Drop In LVEF Research Articles

Left Ventricular Assist Device (LVAD) Explant versus Decommissioning for LV Recovery

<h3>Purpose</h3> Left ventricular assist device (LVAD) explant or decommission for LV recovery is rare (1-2%). Furthermore, details regarding appropriate patient selection, surgical technique and short- and long-term patient outcomes are limited (1,2). Four different surgical techniques have been described for cessation of LVAD support for LV recovery (3). The purpose of our study is to describe our experience for patients undergoing LVAD explantation or decommission. <h3>Methods</h3> We retrospectively reviewed the surgical technique and outcomes for our LVAD patients who were explanted and decommissioned between 2010 and 2020. Baseline demographics were examined. Specific surgical techniques utilized along with outcome analysis including infection, thromboembolic events, LVEF change, need for re-implantation and death were analyzed. <h3>Results</h3> Thirteen patients were identified who underwent either LVAD explant or decommission with a mean age of 43. All patients had underlying non-ischemic cardiomyopathy. Nearly half (53%) of the patients were selected due to a combination of LV recovery (mean LVEF 47% in this group) and an indication for device removal including pump thrombosis or infection (versus LV recovery alone). Surgical technique varied between full sternotomy with pump explant (69%) and thoracotomy with pump decommission (31%) depending on indication. Median follow up was 70 months. Results are displayed in table 1. In those with LV recovery alone, many experienced a drop in LVEF with clinical HF symptoms, but not resulting in re-implantation or mortality. All patients with infection and LV recovery experienced a drop in LVEF and recurrent HF, with a mortality rate of 50%. <h3>Conclusion</h3> LVAD explant or decomissioning can be performed via full sternotomy or thoracotomy depending on the indication. When performed for LV recovery and another reason, such as device infection, recurrent, severe HF can be fatal in this cohort. Careful monitoring of these patients is therefore required after such an operation.

Abstract PS13-39: Efficacy and tolerability of neoadjuvant Pertuzumab, Trastuzumab, and weekly Paclitaxel in Locally advanced Her-2 positive Breast cancer

Abstract Background:Administration of neoadjuvant Pertuzumab (P), trastuzumab (T) along with chemotherapy is the standard of care for the management of locally advanced/inflammatory Her-2 positive breast cancer. Neutropenia and diarrhea are often the significant side-effects observed with the commonly used chemotherapy regimens. We evaluated the efficacy and safety of neo-adjuvant regimen consisting of P and T with weekly paclitaxel (Pac) in locally- advanced Her-2 +ve patients.Methods: Patients with newly diagnosed Her-2 positive tumor were treated in a neo-adjuvant fashion. The schedule of the treatment regimen was; P on D-1 at a loading dose of 840 mg, followed by 420 mg every 3 weeks , T on D-1 at a dose of 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and Pac on D-1/8 at a dose of 80 mg/m2. Cycles were repeated every three weeks. A total of six cycles were given prior to the surgery. Herceptin was continued for a total of one year. NCCN guidelines were followed for adjuvant radiation and hormonal treatments. LVEF was measured at baseline and every 6 weeks during neo-adjuvant treatments.Results: A total of 64 women were treated between Mar 2014 - Mar 2019. Median age was 56 years (30-81). Twelve pts had T-1 disease, 43 had T-2, 7 had T-3 and, 2 pts. had inflammatory breast ca. Twenty five pts. (39%) had lymph node involvement at diagnosis. The receptor profile was: ER/PR +ve: 43 pts., ER+/PR-ve: 5 pts., ER/PR -ve: 16 pts. All patients completed the planned six cycles. Twenty seven pts. achieved a pCR (42.8%). Nine out of 16 ER/PR-ve patients (56.2%) had a pCR. Grade-3/4 neutropenia was seen in 7 patients (10.9%) but febrile neutropenia was not observed in any pt. (0%). Grade-3/4 diarrhea was seen only in 2 pt. (3.1%).Grade-3/4 neuropathy was seen in 4 pts. (6.2%). LVEF drop of more than 10% from baseline to less than 50% was seen in two patient (3.1%). No recurrence has been observed with a median follow-up of 31 months.Conclusions: A combination of Pertuzumab, Trastuzumab and weekly Paclitaxel (PTPac) delivers impressive pCR rates with an acceptable side-effects as compared to other commonly used chemotherapy regimens given along with anti-Her-2 therapy. This combination should be explored in larger studies. Citation Format: Niraj Gupta, Erica Giblin, Tara Spivey, Kristen Govert, Christopher Leagre, Robert Liebross, Vasu Tumati, Thomas Dugan, Rina Yadav, Patrick Henman, Nick Beaudrie, Tessa Bair, Jessica Durk, Marjaorie Hancock, Trisha Engle, Michelle Myers, Julie Schneiders, Thomas Tigges. Efficacy and tolerability of neoadjuvant Pertuzumab, Trastuzumab, and weekly Paclitaxel in Locally advanced Her-2 positive Breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-39.

Integrative characterization of asymptomatic vs. symptomatic patients with moderate-severe primary mitral regurgitation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by NHLBI and Specialized Centers of Clinically Oriented Research grant in cardiac dysfunction, by Department of Veteran Affairs for Merit Review and NIH Grant P01. Background Optimal timing for surgery in primary mitral regurgitation (PMR) is a subject of debate. Purpose Use a combination of imaging, circulating biomarkers and histology to define the transition from asymptomatic (asx) to symptomatic (sx) stage in moderate-severe PMR. Methods 57 controls, 82 sx and 47 asx patients with moderate to severe PMR underwent cardiac MR(CMR), plasma BNP, levels of xanthine oxidase (XO) activity, and circulating markers of collagen (Col) synthesis (propeptide of procollagen type I, PICP) and degradation (Col type I fibers, ICTP). Results A progressive worsening in the severity of adverse LV remodeling was noted based on CMR indices listed in Table 1. The 3D mid-wall LV endocardial curvature to wall thickness was lower in normal and similar in asx and sx patients.Plasma BNP was progressively higher in normal vs. asx vs sx (Figure 1A). The levels of XO activity were higher in sx vs. asx (Figure 1B,1C). Levels of PICP were similar among the three; levels of ICTP were significantly higher in the sx vs the asx (Figure 1D,1E). LV biopsies revealed large areas of patchy replacement fibrosis and areas devoid of interstitial Col (Figure 1F). From the subgroup of 56 patients who underwent CMR 6 months after surgery, 27% had LVEF &amp;lt; 50%. The preoperative LVEF, LVESV, LVESD and LA emptying fraction were predictors of postoperative drop in LVEF. Conclusion Increased COl breakdown coupled with markers of oxidative stress and CMR-based LV remodeling characterize the transition from asx to sx PMR. Longitudinal studies are needed to define cutoff"s for patient selection and optimal timing for MV surgery. CMR indices in normal, asx and sx PMR. Normal (57) Moderate/Severe MR Asymptomatic (56) Pre-Surgery MR Symptomatic (81) P-value Age 48 (34, 55) 54 (46, 62) * 57 (50, 67) * &amp;lt;0.0001 Female/Male 30(53%)/27(47%) 35(63%)/21(38%) 25(31%)/56(69%) LVEF (%) 64 (61, 67) 62 (59, 66) 63 (59, 67) 0.3482 LV EDV (mL/m2) 71 (61, 76) 89 (73, 103) * 100 (83, 123) *# &amp;lt;0.0001 LV ESV (mL/m2) 24 (21, 29) 32 (26, 38) * 36 (28, 47) * &amp;lt;0.0001 LVSV (mL/m2) 43 (37, 50) 54 (43, 66) * 60 (54, 77) *# &amp;lt;0.0001 LVED Mass/Volume 0.7 (0.6, 0.8) 0.6 (0.5, 0.7) * 0.6 (0.6, 0.7) * 0.0012 LVED Mass/Vol x SI 1.29 (1.05, 1.50) 0.97 (0.77, 1.15) * 0.94 (0.77, 1.14) * &amp;lt;0.0001 Regurgitant Volume (mL) ― 38 (26, 54) 57 (38, 83) # 0.001 Regurgitant Fraction (%) ― 39 (28, 50) 46 (36, 56) # 0.042 Table 1 shows the CMR indices of LV remodeling in normal, asymptomatic and symptomatic patients with moderate-severe PMR. p-values *vs. Normal; # vs. Asymptomatic. Kruskal-Wallis test or unpaired t-test Abstract Figure 1.

Impact of early post-stress 99mTc sestamibi ECG-gated SPECT myocardial perfusion imaging on the detection ofischemic LV dyssynchrony: an early step in the stunning cascade.

Transient alterations in ventricular conduction and synchronized cardiac performance have been reported in experimental models of myocardial ischemia. In post-stress 99mTc-sestamibi-gated-SPECT myocardial perfusion imaging (MPI), the time elapsed between tracer injection and image acquisition could influence the detection of ischemic left ventricular mechanical dyssynchrony (LVMD). We aimed at evaluating whether early vs. delayed post-stress MPI improve ischemic LVMD detection using the phase analysis parameters standard deviation (SD) and histogram bandwidth (HB) and to assess the correlation between stress-induced changes in SD and HB and other functional parameters. We prospectively studied 32 control subjects (Group-1) and 60 ischemic patients (Group-2). Stress-induced changes were calculated as stress minus rest (Δ). LVMD was defined as post-stress increases of either SD or HB. Group-2 showed higher ΔSD and ΔHB in early than in delayed images: early ΔSD: 1.63 (-0.37 to 4.83) vs. delayed ΔSD: -0.39 (-3.82 to 1.74); early ΔHB: 2.50 (-4 to 12) vs. ΔHB delayed: -4 (-15.75 to 4), all p < 0.01. ΔSD and ΔHB correlated linearly with ΔLV-ejection-fraction (EF) and ΔLV-end systolic-volume (ESV) in early images, all p < 0.01. Early images detected LVMD in more patients than delayed scans (78% vs. 38%; p < 0.01) All patients with LVEF drop in early post-stress evaluation had LVMD. Early post-stress images improve ischemic LVMD detection. Ischemic LVEF and LVESV changes correlate with ΔSD and ΔHB.

Value of baseline clinical and CMR characteristics for the prediction of cancer therapeutics-related cardiac dysfunction: results from the Cardiotoxicity Prevention Research Initiative (CAPRI)

Abstract Background Whether baseline cardiovascular health status significantly influences the risk of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD) in patients receiving de-novo chemotherapy exposure is an important clinical question for both surveillance and management decisions. The reference standard technique for the serial monitoring of left ventricular (LV) volumes and ejection fraction (EF) is cardiovascular magnetic resonance (CMR). Using this technique, we sought to prospectively evaluate baseline clinical risk factors and CMR-based pre-exposure characteristics for their influence on the incident occurrence of CTRCD. Methods We prospectively enrolled 371 cancer patients referred for baseline (pre-chemotherapy) followed by surveillance CMR imaging as part of the Cardiotoxicity Prevention Research Initiative (CAPRI). We also recruited 62 healthy volunteers to evaluate for referral population differences in CMR-based markers. Study subjects and healthy volunteers underwent identical CMR imaging protocols inclusive of cine imaging, T1 and T2 mapping. CTRCD was defined according to surveillance CMR imaging with criteria established as a drop in LVEF by &amp;gt;5% (meaningful detectable difference for CMR technique) to a value ≤56% (lower limit of normal) at any time point during chemotherapy surveillance. A total of 1474 CMR studies were performed over a median surveillance period of 12.5 months (range 2.3 to 68.9 months). Results The majority of patients were female (77%), being referred for breast cancer (64%) or lymphoma (36%), with a mean age of 54.0±14 years. The baseline prevalence of hypertension, diabetes, hyperlipidemia, and current smoking were 32%, 11%, 46%, and 13%, respectively. Compared to healthy volunteers, cancer patients at baseline showed smaller indexed LV and RV volumes, higher indexed LV mass, and higher native T1 values (mean difference +33 msec; p&amp;lt;0.001). LV and right ventricular (RV) EF and T2 mapping values were not significantly different. CTRCD criteria were met in 22% of patients. Figure 1 shows a forest plot of univariable and multivariable predictors of CTRCD occurrence. Following multivariable adjustment, only combined anthracycline/trastuzumab regimen (OR 4.4, 95% CI 2.0–9.5) and baseline indexed LVEDV (OR 2.3, 95% CI 1.2–4.5) were found to be significant predictors of this outcome. Conclusion Using the reference standard of serial CMR imaging we identified that of all baseline (pre-chemotherapy) clinical and CMR-based markers of cardiovascular health, only indexed LV end-doastolic volume (EDV) was independently associated with future occurrence of CTRCD following adjustment for chemotherapy regimen. We did not observe significant associations with conventional cardiac risk factors in our study population. The observed risk for indexed LVEDV was clinically meaningful (2.3-fold risk per 10 ml/m2) and warrants further investigation as a relevant baseline marker of risk in this referral population. Figure 1. Forest plot of predictors of CTRCD Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Alberta Innovates/Genome Alberta: CAPRI

The broad spectrum of cardiovascular adverse events related to immune check point inhibitors

Abstract Background Immunotherapy is one of the latest and most exciting developments in cancer treatment. Immune checkpoint inhibitors (ICI) have shown to have impressive positive results on several tumours such as melanoma, renal cancer and lung cancer, among others. Along with its benefits come the adverse effects which, concerning the heart, myocarditis is the most well-known and feared event. Yet, the spectrum of cardiovascular adverse events (CVAE) is much broader, ranging from heart failure to arrhythmias, but this has not been well documented until know. Objective Describe the broad spectrum of CVAE related to ICI Methods Observational retrospective, single centre study. We evaluated all the patients that have been referred to the cardio oncology (CO) unit and were under ICI treatment. The referred patients underwent a day case assessment with cardiovascular tests (blood tests, ECG, resting echocardiogram in all cases and MRI, stress echo or CT coronary angiogram if needed). The results were discussed in the multidisciplinary team meeting and the patients were then reviewed by one of the doctors in the team. The conclusions of the assessment were then communicated to the oncology team. Results From the year 2011 until December 2019, 71 patients receiving immunotherapy were referred to the CO unit. Three patients were excluded because they were referred for having an intracardiac tumour, leaving 68 for analysis. The first patient was referred in 2014 and during the first 3 years only 7 patients were reviewed in the CO unit. The frequency increased dramatically in 2017 to 17, 19 in 2018 and 25 in 2019. 21 patients were receiving Nivolumab, 24 on Ipilimumab, and 23 (34%) on combined therapy. The most frequent tumour was Melanoma (26/68, 38%). Regarding the CVAE: 22 patients (32%) were referred for investigtion of myocarditis. 6 had a diagnosis of definite myocarditis, 5 probable and 4 possible. Other CVAE (20/68, 29%) were the supraventricular arrhythmias including atrial fibrilation (20/68, 29%). 8 patients presented with non-inflammatory heart failure with new LVEF drop, 4 with chest pain, and 4 others with syncope. 1 patient developed pulmonary hypertension. Conclusions Myocarditis still remains the most frequent CVAE related to ICI, but the spectrum is broader than initially described. Supraventricular arrhythmias and non-inflammatory LVEF disfunction were very frequent in this series and we suspect that the incidence will increase as cardiologist and oncologists start considering them as probable adverse effects of this treatment. Funding Acknowledgement Type of funding source: None

Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2-positive breast cancer

IntroductionT-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. MethodsWe have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. ResultsIndividual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%–4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77–5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29–5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. ConclusionThe incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.

421 The Utility of Echocardiographic Myocardial Work in the Prediction of Cancer Therapy-Related Cardiac Dysfunction

Myocardial work (MW) is a novel technique which utilises speckle tracking strain derived global longitudinal strain (STGLS) in conjunction with the blood pressure to account for afterload. However there is limited data on the clinical utility of MW in the prediction of cancer therapy-related cardiac dysfunction (CTRCD). Therefore our aim was to determine if MW was superior to STGLS in the prediction of CTRCD. Women requiring anthracycline (A) and/or trastuzumab (T) containing chemotherapy regimens for breast cancer underwent serial cardiovascular magnetic resonance imaging (CMR) and echocardiography at baseline, 1, 4 and 12 months following chemotherapy. STGLS and MW parameters were measured, including global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE). 22 women were included in this study with 16 (73%) having adequate imaging for measurement of STGLS and MW parameters. At 4 months 6 (38%) patients had a drop of ≥10% in LVEF on CMR, although this change was not statistically significant (74.0±6.9% vs 60.8±6.0%, p=0.26) and only 1 patient had LVEF<55%. At 1 month, prior to any change in LVEF, the change in STGLS from baseline was not predictive of the future drop in LVEF at 4 months (p=0.06). Of the MW parameters only GWE was predictive of ≥10% drop in LVEF (4.17±3.7 vs -1.9±6.0%, p=0.04). As MW parameters account for changes in afterload they may be a more sensitive marker of subclinical CTRCD, however larger scale trials will better determine the utility in this patient population.

P249 Iatrogenic aortic cusp laceration causing severe acute traumatic aortic regurgitation secondary to complex percutaneous coronary intervention using rotablator;3DTEE-anatomic correlates

Abstract Clinical case 59 years old male known case of long standing diabetes and dyslipidemia presented to our institute with Non-STEMI.His past history was significant for multiple admissions with acute coronary syndromes and percutaneous coronary interventions(PCI). Echocardiogram in this presentation showed preserved biventricular systolic function with no valvulopathies. He was taken up for coronary angiogram which showed significant calcified angulated lesion in LAD/LCX(Left anterior descending and circumflex) with diffuse disease in Ramus/RCA. Mode of revascularisation was discussed in detail with the patient for Rotablation-guided PCI to LAD/LCX vs CABG.He preferred and underwent complex PCI to LAD. During the procedure he developed acute heart failure which was managed conservatively. Immediate TTE showed new severe aortic regurgitation(AR) with probable left coronary cusp(LCC) perforation and preserved LVEF.After stabilization, he was scheduled for TEE which showed tear in the LCC with complex fragmented jet of holodiastolic AR filling the entire LVOT.There was new late diastolic to early systolic MR.3DTEE Enface view of the aortic valve was evident of ovoid shaped laceration in LCC extending till the free margin (Fig 1C). There were additional tears in Non-coronary cusp(NCC) extending till the free margin of right coronary cusp(RCC).3DTEE colour was notable for regurgitant jet origin from LCC/NCC (Fig 2B). Based on above findings,He was offered aortic valve intervention but was reluctant initially.He presented 2 months later with exertional dyspnoea, mild LV dilatation and drop in LVEF to 50%.He consented for surgery and underwent bioprosthetic Aortic valve replacement because of extensive cusp tear and deformation of the valve along with complete revascularisation of the remaining diseased coronaries.Post-operative course was complicated by vasoplegic arrest and acute renal failure which was successfully managed conservatively. Discussion We report this case for the rarity of this post-PCI iatrogenic complication and the incremental role of 3DTEE in identifying the exact pathology.It was proposed that during PCI multiple stalling of rotatbur in calcified LAD caused traction and eventually disengagement of guide causing rotabur to freely hang in ascending aorta close to the cusps.Possibly this rotablator with very high speed(180000rpm) would have momentarily come in contact with the aortic cusps causing cuspal perforation and heart failure in Cath lab.3DTEE correlated very well with the anatomo-pathology and matched with intraoperative finding as shown in figures 2A &amp; 2C.These findings prior to aortic cross clamp could significantly reduce time of surgery as he had an additional CABG procedure to be performed.There are few isolated case reports of post PCI aortic valve perforation but probably ours is the first one secondary to the use of rotablator with near involvement of all the cusps and reasonably accurate 3DTEE-anatomic characterisation. Abstract P249 Figure.

Predicting for Cardiac Events Following Allogeneic Hematopoietic Stem Cell Transplantation in Adults

Introduction Cardiovascular (CV) complications occur after hematopoietic stem cell transplantation (HCT). Risk factors for events are unclear making it difficult to determine optimal pre-transplant screening. Solid organ transplants programs calculate pre-transplant risk to determine indication for further cardiac testing. Based on this, we investigated whether several commonly used CV risk calculators predicted for CV events after HCT. Methods This was a prospective case control study at a single academic institution. CV risk was estimated using the Framingham General CVD Risk Score (2008), ACC/AHA Pooled Cohort Hard CVD Risk (ASCVD; 2013) calculator, and JBS3 QRISK Lifetime calculator. Results Forty-eight patients transplanted between 2012 and 2016 were analyzed. 27 (56%) were female. Ages ranged from 53-74 with a median of 64. Diseases transplanted were: AML (38%), MDS (31%), Non-Hodgkin's lymphoma (15%), and others 47% had high risk for CVD (score>2) by Framingham score. 67% had high risk by ASCVD calculator (10 year risk >7.5%). 70% had high risk by QRISK Lifetime calculator. 9%were low risk by Framingham score, but high risk by QRISK Lifetime calculator. Cardiac events evaluated included atherosclerotic events (myocardial infarction and stroke), atrial fibrillation (a-fib), and others (other arrhythmia, CHF, drop in LVEF, and cardiac arrest). 40% had any cardiac event. 15% had an atherosclerotic event (MI or CVA). 21% had a-fib. Framingham Risk, ASCVD and QRISK calculators did not predict for either atherosclerotic events or any cardiac events after HCT [Table 1]. Risk factors for a-fib specifically, were also evaluated: history of MI, diastolic or systolic dysfunction, CHF, valvular disease, tobacco use, diabetes, and hypertension. Only CHF was a predictor for a-fib (p=0.08). Conclusion CVD risk calculators commonly used in the general population and by solid organ transplant programs did not predict for CV events post-HCT here. However, this analysis was limited by small study size. Study in a larger population is being planned to allow incorporation of transplant related variables to develop a HCT-specific multivariate risk calculator to accurately predict post-HCT CV events.

IMPACT OF CHEMOTHERAPY EXPOSURE ON RIGHT VENTRICULAR CONTRACTILE FUNCTION: A 12-MONTH SERIAL EVALUATION BY CARDIOVASCULAR MAGNETIC RESONANCE IMAGING

Adverse effects of chemotherapy on left ventricular (LV) performance is receiving intense exploration. However, the relative impact of these therapies on right ventricular (RV) function remains poorly studied. Given emerging evidence supporting prognostic significance for RV function in patients with cardiomyopathy, we aimed to prospectively study the relative impact of cardiotoxic chemotherapies on the RV over a 12-month exposure to Anthracycline-containing (Anthr) or Trastuzumab-alone (Tr) chemotherapy. Baseline, 3-, 6- and 12-month cardiovascular magnetic resonance (CMR) imaging was performed in 57 patients (total 288 CMR studies) referred for curative chemotherapy (Anthr=40, Tr=17) of either Breast cancer (N=52) or Lymphoma (N=5). The CMR imaging protocol included multi-axial cine imaging to allow for standardized, core-laboratory based analyses of LV and RV volumes and ejection fraction for all study time points. Interval changes (versus baseline) were established for chamber volumes and systolic function and analyzed for the entire population and for both of the Anthr and Tr sub-groups. The mean age was 52 ± 11 years (53 female). LVEF was 65.0± 5.3% with RV EF 60.2±5.1% at time of baseline evaluation. A ≥10% drop in LVEF occurred during follow-up in 28% of the Anthr group and 24% of the Tr group. A corresponding ≥10% drop in RVEF occurred in 43% of the Anthr group and 35% of the Tr group. Anthr patients showed an immediate and significant reduction in RVEF at the three-month study visit with a mean change of -4.6±6.1% (p<0.001) that persisted to 12 months. In the same group the LVEF dropped progressively over the 12-month period (-3.0±6.1% at three months, -3.9±6.1% at 6 months, and -4.2±6.1% at 12 months, p<0.001). Tr patients showed a modest reduction in RVEF at three months (-2.8±4.9%, p<0.05) followed by progressive recovery out to 12 months (-0.7±6.7%, p=0.7). In the same group the LVEF dropped progressively until six months (-5.2±5.0%, p=0.001) followed by recovery at 12 months (-2.4±4.9%, p=0.06). This study provides strong evidence for the RV having greater sensitivity to Anthracycline-based chemotherapy with earlier and a higher prevalence of contractile dysfunction versus the LV, each persisting out to 12 months. Trastuzumab monotherapy was associated with more modest and transient reductions. The prognostic significance of RV dysfunction in patients receiving Anthracycline based chemotherapy warrants expanded investigation.

Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.

577 Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m2) x 12 followed by FE(75 mg/m2)C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age &lt;65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to &lt; 50% following completion of chemotherapy. Thirteen patients (27%) had a &gt;10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828.

Safety of trastuzumab in women with HER2+ breast cancer.

e12522 Background: Trastuzumab is widely used in management of HER2+ breast cancer patients. A known adverse effect of trastuzumab use is cardiac dysfunction, which can often be reversed with cessation of therapy. Our objectives were to 1) assess if trastuzumab can be safely administered to breast cancer patients with reduced cardiac function and 2) identify patient characteristics that predict susceptibility to trastuzumab-induced cardiac dysfunction. Methods: A retrospective analysis was performed on female patients seen at Mayo Clinic for HER2+ breast cancer and treated with trastuzumab for localized or metastatic disease between January 1, 2000 and August 31, 2015. Eligibility criteria included documentation of and results from at least one echocardiogram prior to and at least one after trastuzumab initiation. Left ventricular (LV) ejection fraction (EF) of 53% or more was considered normal. Any LVEF reduction of 10% or more was considered significant. Among patients with normal EF, age strata of &lt; 45, 45-60, and &gt; 60 at time of trastuzumab initiation were used to assess risk factors for clinically diagnosed cardiac dysfunction (defined as EF &lt; 53 or abnormal strain and physical symptoms of heart failure (HF)). Results: We identified 335 women (mean age 53.3, with 25.3% age &lt; 45, 44.5% age 45-60, and 30.1% age &gt; 60) who had normal LVEF (median EF 64, range: 53-75) and 23 women (mean age 53.4, with 30.4% age &lt; 45, 43.5% age 45-60, and 26.1% age &gt; 60) who had low LVEF at baseline (median EF 52, range: 25-52). Approximately a third (34.3%) of women with normal LVEF prior to initiation of therapy had at least one subsequent echocardiogram showing a drop of 10% or a low LVEF ( &lt; 53). Approximately a quarter (26%) of women with low LVEF at baseline had a 10% drop in LVEF. HF incidence increased with age. Predictive factors for trastuzumab-induced cardiac dysfunction were obesity and history of coronary artery disease (CAD) across all age strata, and chest irradiation (IR) for those aged 45-60 only. Conclusions: Our results suggest that trastuzumab can be administered in women with reduced cardiac function at no greater risk than in those with preserved cardiac function. Some women with no obesity, history of CAD, or history of chest IR may not need echocardiograms during trastuzumab therapy.

Cardiotoxicity associated with carfilzomib: Systematic review and meta-analysis.

e21674 Background: Carfilzomib (Carf)is a novel proteasome inhibitor (PI) that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated cardiotoxicity (CT) is not well defined. We hypothesize that CT is more frequent than that seen with other PIs. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used 29 publicatons; phase I/II, phase II and phase III (n = 3) clinical trials in which Carf was used as monotherapy or in combination with other chemo agents. We excluded phase I studies and studies without CT data. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity was reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidence of all grades and high grades (≥ 3) CT (including arrhythmias, CHF with LVEF drop, and coronary syndrome) were 7.8% and 4.72%, respectively. When compared to control group taken from phase III clinical trials, the risk of developing CT due to Carf was significantly higher with OR of 1.90 and 2.03 (P &lt; 0.01) for all grades and high grades, respectively. Moreover, incidence of CT was significantly higher in Carf combination therapy (9.85%) compared to Carf monotherapy (5.40%) (P = 0.01). Furthermore, incidence of high grade CT was 7.5% and 5% with and without concomitant immunomodulatory agent (IMiD), respectively (P = 0.004). There was no variation in the incidence of CT among newly diagnosed versus RMM (P = 0.6), and no Carf dose effect. Mortality rate associated with cardiotoxicity was 1.5%. Conclusions: Overall incidence of Carf related CT seems to be higher than that reported with other PIs. Although, the pathophysiology is poorly understood, this trend could potentially be secondary to irreversible nature of proteasome inhibition by Carf. There seems to be a significant increase in CT with combination of Carf and an IMiD. Prior therapies and higher Carf doses have no effect on CT incidence.

Abstract P2-07-06: Obesity, dyslipidemia, and diabetes as risk factors for trastuzumab-related cardiotoxicity in breast cancer patients

Abstract Background. Clinical trials have demonstrated an increased risk of cancer treatment related cardiac dysfunction (CTCD) during trastuzumab(H) therapy. Diabetes, dyslipidemia, and obesity are also known risk factors for cardiovascular disease. The primary objective of this study was to evaluate the incidence of asymptomatic drop in left ventricular ejection fraction (AD-LVEF) and symptomatic CTCD (S-CTCD) in women with BC and co-morbidities receiving H, referred to a dedicated cardio-oncology clinic (COC). Methods. This was a retrospective cohort study of women with BC (all stages) referred to The Ottawa Hospital COC between 2008 and 2015, who received chemotherapy (CT) and H. Data collected included: demographics, reason for referral, cardiac testing (MUGA/ECHO) co-morbidities (diabetes, dyslipidemia) and cardiac outcomes. Obesity defined as body mass index &amp;gt; 30. Symptomatic CTCD include SOB, PND, orthopnea, peripheral edema, congestive heart failure. Asymptomatic drop in LVEF defined as decrease of at least 15% from baseline; normal LVEF, or a decrease of at least 10% in LVEF, less than 53%. Results. Chemotherapy (A-CT) followed by H, 62 received H without A-CT. 139 patients with no history diabetes, dyslipidemia, or obesity, referred with AD-LVEF (68%), with S- CTCD (30%), pre-CT assessment (2%). Obesity (O) pre-existing co-morbidity in 63 (26%) patients, (20 (32%) with S-CTCD, 40 (63%) referred with AD-LVEF, 3(5%) referred for pre-CT assessment). Dyslipidemia (L) – 52 (21%); referred with S-CTCD 15; 29%), with AD-LVEF 31 (60%), pre-CT assessment 6 (11). Diabetes (D) – 29 (12%) - (6 (21%) with S-CTCD, 19 (66%) referred with AD-LVEF, 4(13%) referred for pre-CT assessment). Combination of two or three conditions significantly increase incidence of S-CTCD: O+L – 67%, O+D – 69%, O+L+D – 72%. Combination of obesity and other conditions significantly increase incidence of S-CTCD: O+L – 67%(Relative Risk -2.2, p=0,04), O+D – 69% (RR-2.3, p=0,02), O+L+D – 72% (RR-2.4, p=0,08). Conclusion. The combination of two or three co-morbidities significantly increases the incidence of S-CTCD. BC patients experiencing CTCD with pre-existing history of diabetes, dyslipidemia, and obesity may require more proactive strategies for prevention, detection and treatment of cardiotoxicity during trastuzumab-based treatment. Citation Format: Aseyev O, Johnson C, Turek M, Stadnick E, Law A, Gosh N, Dent S. Obesity, dyslipidemia, and diabetes as risk factors for trastuzumab-related cardiotoxicity in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-06.

Abstract P4-21-09: Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06)

Abstract Background:Anti-HER2 agents are associated with an increased risk of cardiotoxicity, occurring mostly during treatment and being generally reversible. To date, no cardiac biomarkers have been validated as predictive markers of cardiotoxicity in patients (pts) receiving anti-HER2 therapies. We evaluated high sensitivity (HS) troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pts treated with neoadjuvant anti-HER2 therapies to evaluate if early elevation of cardiac biomarkers predicts early or late cardiac events. Material and Methods: 455 pts were randomized to receive either lapatinib (154 pts), trastuzumab weekly (149 pts), or lapatinib with trastuzumab for a total of 6 weeks (152 pts). After this biological window, pts continued on the same targeted therapy plus 12-weekly paclitaxel until definitive surgery. After surgery, patients received adjuvant FEC (3x) followed by the same HER2 therapy as in the neoadjuvant phase for further 34 weeks (to complete 52 weeks in total). Eligible pts had an LVEF ≥50%. Cardiac biomarkers were centrally tested in plasma samples collected at baseline, week 2 (W2) and at surgery. Elevated biomarker was defined as either TNT &amp;gt;0.015 μg/L or NT-proBNP &amp;gt;125 pg/mL. The small number of pts and rarity of marker elevations allowed only descriptive analyses. Results: At a median follow-up of 3.8 years, 280 pts had cardiac biomarkers tested at baseline (61.5%) and NT-proBNP was elevated in 39 pts (13.9%) while TNT was elevated in only 1 pt (0.35%). From those 39 pts with NT-proBNP elevated at baseline, only 1 pt experienced a cardiac event. Also, hypertension was presented in 14 pts (24.5%) with elevated NT-proBNP. Serial measurements were available in 173 pts (61.7%) and NT-proBNP was elevated in 25, 10 and 21 pts at baseline, W2 and at surgery, respectively, while among 171 pts (61%) TNT was elevated in 1, 1 and 5 pts, respectively. There were 13 cardiac events in 11 pts in the entire trial. Five of these pts had a measurement of cardiac biomarkers at baseline (non-elevated NT-prBNP and TNT were observed in 4 and 5 pts), 9 of them had a measurement at week 2 (non-elevated NT-prBNP and TNT were observed in 8 and 9 pts) and 3 of them at surgery (non-elevated NT-prBNP and TNT were observed in 3 and 3 pts), respectively. The following table show the low specificity of the cardiac biomarkers. Patients without cardiac event (N)Patients with cardiac event (N)Patients with elevated markerElevated NT-proBNP Baseline38139Week 229130Surgery40040Elevated TNT Baseline101Week 2101Surgery606 During adjuvant phase, 13 pts experienced LVEF drop to &amp;lt;50% and none had either NT-proBNP elevated or TNT at surgery. Conclusions: Despite the small sample size, we demonstrated that cardiac biomarkers are rarely elevated in pts receiving anti-HER2 therapies, which is probably due to the absence of myocyte necrosis with respect to TNT, and the lack of chamber dilation in the case of NT-proBNP after exposure to these drugs. In addition, few cardiac events were present in this population not previously exposed to anthracycline-based chemotherapy; therefore the use of cardiac biomarkers in this population may be unnecessary. Citation Format: de Azambuja E, Bradbury I, Ewer M, Campbell C, Zardavas D, Ameels H, Baselga J, Huober J, Izquierdo M, Bozovic-Spasojevic I, Maetens M, Harbeck N, Pusztai L, Piccart M, Rodeheffer R, Sutter T. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-09.

Early Evidence of Cardiotoxicity and Tumor Response in Patients with Sarcomas after High Cumulative Dose Doxorubicin Given as a Continuous Infusion.

Background Despite the dose-dependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. This study evaluates early evidence of cardiotoxicity in patients treated with high-dose doxorubicin given as a continuous infusion. Methods Data was collected on patients who received 90 mg/m2 doxorubicin as a continuous infusion and 10 gm/m2 ifosfamide for up to 6 cycles as part of a phase II study. Cardiotoxicity was assessed with serial echocardiograms or multigated acquisition scans and serum brain natriuretic peptide and troponin levels. Tumor responses were determined by serial radiographic imaging per RECIST. Result Out of the 48 patients enrolled, no patient developed heart failure symptoms; however, 4 out of the 38 (10%) patients with serial left ventricular ejection fraction assessments developed subclinical cardiotoxicity (asymptomatic drop in LVEF ≥ 10%). Twenty-three patients received all six 72-hour cycles of doxorubicin with a mean cumulative dose of 540 mg/m2. Among these patients, 4% (n = 1) developed subclinical cardiotoxicity. In the advanced disease group (n = 39), patients with a complete or partial response received a higher mean cumulative dose than those with stable disease (p < 0.033). Conclusions Doxorubicin cardiotoxicity can be limited by administering doxorubicin as a continuous infusion, allowing higher cumulative dosing to maximize efficacy.

Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up.

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Abstract P2-11-02: Robust generation of T cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine

Abstract Background: Recent studies have indicated that vaccination can protect against cancer development. One key aspect of developing vaccines is circumventing peripheral tolerance by identifying subdominant epitopes that are unique to the deregulated tumor microenvironment. While existing subdominant epitope vaccines are showing efficacy in preventing cancer, these vaccines are applicable only for subsets of patients with specific HLA subtypes. Therefore, we recently developed a degenerate HER2 subdominant epitope-based vaccine that should be useful in approximately 85% of all patients. The vaccine consists of a pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) that are naturally processed and are designed to elicit helper T cell immunity, the cornerstone of immune surveillance. Here we present Phase I trial results of this multi-peptide HER2 vaccine. Methods: Eligible women had HER2+ breast cancer (Stages II-III) and had completed standard treatment (i.e. surgery, chemotherapy, and trastuzumab) at least 90 days prior to enrollment and were rendered disease free. Vaccine included the above epitope pool along with adjuvant GM-CSF. Patients were vaccinated six times over six months and were monitored for toxicity at each visit. Peripheral blood samples were collected for immune responses evaluating for T cell and antibody immunity. Endpoints were safety and immunogenicity leading to the development CD4 helper T cells that recognized naturally-processed HER2. Results: Twenty-two subjects (age 33 to 69 years) were enrolled. At the present analysis, 21 have completed all 6 vaccination cycles; one patient withdrew after developing a grade 1 injection site reaction during the first vaccination cycle. Twenty patients have had LVEF measured after vaccination; only 2 patients had an LVEF drop of 10% or more but remained in the normal LEVF range. One severe toxicity was reported: a grade 3 INR increase considered unrelated to treatment. Mild to moderate (grade 1-2) toxicities included injection site reactions, fatigue, and white blood cell count decreases. All patients were alive at analysis and only one experienced a recurrence (median follow-up 507 days, range 22 – 844). Twenty patients have had immune response assessments. Vaccine induced T cell immunity was observed in 94% of patients to p59, in 94% of patients to p88, in 82% of patients to p422, and in 74% of patients to p885. Importantly, T cell immunity to naturally processed HER2 proteins occurred in 94% of patients. The mean number of T cells specific for each peptide, post vaccination, ranged from 349–528 T cells per million peripheral blood mononuclear cells (PBMCs). The mean number of T cells specific for whole HER2 protein was 783 T cells per million PBMCs compared to a mean of 898 T cells/million PBMCs specific for the foreign tetanus toxin. In contrast to T cell responses, modestly increased antibody immunity to HER2 occurred in 35% of patients, consistent with the T cell-inducing design of the vaccine. Conclusion: Our results show that it is possible to develop vaccines with broad HLA coverage that circumvent natural tolerance and induce tumor antigen-specific immunity in the vast majority of patients. Citation Format: Knutson KL, Kalli KR, Block MS, Hobday TJ, Padley DJ, Erskine CL, Dockter T, Suman VJ, Wilson G, Degnim AC. Robust generation of T cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-02.

32. Incidence and predictors of progression of Coronary Artery Disease among high risk patients with recurrent symptoms

Background: Coronary Artery Disease (CAD) is the leading cause of mortality worldwide. In the current era with highly potent medical therapy, the rate of progression of angiographic CAD is not well described. Thus, the aim of this analysis is to describe the rate and predictors of progression of CAD among patients with recurrent symptoms. We reviewed 259 patients (Mean age 60;± 11 years, 71% males) who underwent two coronary angiograms between 2008 and 2013. Patients were excluded if they underwent bypass surgery between the two angiograms. Progressive CAD was defined as (A) obstructive CAD in a previously disease-free segment; or (B) new obstruction in a previously non-obstructive segment. Multivariate logistic regression was used to determine the independent predictors of progression of CAD. The mean duration between the two angiograms was 29 ± 13 months. A total of 159 patients (61%) had progression of CAD. Included patients had high prevalence of coronary risk factors (Hypertension 71%, diabetes mellitus 69%, Dyslipidemia 75%). Most patients had controlled dyslipidemia (64% had LDL <70 mg/dl); however, 72% and 40% of patients had glycosylated hemoglobin more than 7% and 8% respectively; 32% of patients had systolic blood pressure more than 140 mmHg. Using multivariate logistic regression, a drop in the left ventricular ejection fraction >5% was the only predictor of CAD progression (adjusted odds ratio 5.8, p = 0.042, 95% CI 1.1–31.2). Among high risk patients with recurrent symptoms, the short term rate of progression of CAD is high. A drop in LVEF >5% is the best predictor of progression of CAD. Further studies are needed to determine the prognostic value of CAD progression in the era of potent medical therapy.