Decline In LVEF Research Articles

Abstract P5-13-07: Tolerance of HER-2 directed therapy for early stage breast cancer in a predominantly Hispanic population with high prevalence of cardiovascular risk factors

Abstract Introduction: Trastuzumab based therapy is recommended for patients with early stage HER-2 overexpressing breast cancer, because it improves survival. Significant racial disparities exist in the receipt of trastuzumab with minorities being 25% less likely than whites in being treated with it. (Reeder-Hayes K et al, JCO 2016; 34:2003-2009). Trastuzumab can affect cardiac function. Cardiac complications associated with trastuzumab are influenced by age and pre-existing risk factors including obesity, hypertension and diabetes mellitus. These co-morbidities occur more frequently in medically underserved minority populations and might influence the practitioner's decision regarding withholding the drug. We previously identified a high prevalence of metabolic syndrome and obesity in our predominantly Hispanic, medically underserved patient population (SABCC 2015 abstract P1-09-07)). For this study, we analyzed the echocardiographic data and cardiac complications associated with trastuzumab use in this patient population. Methods: All patients diagnosed with early stage (stage 1, 2 or 3) HER 2 positive breast cancer between Jan 1st, 2010 and Jan 1st, 2015 at our institution were identified. Age, race, body mass index, pre-existing cardiovascular risk factors, and antihypertensive medication use was collected. Tumor size, nodal status, ER, PR and HER 2 status was recorded. All echocardiograms obtained were reviewed for ejection fraction changes. Repeated measures one sided ANOVA was used to analyze changes in EF. Hospitalization for cardiac complications was recorded. Early interruption of planned therapy and its reasons were recorded. Study was approved by the institutional IRB. Results: Sixty patient were treated with trastuzumab based chemo immunotherapy over the study period. 93% were Hispanic, median age was 61 years (Range 31-83), 40% had hypertension, 35% had dyslipidemia, 35% had glucose intolerance or type II diabetes mellitus and 70% were overweight or obese. 33% were dependent on charity care. 26% had stage 1, 37% had stage 2 and 37% had stage 3 cancer. Docetaxel, carboplatin, trastuzumab (TCH) was the most commonly used regimen (63%) followed by doxorubicin, cyclophosphamide, paclitaxel and transtuzumab (28%). Ten patients (16.6%) required early discontinuation of cytotoxic chemotherapy. Only 1 patient was unable to complete planned 1 year of trastuzumab due to declining ejection fraction. There were no hospitalizations related to cardiac events during therapy. Trastuzumab based treatment elicited statistically significant changes in LVEF over time, F (2,98) =13.974, p<.0005, with LVEF decreasing from 65.4±.844 prior to therapy to 64.7±.724 during 3-6months of therapy and 62.2±.81 at the end of therapy. Two patients had a decline in LVEF ≥ 10%. Of these, 1 resolved at follow up ECHO in 6 weeks. Conclusion In a predominantly Hispanic, HER 2+ breast cancer cohort, with a high prevalence of cardiovascular risk factors and limited health care access, we found that the vast majority were able to complete 1 year of trastuzumab without significant cardiac complications. As trastuzumab improves survival, practitioners should adhere to national guidelines regarding its use as much as possible. Citation Format: Gaur S, McAlice M, Alshaban A, Mahfoud A, Corral J, Philipovskiy A. Tolerance of HER-2 directed therapy for early stage breast cancer in a predominantly Hispanic population with high prevalence of cardiovascular risk factors [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 P5-13-07.

Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.

Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.

Progressive Cardiomyopathy in TTR Amyloidosis after Liver Transplant

Introduction Familial transthyretin (TTR) amyloidosis is a rare disorder characterized primarily by progressive neuropathy and cardiomyopathy. The source of amyloid protein is the liver, thus early liver transplantation can significantly slow disease progression. Unfortunately, for some patients without significant cardiomyopathy at the time of transplant, cardiac disease can subsequently progress due to enhanced deposition of wild-type amyloid protein. Promising new medical therapies may soon replace liver transplant as the gold standard treatment. Case report A 67 year-old male with bilateral carpal tunnel syndrome presented with hematuria and was found to have bladder masses that stained positive for amyloidosis. A work-up for systemic amyloidosis included a normal bone marrow biopsy and an echocardiogram with LVH in the absence of increased voltage on ECG. Two years later he had a cardiac arrest in the setting of sustained VT. A left heart catheterization revealed normal coronary arteries. His endomyocardial biopsy Congo red stain was positive. He was diagnosed with a previously undiscovered mutation of familial TTR amyloidosis (Glu61Gly) and five years later underwent liver transplantation. He was NYHA Class I and did well for ten years before his functional capacity gradually declined. Serial echocardiograms showed a slow progression of LV wall thickness from 1.3 to 1.7 cm and a decline in LVEF from 50% to 30%. In addition, the defibrillation threshold of his ICD progressively increased. He underwent heart transplantation due to end stage amyloid cardiomyopathy. Postoperatively he developed ulcerative esophagitis and ultimately expired due to fungal pericarditis. Discussion Although liver transplantation can slow the progression of TTR amyloidosis and is an appropriate treatment for select individuals, new alternative medical therapies may replace early transplantation. Diflunisal, an anti-inflammatory drug, stabilizes the TTR tetramer in vitro and in a randomized trial slowed progression of neuropathy in familial TTR. Combined doxycycline and tauroursodeoxycholic acid disrupt TTR amyloid fibrils and appear to slow disease progression. Tafamadis, a small molecule that inhibits the dissociation of TTR tetramers has been shown in phase 2 and 3 trials to slow neuropathy progression and decrease mortality and heart failure hospitalizations. Patisiran is a small interfering RNA that blocks TTR synthesis and has demonstrated stabilization of neuropathy. Inotersen is an antisense oligonucleotide that has also shown promise in familial TTR patients with polyneuropathy. Most recently, an investigational monoclonal antibody has been designed to target and remove amyloid deposits. Conclusion Familial TTR amyloidosis is characterized by progressive neuropathy and cardiomyopathy for which patients may undergo liver transplant, though cardiac disease can subsequently progress. Promising new medical therapies may soon replace liver transplant as the gold standard.

Reduced Left Ventricular Ejection Fraction in Patients With Aortic Stenosis

BackgroundLeft ventricular ejection fraction (LVEF) is reduced in a subset of patients with severe aortic stenosis (AS). ObjectivesThe authors sought to determine the temporal course of reduced LVEF, its predictors, and its impact on prognosis in severe AS. MethodsSerial echocardiograms of 928 consecutive patients with first-time diagnosis of severe AS (aortic valve area [AVA] ≤1 cm2) who had at least 1 echocardiogram before the diagnosis were evaluated. A total of 3,684 echocardiograms (median 3 studies per patient) within the preceding 10 years were analyzed. ResultsAt the initial diagnosis, 196 (21%) patients had an LVEF <50% (35.1 ± 9.7%) and 732 (79%) had an LVEF ≥50% (64.2 ± 6.1%). LVEF deterioration had begun before AS became severe for those with an LVEF <50% and accelerated after AVA reached 1.2 cm2, whereas mean LVEF remained >60% in patients with LVEF ≥50% at initial diagnosis. The strongest predictor for LVEF deterioration was LVEF <60% at 3 years before AS became severe (odds ratio: 0.86; 95% confidence interval: 0.83 to 0.89; p < 0.001). During the median follow-up of 3.3 years, mortality was significantly worse, not only for patients with an LVEF <50%, but for patients with an LVEF of 50% ≤ LVEF <60% compared with patients with an LVEF ≥60% even after aortic valve replacement (p < 0.001). ConclusionsIn patients with severe AS and reduced LVEF, a decline in LVEF began before AS became severe and accelerated after AVA reached 1.2 cm2. LVEF <60% in the presence of moderate AS predicts further deterioration of LVEF and appears to represent abnormal LVEF in AS.

Abstract P1-15-02: Gene expression profiling of doxorubicin cardiotoxicity in peripheral blood cells of breast cancer patients

Abstract Background: Doxorubicin (DOX), a widely used anti-cancer drug for treatment of breast cancer is known for its cardiotoxicity. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. To date, no biomarker for early presymptomatic detection of DOX cardiotoxicity has been validated. Our previous data indicated that peripheral blood mononuclear cells (PBMCs) can be used as a surrogate tissue for identification of biomarkers for DOX cardiotoxicity. The aim of this study was to analyze PBMC gene expression induced by a single dose of DOX-based chemotherapy in breast cancer patients and correlated the data with DOX-induced cardiotoxicity. Materials and Methods. Blood samples of 33 women treated for breast cancer with DOX-based chemotherapy were collected before the start and after the first cycle of chemotherapy. Total RNA was isolated from PBMC and whole-genome gene expression was performed using Illumina HumanHT-12 v4 Expression BeadChip array. Gene expression data were log2 – transformed and gene transcripts with average log2-intensities &amp;gt; 7 were considered to be expressed. The group-specific means were analyzed via repeated-measures with ANOVA for expression changes after DOX. Genes with p-value&amp;lt;0.05 were considered differentially expressed. Cardiac function was assessed before and after the completion of chemotherapy by echocardiogram and/or multigated acquisition scan. An absolute decrease of left ventricle ejection fraction &amp;gt;10% or &amp;lt;55% was considered abnormal. Differentially expressed genes (DEG) of patients who developed abnormal LVEF decrease were compared with DEG of patients who did not. Results. A single dose of DOX-based chemotherapy resulted in 235 DEG in PBMC (P&amp;lt;0.05, FDR&amp;lt;0.05), mapped to cell death, oxygen transport and iron ion binding. Further analysis identified 87 DEG in the PBMC of eight (n=8) women who developed abnormal decline in LVEF from the baseline in comparison with women who did not (n=25). Most of the 87 DEG encode proteins secreted by activated neutrophils, such as alpha-defensins, arginase, cathepsin G, elastase, haptoglobin. The functional analysis of the 87 DEG showed enrichment for inflammatory response, immune response, cell death and peptidase activity. Discussion. The results from this study indicated that elevated neutrophil-associated transcripts in the early stages of DOX-based chemotherapy were independent of the neutrophil count. These data suggest an association between the neutrophils activation after a single dose of DOX-based chemotherapy and later impairment of cardiac function. The early PBMC transcriptome signature can be used in the future development of biomarkers for DOX-associated cardiotoxicity. Citation Format: Todorova VK, Siegel ER, Makhoul I, Marquette M, Wei JY, Klimberg VS. Gene expression profiling of doxorubicin cardiotoxicity in peripheral blood cells of breast cancer patients. [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 P1-15-02.

DO STANDARD HEART FAILURE MEDICATIONS PREVENT FALL IN LVEF IN BREAST CANCER PATIENTS GIVEN TARGETED THERAPY?

Beta blockers and angiotensin modulators form the cornerstone of heart failure management in the general population. The benefit of these inexpensive agents is ill-defined in HER2-positive breast cancer patients with known cardiac-related comorbidities who are treated with trastuzumab, which is the gold standard targeted therapy in this patient population plus a known cause for reversible cardiotoxicity in many patients. We sought to determine if being on these cardiovascular medications up-front to exposure to targeted therapy prevents the decline in LVEF in patients with known cardiac-related comorbidities. Adhered to the PRISMA statement for pooled-analysis. Selection criteria: Clinical trials involving patient cohorts already on cardioprotective medications when treated with trastuzumab. Search strategy: PubMed, the Cochrane Library, Google Scholar, Web of Science, and Scopus databases from 1998 to 2013, plus www.asco.org and www.clinicaltrials.gov. Outcome measure: Decline in LVEF >10% of baseline per ECHO or MUGA while on beta blocker +/− angiotensin modulator (ACEi or ARB), plus trastuzumab. Statistical analysis: Dedicated pooled-analysis statistical software (BioStat Inc., NJ, USA). From 218 articles, 6 clinical trials (n = 329) were selected with extractable data. Patients on beta blocker +/− angiotensin modulator tended to be older and heavily pretreated with chemotherapy. Being on cardioprotective medications during trastuzumab therapy was beneficial for stability of LVEF in patients at above-average risk for cardiotoxicity [mean odds ratio (OR): 0.664, 95%CI 0.44 to 0.99; random effects model p = 0.05 versus fixed effect model p = 0.004]. Statistical analyses revealed robustness of our analysis for comorbidity index (p < 0.05). Evidence to support the up-front use of beta blockers as a cardioprotective strategy in breast cancer patients at highest risk for cardiotoxicity secondary to targeted therapy has yet to be fully investigated in a randomized clinical trial -- the results of the MANTICORE 101 clinical trial are pending. However, our hypothesis-generating analysis suggests that use of a beta blocker +/− angiotensin modulator while receiving targeted therapy blunts the decline in LVEF in breast cancer patients with known cardiac risk factors or comorbidities. Although our analysis only represents a statistical signal of possible clinical benefit, further investigation is warranted.

Comparison of left ventricular systolic function and mechanical dyssynchrony using equilibrium radionuclide angiography in patients with right ventricular outflow tract versus right ventricular apical pacing: A prospective single-center study

BackgroundChronic ventricular pacing is known to adversely affect left ventricular (LV) function. Studies comparing right ventricular outflow tract (RVOT) pacing with RV apical (RVA) pacing have shown heterogeneous outcomes. Our aim was to objectively assess LV function and mechanical dyssynchrony in patients with RVOT and RVA pacing using equilibrium radionuclide angiography (ERNA). MethodsFifty-one patients who underwent permanent pacemaker implantation and had normal LV function were prospectively included. Twenty-nine patients had pacemaker lead implanted in the RVOT and 22 at the RVA site. All patients underwent ERNA within 5 days post-pacemaker implantation and follow-up studies at 6 and 12 months. Standard deviation of LV mean phase angle (SD LV mPA) expressed in degrees, which was derived by Fourier first harmonic analysis of phase images, was used to quantify left intraventricular dyssynchrony. ResultsNo significant difference was observed between the two groups with respect to indication (P = .894), Type/mode (P = .985), and percentage of ventricular pacing (P = .352). Paced QRS duration was significantly longer in RVA group than RVOT group (P = .05). There was no statistically significant difference between the RVA and RVOT groups at baseline with respect to LVEF (P = .596) and SD LV mPA (P = .327). Within the RVA group, a significant decline in LVEF was observed over 12-month follow-up (from 57.3% ± 5.32% to 55.6% ± 6.25%; P = .012). In the RVOT group, the change in LVEF was not statistically significant (from 56.7% ± 4.08% to 54.3% ± 6.63%; P = .159). No significant change in SD LV mPA was observed over 12-month follow-up within the RVA group (from 10.5 ± 2.58° to 10.4 ± 3.54°; P = 1.000) as well as in the RVOT group (from 9.7 ± 3.28° to 9.4 ± 2.85°; P = .769). However, between the RVA and RVOT groups, no significant difference was observed at 12-month follow-up in terms of LVEF and dyssynchrony (LVEF P = .488; SD LV mPA P = .296). ConclusionNo significant difference was observed between RVOT and RVA groups with regard to LV function and synchrony over a 12-month follow-up. RVOT pacing offers may lead to better preservation of LV function on longer follow-up.

Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.

BackgroundVariations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case–control study.Methods140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF <55%, a decline in LVEF of 10%) that resulted in at least temporary discontinuation of trastuzumab, whereas controls had no decline in their LVEF. Eleven ErbB2 single gene SNPs that resulted in an alteration in the HER2-neu protein amino acid sequence were studied. Single gene SNP analysis was carried out using SNP genotyping assays from genomic DNA obtained from peripheral blood or buccal swab.ResultsOnly two of the ErbB2 SNPs (Ile 655 Val and Pro 1170 Ala) were found to have variation. There was no association between codon 665 and cardiotoxicity; however the proline variant of amino acid 1170 was more likely than the alanine variant to be found in cases with trastuzumab cardiotoxicity (35% of case patients as compared to 17% of controls, p = 0.04). This association remained significant in multivariable analysis taking into account age, race, and history of hypertension (adjusted OR = 2.60, 95% CI = 1.02, 6.62, p = 0.046).ConclusionsThe Her2/neu Pro 1170 Ala polymorphism can be used to identify a subset of patients who are at increased risk of cardiotoxicity from trastuzumab therapy. Her2/neu single nucleotide polymorphisms may be useful in conjunction with other biomarkers to risk stratify patients in order to optimize clinical management.

P082 CBCSG-10, the addition of capecitabine to adjuvant chemotherapy in triple-negative breast cancer

benefit of these agents is ill-defined in HER2-positive breast cancer patients with known cardiac-related comorbidities given trastuzumab. We sought to determine if being on these medications when given trastuzumab prevents decline in LVEF in patients with known cardiac-related comorbidities. Methods: Adhered to the PRISMA statement for pooled-analysis. Selection criteria: Clinical trials involving patient cohorts already on cardioprotective medications when treated with trastuzumab. Search strategy: PubMed, the Cochrane Library, Google Scholar, Web of Science, and Scopus databases from 1998 to 2013, plus www.asco.org and www.clinicaltrials.gov. Outcome measure: Decline in LVEF >10% of baseline per ECHO or MUGA while on b-blocker +/− ACEi or ARB, plus trastuzumab. Statistical analysis: Dedicated pooled-analysis statistical software (BioStat Inc., NJ, USA). Results: From 218 articles, 6 clinical trials (n = 329) were selected with extractable data. Patients on b-blocker +/− ACEi or ARB tended to be older and heavily pretreated with chemotherapy. Being on cardioprotective medications during trastuzumab therapy was beneficial for stability of LVEF in patients at above-average risk for cardiotoxicity [mean odds ratio (OR): 0.664, 95%CI 0.44 to 1.01; random effects model p = 0.05 versus fixed effect model p = 0.004]. Statistical analyses revealed robustness of our analysis for comorbidity index (p < 0.05). Conclusion: This hypothesis-generating analysis suggests that use of b-blocker +/− ACEi or ARB during trastuzumab therapy prevents decline in LVEF in breast cancer patients with known cardiac risk factors or co-morbidities. Disclosure of Interest: No significant relationships.

Early Cardiac Changes Due to Doxorubicin Based Chemotherapy and Radiotherapy in Early and Locally Advanced Carcinoma Breast Patients: An Observational Study

Objective: To evaluate prospectively the early cardiac changes from doxorubicin based chemotherapy and radiotherapy in breast cancer patients. Methods and Materials: 56 patients with early or locally advanced breast cancer were included in the study. ECG, ECHO and Equilibrium Radionuclide Ventriculography (ERV) was done at baseline, after chemotherapy, after radiotherapy and at 6 months of follow up. Results: In Group 1 patients who completed six cycles of chemotherapy before starting radiation, the mean LVEF decreased after chemotherapy and after RT(from 66.79 ± 3.73 to 63.45 ± 3.54 and 61.64 ± 4.26, p<0.05). In Group 2 patients who received six cycles of chemotherapy after completion of radiotherapy, mean LVEF decreased post RT and post chemotherapy (from 66.67 ± 4.33 to 66 ± 4.975 and 62.7 ± 2.92, p<0.05).In Group 3 patients also who received neoadjuvant chemotherapy, radiation and adjuvant chemotherapy there was a decline in mean LVEF.In Group 4 patients who received only adjuvant chemotherapy mean LVEF decreased after chemotherapy (from 67.25 ± 4.33 to 64.75 ± 2.062, p<0.05). LVEF was also measured by MUGA/ERV. In Group 1, mean LVEF decreased after chemotherapy and RT (from 58.14 ± 2.997 to 56.15 ± 3.144 and 56.21 ± 3.81, p<0.050. In Group 2 mean LVEF decreased after RT and chemotherapy (from 59.11 ± 1.41 to 58.67 ± 2.872 and 54.44 ± 1.81, p<0.05).In Group 3 patients, there was a decline in mean LVEF post neoadjuvant chemotherapy, after radiation and after adjuvant chemotherapy. In Group 4 mean LVEF decreased after chemotherapy (from 60 ± 1.63, to 58.75 ± 1.89, p<0.05). Conclusion: Our prospective study shows that a significant number of patients can develop a significant transient depression in ventricular function acutely after chemotherapy and radiotherapy as demonstrated by a decrease in LVEF by conventional ECHO and ERV scan.

Abstract 12450: Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and is Modified by Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy

Background: Patients with Duchenne muscular dystrophy (DMD) typically exhibit progressive cardiac and skeletal muscle dysfunction, and are commonly treated with corticosteroids to prolong ambulation. Myocardial fibrosis and steroid treatment may modulate the progression of cardiac dysfunction in DMD patients. We aimed to longitudinally characterize the impact of myocardial fibrosis and steroid treatment on the progression of cardiac dysfunction using cardiac magnetic resonance (CMR) in a large DMD cohort. Methods: Serial CMR studies performed on DMD patients were reviewed for LVEF and late gadolinium enhancement (LGE) status, a marker for myocardial fibrosis. LVEF was modeled by examining effects of patient age, steroid treatment duration, LGE status, and myocardial fibrosis burden, as assessed by the number of LGE positive (LGE+) LV segments. Results: We analyzed 469 CMR studies from 99 DMD patients with ≥4 CMRs. Patient age at time of CMR ranged from 6.6 to 29.4 (median 12.3) years. There were 146 (31.1%) LGE+ studies and 59 studies (12.6%) that demonstrated depressed LVEF (LVEF&lt;55%). An age-only model demonstrated that LVEF declined 0.58±0.10%/yr (p&lt;0.0001, r 2 =0.067). Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE+ LV segments; multivariate modeling showed that LVEF declined by 0.93±0.09% for each LGE+ LV segment (p&lt;0.0001, r 2 =0.171), while age and steroid treatment duration were no longer significant. The number of LGE+ LV segments increased with age by 1.2 segments/year (95% confidence interval 1.1-1.2), and steroid treatment partially mitigated this increase (interaction term β=-0.01±0.005, p=0.010). Conclusions: Progressive myocardial fibrosis, as imaged by LGE on CMR, is a strong marker for the decline in LVEF in DMD patients. Steroid treatment partially attenuates the age-related increase in myocardial fibrosis burden.

The effect of a repeated immunoadsorption in patients with dilated cardiomyopathy after recurrence of severe heart failure symptoms.

In patients suffering from dilated cardiomyopathy (DCM), immunoadsorption with subsequent IgG substitution (IA/IgG) leads to an acute and prolonged improvement of hemodynamics and heart failure symptoms. However, some patients receiving IA/IgG experience recurrence of heart failure after an initial benefit. The aim of this study was to investigate whether a second IA/IgG treatment episode improves left ventricular systolic function and further mitigates heart failure symptoms in these patients. We retrospectively analyzed 15 DCM patients who experienced a significant improvement of LVEF (≥ 5% absolute or ≥ 20% relative) and heart failure symptoms (≥ 1 NYHA functional class) but a subsequent deterioration (decline in LVEF ≥ 5% absolute or ≥ 20% relative and NYHA worsening ≥1 class) after the first IA/IgG. These patients underwent a second IA/IgG treatment 41.7 ± 27.4 months after the first cycle. Follow up data were acquired 3-6 months after both IA/IgG treatments. The first IA/IgG induced an improvement of LVEF from 33 ± 6.4% to 43.2 ± 7.9% (P < 0.001) and of mean NYHA functional class from 2.9 ± 0.26 to 1.8 ± 0.56 (P < 0.001). The second treatment was associated with a significant improvement in LVEF (from 29.7 ± 4.6% to 34.9 ± 8.3%, P = 0.013) and NYHA functional class (2.87 ± 0.64 to 2.33 ± 0.72; P = 0.02). This improvement was less pronounced compared to the first treatment with respect to both, LVEF (P = 0.09) and NYHA improvement (P = 0.04). In DCM patients, who experience a significant improvement of LVEF and heart failure symptoms after IA/IgG but a subsequent relapse during follow up, repeated IA/IgG may be considered.

7 * Reduced global longitudinal strain one month after RV pacing predicts progression to pacing induced heart failure

Introduction: Right ventricular (RV) pacing causes heart failure in up to 9% of patients. A priori identification of patients who will develop pacing induce heart failure (PIHF) represents an important challenge. We aimed to establish whether speckle tracking strain echocardiography (STE), performed soon after pacemaker implantation, can predict development of PIHF. Methods: Fifty-five patients with high-grade atrioventricular block underwent dual chamber pacemaker implantation. At baseline all patients had preserved LV ejection fraction (LVEF > 55%). Two-dimensional echocardiography and 12-lead electrocardiograms were performed before pacemaker implantation and repeated alongside pacemaker interrogation at one and six months. As a function of time, patients were grouped according to the cumulative percentage of ventricular pacing (Cum%VP), determined from pacemaker diagnostics at six months. Baseline, one and six month LVEF and STE findings for group 1 (Cum% VP > 40) were compared to cases where Cum%VP was <40% (Group 2, n=25). Results: At one month there were no cases of PIHF (LVEF <45%). At 6 months, PIHF was observed in 4/30 (13%) group 1 patients. Global longitudinal strain (GLS) values for these cases were compared to strain values for group 1 patients without PIHF and to group 2. Baseline GLS value were comparable between the three groups (−16.0 vs. −16.5 and −17.0; p=0.642). One month GLS was significantly lower in patients with PIHF (−11.3 vs. −14.4 and −16.1; p=0.035). Conclusion: Significant reductions in GLS precede development of PIHF and may be used to identify patients at greatest risk of PIHF before a decline in LVEF occurs.

Assessment of the early stage of cardiac remodeling of spontaneously hypertensive heart failure rats using the quantitative 3-dimensional analysis provided by acipimox-enhanced FDG-PET

Spontaneously hypertensive heart failure rats (SHHF) appear to constitute an original model for analyzing the evolution of the metabolic syndrome towards heart failure. This study aimed to characterize early cardiac dysfunction and remodeling in SHHF rats: (1) as compared with spontaneously hypertensive rats (SHR) and with a control group of Kyoto rats (WKY), and (2) by using the 3-dimensional quantitative analysis provided by acipimox-enhanced positron emission tomography (PET) with (18)F-fluorodesoxyglucose (FDG). Left ventricular (LV) ejection fraction (EF) and volume were quantified by automatic software on the FDG-PET images recorded in SHR (n = 20), SHHF (n = 18) and WKY-rats (n = 19) at ages 3 or 10 months old. Arterial blood pressure was determined by cardiac catheterization and cardiac fibrosis was quantified after sacrifice. Blood pressure was similarly elevated in SHR and SHHF rats (respective systolic blood pressures at 10-months: 199 ± 39 vs. 205 ± 2 mmHg), but SHHF rats had higher body mass than SHR rats (at 10-months, 630 ± 36 vs. 413 ± 27 g, p < 0.05) and higher blood levels of cholesterol and of triglycerides. At 3 months, cardiac parameters did not show significant differences between groups but at 10-months, SHHF and SHR rats exhibited an enhancement in myocardial mass and fibrosis associated with a clear decline in LV-EF (SHHF: 46 ± 6 %; SHR: 47 ± 5 %) as compared with WKY (56 ± 6 %, p < 0.01 for both comparisons). Cardiac remodeling of SHHF rats was clearly observable by FDG-PET from the age of 10-months, but in a similar way to that observed for SHR rats, suggesting a predominant role of hypertension.

Abstract P6-05-06: Association of HER2/neu single nucleotide polymorphism with trastuzumab-related cardiotoxicity

Abstract Background: Treatment with trastuzumab prolongs overall survival when given to patients (pts) with Her2/neu+ breast cancer (BC). The primary toxicity of trastuzumab is cardiotoxicity and the incidence is estimated at 2-4% in the adjuvant setting. The mechanism for trastuzumab-induced cardiotoxicity is not known. Although Her2neu expression is usually not seen on cardiac myocytes, its expression has been shown to be upregulated after chemotherapy. Trastuzumab is a monoclonal antibody that binds to the extracellular domain of Her2/neu. We hypothesized that single nucleotide polymorphisms (SNPs) in the Her2/neu receptor may play a role in trastuzumab associated cardiotoxicity. Methods: 140 pts with BC who were treated with chemotherapy and trastuzumab were enrolled into an IRB approved protocol at the Weill Cornell Medical College between July 2008 and March 2013. Cardiotoxicity was defined as either symptomatic CHF, or a decline in LVEF of 15% (or if LVEF &amp;lt;55% a decline in LVEF of 10%) that required management with medications and led to temporary or permanent discontinuation of trastuzumab. 11 nonsynonomous human ErbB2 SNPs were identified in the National Center for Biotechnology Information SNP database (rs1136201, rs2172826, rs28933368, rs28933369, rs28933370, rs34602395, rs36085723, rs4252633, rs55943169, rs56366519, rs61552325). Genotyping of SNPs was performed on DNA prepared from blood or buccal washes. The relationship between SNP characteristics and cardiotoxicity status was assessed by the chi-square test and multivariable logistic regression analysis. Results: 140 subjects (29 with cardiotoxicity and 111 without) had 11 SNPs sequenced. Median age of subjects was 56 years (range: 32-85), mean baseline LVEF was 65% (±6%). 16.4% of subjects had hypertension (HTN). 80% of patients were Caucasian, 10% East Asian, 7.1% African American, 2.9% South Asian. There were two SNPs for which there was variation seen among subjects: rs 1136201 (corresponding to codon 655) and rs61552325 (codon 1170). The frequencies of the codon 655 polymorphisms were: AA (Ile/Ile) 67.9%, AG (Ile/Val) 29.3%, and GG (Val/Val) 2.9%. The frequencies of the codon 1170 polymorphisms were: CC (Pro/Pro) 20.7%, GC (Ala/Pro) 45.7%, and GG (Ala/Ala) 33.6%. There was no association observed between the codon 655 polymorphism and cardiotoxicity (p = 0.96). A significant association between cardiotoxicity and the codon 1170 polymorphism was observed, with subjects having cardiotoxicity being more likely to carry the CC allele compared with subjects without cardiotoxicity (34.5% vs 17.1%, p = 0.04). This association persisted after multivariable adjustment for age, race, and HTN status (adjusted OR = 2.60, 95% CI = 1.02-6.62, p = 0.046). Conclusion: In this study, the Her2/neu 1170 Pro/Pro polymorphism was associated with trastuzumab cardiotoxicity. If confirmed in a larger series, this polymorphism could be used to identify pts who may be at increased risk for cardiotoxicity and who may benefit from treatments associated with less cardiotoxicity. Furthermore, the Her2/neu 1170 SNP has previously been implicated as a minor histocompatibility antigen, and our findings raise the possibility that immune mediated mechanisms may play a role in trastuzumab related cardiotoxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-06.

Abstract 9317: Impact of Trastuzumab-Induced Cardiotoxicity and Subsequent Trastuzumab Interruption on Breast Cancer Outcome

Background: Trastuzumab (T) improves disease free and overall survival among pts with HER2 (+) breast cancer (BCA); however this benefit is attenuated by the risk of trastuzumab-induced cardiotoxicity (TIC). Current guidelines recommend interruption of T for CHF or a significant reduction in LVEF, but the impact of this practice on BCA outcomes is unknown. Methods: All patients with HER2 (+) BCA receiving adjuvant T with chemotherapy in clinical practice at a single cancer center between January 2005 and June 2010 were studied. Tumor characteristics, cardiac risk factors, LVEF, BCA chemotherapy, and BCA outcomes were obtained from the medical record. The log rank test and Cox proportional model were used to evaluate the association between these variables and time to BCA recurrence. Results: Overall, 546 pts with HER2 (+) BCA treated with T were studied; 448 (82%) pts were treated with anthracyclines prior to T. Mean age was 51 yrs (range 26-81); mean follow-up was 4.4 yrs (range 0.6-7.6). T was interrupted for &gt; 1 cycle (&gt; 6 weeks) in 83 (15%) pts. TIC was the reason for interruption in 54 (9.9%) pts; 18 (3.3%) had symptoms of CHF with a decline in LVEF, while 36 (6.6%) had an asymptomatic decline in LVEF. Other reasons for interruption included non-cardiac adverse events (n=11), BCA progression (n=7), and pt request (n=7). Cumulative dose of T was lower among pts with interruption (median 76 vs. 106 mg/kg, p &lt; 0.0001). Early recurrence of BCA was associated with number of positive lymph nodes (p&lt;0.0001), negative progesterone receptor status (p=0.005), interruption of T &gt; 1 cycle for any cause (p=0.006), and interruption of T &gt; 1 cycle due to TIC (p=0.049, Table). Conclusions: TIC was the most common reason for interruption of T and was significantly associated with BCA recurrence. These results suggest that coordination of care between cardiologists and oncologists to limit T interruptions while effectively treating cardiotoxicity has the potential to improve outcomes in women with BCA.

Cardiac MRI in the Assessment of Cardiac Injury and Toxicity From Cancer Chemotherapy

During the past 30 years, there has been a significant decrease in cancer mortality rates, predominantly attributable to improvements in treatment options.1 However, survivors are at increased risk of premature cardiac disease,2 both because of the overlap in risk factors for cancer and cardiovascular disease3 and the cardiotoxic effects of cancer chemotherapy. Two chemotherapeutic agent classes that are commonly associated with cardiotoxicity are the anthracyclines and tyrosine kinase inhibitors, both of which can cause left ventricular (LV) dysfunction and heart failure (HF).4,5 Mechanisms of cardiac injury from cancer therapy have been summarized elsewhere.4,6 Briefly, anthracycline cardiotoxicity has been attributed to reactive oxygen species formation, transcriptional changes in intracellular adenosine triphosphate production in cardiac myocytes, and, more recently, through interaction with cardiac topoisomerase IIβ.4,6 Trastuzumab cardiotoxicity seems to be because of inhibition of cardiomyocyte human epidermal growth factor receptor 2, resulting in ATP depletion and contractile dysfunction.4 Other proposed mechanisms include immune-mediated destruction of cardiomyocytes.4,6 At the tissue level, early anthracycline toxicity has been associated with myocardial inflammation,7–9 vacuolization,9–12 and cell swelling/edema.11,13 These changes seem to occur before myocardial functional abnormalities.11,13 Later stages of toxicity are associated with myocardial fibrosis.14,15 Unfortunately, the use of myocardial biopsy is not feasible for diagnostic purposes in this setting. However, once HF manifests, the 2-year mortality can be as high as 60%.16 This emphasizes the importance of early recognition of cardiac injury and institution of cardioprotective therapy in an effort to prevent development of HF and allow uninterrupted completion of cancer therapy.17 Thus, the diagnosis is dependent on either direct evidence of myocardial damage or functional disturbance. Either signal may be identified …

T1 mapping is abnormal before decline in EF in patients with Becker and Duchenne muscular dystrophy

Background Patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy (CM) at an earlier age compared to Becker muscular dystrophy (BMD), but the age of onset within each diagnosis is variable. A method to predict CM onset associated with dystrophinopathy could alter therapeutic approaches and improve outcomes. Shortened post-contrast T1 relaxation times are an early marker of myocardial fibrosis and are abnormal in patients with DMD as described in our previous work. To our knowledge, T1 mapping has not been evaluated in BMD patients. We hypothesized that patients with BMD would also have abnormal T1 times and that these abnormalities would precede LV dysfunction. Methods Twenty-six CMR scans from these 2 dystrophinopathy populations (N=5 BMD and N=21 DMD) were compared with 10 CMR scans from control patients without cardiovascular disease. T1 maps were created from the Look-Locker sequence, obtained 10 minutes after gadolinium injection, using MRMap. Using MatLab, T1 times were obtained for every voxel in 6 standard myocardial segments in the short axis at the level of the papillary muscles. Mean T1 times were compared between BMD, DMD and controls using a Kruskal Wallis test. A subset of patients with normal LVEF and dystrophinopathy (BMD or DMD) was compared to controls using a Mann-Whitney U test. Results The mean age of patients was 25.4 ± 8.1 years in the BMD group, 15.7 ± 4.3 years in the DMD group, and 16.9 ± 1.3 years in controls. One patient with BMD and 13 patients with DMD had LVEF < 55%. Two patients from both BMD and DMD had LV dilatation. BMD and DMD patients had significantly shorter mean postcontrast T1 compared with controls (BMD: 355 ms, 95% CI (314, 395), DMD:357 ms, 95% CI (323, 390), control: 420 ms, 95% CI (389, 451), p=0.035) (Figure 1). The subset of BMD and DMD patients and normal LVEF also had a significant decrease in post-contrast T1 when compared to controls (-52.4 ms, 95% CI (-7.2, -97.5), p=0.018) (Figure 2). Conclusions Myocardial post-contrast T1 relaxation times in BMD and DMD are significantly shorter than in controls. They remain significantly decreased in the subset of patients with normal LVEF, suggesting that CMR may have prognostic utility in detecting subclinical myocardial damage associated with loss of dystrophin prior to a decline in LVEF. Further longitudinal study is necessary to evaluate whether T1 times can predict future onset of CM in BMD and DMD. Funding none.

Evaluation of Ile655Val HER2 polymorphism associated with cardiac toxicity following the administration of trastuzumab in women with breast cancer.

634 Background: Trastuzumab is well tolerated without major side effects except for cardiac toxicity. Although a number of clinical parameters have been associated with trastuzumab-associated cardiac toxicity (TACT), there is some indication that genetic variation of the HER2 gene may play a toxic role in a population of metastatic breast cancer patients. However, this finding needs confirmation and we looked at a population of non-metastatic breast cancer. This study aimed to evaluate the association between cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic breast cancer patients treated with trastuzumab. Methods: The Ile655Val HER2 polymorphism was assessed in 73 women using TaqMan technology. For this study, the genotyping was performed using DNA extracted from normal breast tissue located at more than 1 cm of any other lesions. Charts review was used to collect information on TACT which was defined as any decline in LVEF &gt; 10 % from the baseline to &lt; 55 % or a decline in LVEF &gt; 5 % to &lt; 50 % (lower limit of normal). The Fisher exact test was used to evaluate the association between cardiac toxicity and HER2 polymorphism. Results: No deviation from the Hardy-Weinberg equilibrium has been observed for the allele and genotype frequencies. The distribution of HER2 polymorphism was 3 Val/Val (4%), 18 Ile/Val (25%) and 52 Ile/Ile (71%). In this population, 19% (14/73) developed a cardiac toxicity. We found that 29% (6/21) of Ile/Val or Val/Val carriers compared to 15% (8/52) of Ile/Ile carriers showed TACT, but this association did not reach statistical significance (P = 0.21). Conclusions: HER2 Ile655Val polymorphism may be an efficient marker of TACT considering this tendency with this small cohort of patients. Larger sample is needed to strengthen this conclusion, since this result may influence on prescribing decision for adjuvant chemotherapy and anti-HER2 therapy in HER2 positive patients.

Optimizing outcomes in patients (pts) with HER2+ metastatic breast cancer (MBC) through continuous inhibition of HER2 activity: A single institution study.

e11067 Background: Anti-HER2 therapies are effective in HER2+ breast cancer; even if resistance occurs, continued HER2 inhibition is required for antitumor effect. There are no definitive data on the clinical benefit of continued trastuzumab (T) beyond progression in MBC and the optimal duration of T in pts with long-term control of disease. This study explores outcomes of MBC pts treated with T in multiple sequential lines. Methods: From 2001 to 2009 we evaluated OS and cardiac toxicity in 50 pts with HER2+ (ASCO/CAP criteria) MBC who received T-based therapy for ≥ 12 months. OS was measured from the beginning of T-based CT to the last follow up visit or death. Cardiac event was any decline in LVEF by >10% from baseline or drop to <50%, III/IV NYHA CHF, new onset angina myocardial infarction, significant arrhytmias or sudden cardiac death. Results: Median age was 59 (33-79), visceral disease in 60% and multiple site in 34%; 8 (16%) pts developed brain metastasis during T. All had overexpression of HER2 by IHC, FISH was centrally assessed in 78% and not amplified in 8%. T was administered for a median duration of 23 months (12-120). All pts received a median of 2 CT regimens (1-8); 9 out of 25 pts with endocrine responsive disease received endocrine therapy plus T after at least 1 CT regimen; 20 pts (40%) experienced CR and received T alone as maintenance for a median duration of 9 months (3-46); 23 (46%) pts received lapatinib, when the drug was licensed in Italy, after failure of at least two T-based CT lines. Median OS was 34 months (12-120). There were 3 cardiac events (6%) and consisted in asymptomatic decrease in LVEF to less than 50%; T-based CT was interrupted in 1 patient because of LVEF decrease to ≤ 40%. Conclusions: T in multiple sequential lines demonstrated highly favorable outcomes in MBC pts. Overall the incidence of cardiac dysfunction was low.