models suggest that cardiac fibrosis preceeds hypertrophy and cardiac dysfunction, implying that fibrosis related signaling may be one of the initial signs of developing cardiac disease. We wished to determine if cardiomyocyte-autonomous TGFβ signaling is sufficient to initiate pathogenic fibrosis in the heart in the context of a cMyBP-C-induced disease. Methods and Results: Neonatal rat ventricular cardiomyocytes (NRVMs) expressing either wild-type or Mybpc3 mutations were mediated by adenovirus for 48 hours. Both cells and culture medium (conditional medium) were harvested. The fibrotic effects of the conditional medium on neonatal rat ventricular fibroblasts (NRVFs) were determined using “fibrotic” gene promoters driving luciferase (luc) expression ( αSMA-luc , postn-luc and col1a1-luc ). TGFβ levels in the conditional medium were determined using ELISA assays. Expression of cMybpc3 mutations activated TGFβ promoter activity ( Tgfb1-luc , Tgfb2-luc and Tgfb3-luc ) in a TGFβ receptor(s) (TβRs) dependent manner. Upregulation of TGFβ was also confirmed in transgenic mice expressing a fragment of cMyBP-C (cMyBP-C 40kDa ) whose expression results in significant fibrosis and cardiac disease. To establish causality, we genetically ablated TGFβ receptors ( Tgfbr1 and Tgfbr2 ) in the cardiomyocytes of the cMybpc3 40kDa mice. TGFβ receptors ablation blocked the induction of TGFβ expression, alleviating cardiac fibrosis and decreasing cardiac hypertrophy. Cardiac function was significantly improved and survival of the cMyBP-C 40kDa mice was increased. Conclusions: Cardiomyocytes are a critical source of TGFβ in cMyBP-C 40kDa hearts during the initial stages of pathogenesis. Thus, TβRs ablation at the early stage completely prevent the progression of the pathological process in vivo .

Multidisciplinary care for pregnant women with cardiac disease: A mixed methods evaluation

BackgroundCardiac disease is associated with adverse outcomes in pregnancy and is the leading cause of indirect maternal death in the United Kingdom (UK) and internationally. National and international guidelines recommend women should receive care from multidisciplinary teams; however evidence is lacking to inform how they should be operationalised. ObjectivesTo describe the composition and processes of multidisciplinary care between maternity and cardiac services before, during and after pregnancy for women with cardiac disease, and explore clinicians’ (cardiologists, obstetricians, nurses, midwives) and women’s experiences of delivering/receiving care within these models. DesignMixed-methods comprising case-note audit, interviews and observation. SettingTwo inner-city National Health Service (NHS) maternity units in the south of England serving similar obstetric populations, selected to represent different models of multidisciplinary team care. ParticipantsWomen with significant cardiac disease (either arrhythmic or structural, e.g. tetralogy of fallot) who gave birth between June 1 st 2014 and 31 st May 2015 (audit/interviews), or attended an multidisciplinary team clinic (obstetric/cardiac) during April 2016 (observation). MethodsA two-phase sequential explanatory design was undertaken. A retrospective case-note audit of maternity and medical records (n = 42 women) followed by interviews with a sub-sample (n = 7 women). Interviews were conducted with clinicians (n = 7) and observation of a multidisciplinary team clinic in one site (n = 8 women, n = 4 clinicians). ResultsThe interests and expertise of individual clinicians employed by the hospital trusts influenced the degree of integration between cardiac and maternity care. Integration between cardiac and maternity services varied from an ad-hoc ‘collaborative’ model at Site B to an ‘interdisciplinary’ approach at Site A. In both sites there was limited documented evidence of individualised postnatal care plans in line with national guidance. Unlike pathways for risk assessment, referral and joined care in pregnancy for women with congenital cardiac disease, pathways for women with acquired conditions lacked clarity. Midwives at both sites were often responsible for performing the initial maternal cardiac risk assessment despite minimal training in this. Clinicians and women’s perceptions of ‘normality’ in pregnancy/birth, and its relationship to ‘safe’ maternity care were at odds. ConclusionThe limited evidence and guidance to support multidisciplinary team working for pregnancy in women with cardiac disease – particularly those with acquired conditions – has resulted in variable models and pathways of care. Evidence-based guidance regarding the operationalisation of integrated care between maternity and cardiac services – including pathways between local and specialist centres – for all women with cardiac disease in pregnancy is urgently required.

Significant cardiac disease complicating Graves' disease in the young

Significant cardiac disease complicating Graves' disease in the young

Abstract GS3-04: A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer (the SOLD study)

Abstract Background: The optimal duration of trastuzumab (T), when given together with chemotherapy and after chemotherapy as adjuvant treatment in patients with HER2+ breast cancer (BC), is unknown. Whilst the international standard is 12 months of T, the benefits and harms of T treatment continued beyond the chemotherapy are unclear. Methods: Women with histologically confirmed node-negative or node-positive HER2+ BC were eligible for the trial (NCT00593697). The primary tumor diameter was required to be &amp;gt;5 mm in node-negative cancer. Patients with distant metastases, inflammatory cancer, clinically significant cardiac disease, left ventricular ejection fraction (LVEF) &amp;lt;50%, unknown estrogen receptor (ER) status, World Health Organization performance status &amp;gt;1, and those who had received neoadjuvant systemic cancer therapy were excluded. Patients were randomly assigned to 2 groups prior to starting systemic cancer therapy. The initial systemic treatment was identical in the groups consisting of 3 cycles of 3-weekly docetaxel plus T followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (FE75C). Thereafter, no further T or chemotherapy was administered in Arm A, whereas in Arm B single-agent T was administered 3-weekly for 14 cycles to complete 1 year of T treatment. The docetaxel dose was either 80 mg/m2 or 100 mg/m2 (prespecified for each center). Radiation therapy and endocrine therapy (for patients with ER+ cancer) were given according to the institutional practice; the minimum scheduled duration of endocrine therapy was 5 years. The LVEF was measured pretreatment, and on study weeks 18, 31, 43, and 61 and month 36. The primary endpoint was disease-free survival (DFS) compared between the groups using a Cox model and the non-inferiority approach. Results: A total of 2,176 patients were entered into the study from 63 centers in 7 countries from Jan. 3, 2008 to Dec.16, 2014. The median follow-up time was 5.2 years at data collection closure (Dec. 31, 2016). The efficacy and safety data will be presented at the meeting. Citation Format: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Yachnin J, Turpeenniemi-Hujanen T, Ritchie D, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen P-L, Lindman H. A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer (the SOLD study) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-04.

Perioperative transesophageal echocardiography for non-cardiac surgery.

The use of transesophageal echocardiography (TEE) has evolved to include patients undergoing high-risk non-cardiac procedures and patients with significant cardiac disease undergoing non-cardiac surgery. Implementation of basic TEE education in training programs has increased across a broad spectrum of procedures in the perioperative arena. This paper describes the use of perioperative TEE in non-cardiac surgery and provides an overview of the basic TEE examination. Perioperative TEE is used to monitor hemodynamic parameters in non-cardiac procedures where there is a high risk of hemodynamic instability. Its use extends to include moderate-risk procedures for patients with significant cardiac diseases such as low ejection fraction, hypertrophic cardiomyopathy, severe valve lesions, or congenital heart disease. Vascular procedures involving the aorta, blunt trauma, and liver transplantation are all examples of procedures that may benefit from TEE. Transesophageal echocardiography examination allows assessment of volume status, ventricular function, diagnosis of gross valvular pathology and pericardial tamponade, as well as close monitoring of cardiac output, response to therapy, and the impact of ongoing surgical manipulation. In patients with unexplained and unexpected hemodynamic instability, "rescue TEE" can be used to help identify the underlying cause. Perioperative TEE is emerging as a preferred tool to manage hemodynamics in high-risk procedures and in high-risk patients undergoing non-cardiac surgery. A rescue TEE examination protocol is a helpful approach for early identification of the etiology of hemodynamic instability.

Cardiomegaly Associated With Tacrolimus Use in Pediatric Liver Transplantation

Introduction: There have been multiple case reports and autopsy studies associating the use of tacrolimus in organ transplant recipients with the development of cardiomegaly and left ventricular hypertrophy. There has been one prospective study reporting two cases of cardiac toxicity associated with tacrolimus; however, both the cases occurred in patients whose tacrolimus levels were above 30 ng/ml. Further studies are required to evaluate the association between tacrolimus use and cardiotoxicity. We aim to evaluate the association between tacrolimus use within therapeutic drug level goal of 8-12 ng/ml with cardiomegaly in pediatric liver transplant recipients at our institution. Methods: This is a retrospective study involving pediatric liver transplant recipients, with no prior cardiomegaly, who received tacrolimus for maintenance immunosuppression. All patients between the ages of 0-19 years, who were transplanted between January, 2007 to December, 2016, were included in the study. Patients with previous history of cardiomegaly were excluded from the study. We reviewed their electronic medical records for findings of cardiomegaly or ventricular hypertrophy on chest x-ray, EKG, echocardiogram and CT chest. Patients with positive findings on either of these were evaluated for clinically significant cardiac disease based on change in medication or cardiology consultation. Results: Total 63 patients were included in this study. Two patients who died in the immediate post-operative period were excluded from the study. Out of 61 patients, 8 patients (13%) had chest x-ray findings of cardiomegaly or enlargement of cardiac silhouette and 7 patients (11%) had EKG findings of ventricular hypertrophy. Only 2 patients (3%) had positive echocardiogram. None of these patients had any clinical implications of cardiomegaly as evidenced by the absence of cardiology consultation, tacrolimus dose modification or discontinuation. Conclusion: Tacrolimus-related cardiomegaly seems to be associated with higher drug levels. Tacrolimus drug level required for maintenance immunosuppression in liver transplant patients does not seem to be associated with tacrolimus-related cardiomegaly. Thus, tacrolimus can be safely used for long-term immunosuppression in liver transplant patients as long as there is close drug level monitoring.

An evaluation of cardiac murmurs in new-born

Background: Congenital heart disease (CHD) is defined as a structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance. The aim of the study is to assess the prevalence of congenital heart disease in new-borns with cardiac murmurs and to study the spectrum of cardiac diseases in new-borns with cardiac murmur.Methods: All the new-borns with cardiac murmurs were evaluated with ECG, Chest X ray and ECHO. They were classified into normal, mild, moderate and severe heart disease.Results: Of the 3375 babies analysed, 80 babies had murmur. ECHO could not be done in 8 babies. Of the 72 babies, 75% of new-borns with murmur had cardiac disease. The prevalence of cardiac disease in this population is 16 per 1000 new-borns. The prevalence of cardiac disease in new-borns with murmur is 750 in 1000 new-borns .94.5% had acyanotic heart disease and 5.5% had cyanotic heart disease. VSD was the most common lesion. 13.9% had severe heart disease, 20.8% had moderate heart disease and 40.3% had mild cardiac disease. There was good correlation between the degree of murmur and the severity of the cardiac disease. Chest X ray contributed only 12.5% to diagnosis of cardiac disease and ECG contributed only 5.3% to the diagnosis. If both ECG and Chest X ray were abnormal,there was 100% association with significant cardiac disease. No correlation was found between gestational age and birth weight and severity of heart Disease.Conclusions: Present study has proved that any murmur in newborn requires evaluation with ECHO as 75% of new-borns with audible murmur had cardiac disease of which 34.7% was moderate to severe heart disease. Abnormal ECG and Chest X ray was 100% associated with severe heart disease.

Study of Serum Irisin in Patients with Thyroid Dysfunction

Background: irisin, identified as a proteolytic cleavage product of the fibronectin type III domain-containing protein 5 (FNDC5), It is a novel myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via ‘browning’ of white adipose tissue. Irisin causes a significant increase in total body energy expenditure and resistance to obesity-associated insulin resistance in mice, while controversy still exists concerning irisin origin, regulation and function in humans. Aim of the work: our study aimed to detect relation of thyroid status (hypo, hyperthyroid) with serum irisin, ck and peripheral neuropathy. Patient and methods: this study was conducted on 60 candidates consisted of 40 patients with thyroid dysfunction selected from Endocrine outpatient Clinic and Inpatient Department of Ain Shams University Hospitals and 20 healthy volunteers from April 2016 to October 2016. Informed consent was obtained from all participants. Patients of both genders, age more than 18 years old, 20 patients with hypothyroidism, 20 patients with hyperthyroidism and 20 healthy volunteers. We excluded significant renal, hepatic and cardiac disease, severe associated acute illness or depression, pregnant females, diabetes, hypercortisolism, hypocortisolism, muscular or neurological disorders, routinely taking drugs as statins, intensively involved in a sport or any strenuous physical activity. All participants were subjected to full medical history taking, general clinical examination and laboratory investigations as thyroid and thyroid-related hormone concentrations as well as a thyroid ultrasound examination and thyroid scan for patients with hyperthyroidism. Serum irisin level, CK and nerve conduction velocity were measured. Results: irisin level was higher in hyperthyroid group than euthyroid group with a significant difference. In comparison with normal NCV candidates and reduced NCV candidates with other variables there was only border line significant difference with irisin p-value. Non significant value of irisin and CK level were detected for diagnosis of hypothyroidism. Irisin has highly significant value for diagnosis of hyperthyroidism with (sen 95%, sp 42.5). Increased BMI is the only independent predictor for hypothyroidism by using multivariable binary logistic regression analysis. Decreased BMI and irisin are independent predictors for hyperthyroidism. Conclusion: serum irisin level is one of predictors for hyperthyroidism, on the other hand irisin does not have a significant value to predict hypothyroidism. Serum irisin was found to be higher in patients with hyperthyroidism in comparison with euthyroid participant with non statistically significant difference between hypo and hyperthyroidism. Serum CK level does not have a significant value in diagnosis of thyroid dysfunction (hypothyroidism or hyperthyroidism). Serum irisin level was low in thyroid dysfunction cases with delayed NCV compared to thyroid dysfunction cases and normal NCV with border line significant difference.

PVCs, PVC-Induced Cardiomyopathy, and the Role of Catheter Ablation.

Premature ventricular contractions (PVCs) are common arrhythmias noticed in the clinical setting because of premature depolarization of the ventricular myocytes. Although often thought to be reflective of underlying disease rather than intrinsically harmful, PVCs have recently been linked with worse outcomes in patients without significant cardiac disease. Long-term exposure to a high PVC burden can lead to the development of PVC-induced cardiomyopathy. The pathogenesis of this condition is poorly understood at the current time. Many studies have suggested that catheter ablation of these PVCs may result in reversal of the PVC-induced cardiomyopathy. This article will go over the natural history of PVCs and PVC-induced cardiomyopathy, as well as review the current literature on the role of catheter ablation in treating PVC-induced cardiomyopathy.