Risk Of Congestive Heart Failure Research Articles

Utility Of Routine Left Ventricular Ejection Fraction (LVEF) Measurement Prior To Administration Of Anthracycline-Based Chemotherapy In Patients With Diffuse Large B-Cell Lymphoma (DLBCL)

Anthracycline-based chemotherapy regimens are considered the gold standard for treating patients with DLBCL. Prior to administration of chemotherapy, LVEF is routinely measured, usually by multiple-gated acquisition (MUGA) scans or echocardiography, as a screening tool for detecting asymptomatic left ventricular dysfunction. LVEF screening is recommended by the National Comprehensive Cancer Network clinical practice guidelines, is endorsed by the American Heart Association and the American College of Cardiology, appears on Federal Drug Administration-approved labeling guidelines, and is often required for patients to participate in US cancer cooperative group clinical trails. However, despite these recommendations, evidence supporting the utility of LVEF measurement prior to administration of anthracycline-based chemotherapy in patients with DLBCL is lacking (Conrad, J Oncol Pract 2012).The most common chemotherapy regimen currently administered to DLBCL patients is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients with stage III or IV DLBCL typically receive 6 to 8 cycles of R-CHOP, with cumulative doses of doxorubicin ranging from 300 - 400 mg/m2. Cumulative doses of doxorubicin greater than 400 mg/m2have been associated with an increased risk of congestive heart failure (CHF) (Von Hoff, Ann Intern Med 1979).We are performing a retrospective analysis of approximately 325 patients with DLBCL who received treatment at Virginia Mason Medical Center from 2001-2011. Our objectives include the following: (1) to determine whether LVEF was measured by echocardiogram or MUGA scan prior to administration of anthracycline-based chemotherapy, (2) to establish whether the chemotherapy treatment regimen was modified based on LVEF values, and (3) to document the incidence of CHF in patients with DLBCL who did receive anthracycline-based chemotherapy.Patients were identified through a search of the Virginia Mason Cancer Registry. Specific data currently being collected through chart review include the following: age at diagnosis; Ann Arbor lymphoma stage; type of chemotherapy given; cumulative doxorubicin dose administered (mg/m2); LVEF measurement and modality used to assess LVEF; and incidence of CHF. We are also recording the number of CHF risk factors that patients possess, including male sex, obesity, hypertension, hyperlipidemia, prior cardiac disease, diabetes mellitus, smoking history, prior chemotherapy, radiation to the chest area, and other cardio-toxic exposures. Statistical analyses will include a Fischer's exact or Chi-squared test to compare study groups and a Wilcoxon rank sum test to compare the number of CHF risk factors. A P value of less than 0.05 will be used to determine if an association is significant.In a preliminary sample of DLBCL patients (n = 50), 28 are men (56%). LVEF was measured in 40 patients (80%) prior to initiation of chemotherapy using echocardiogram (95%) and MUGA scan (5%). LVEF values were normal (55 – 75%) in 36 patients (90%), low (< 55%) in 3 patients (8%), and unknown in 1 patient (2%). Of the 36 patients with normal LVEF values, 30 received CHOP or R-CHOP regimens (83%), 2 received non-anthracycline chemotherapy (5%), 1 was treated by surgical excision alone (3%), 2 received no treatment (6%), and 1 patient's treatment was unknown (3%). Of the 3 patients with initial low screening LVEF values, none had a prior history of CHF and all received R-CHOP (100%). Three patients did have CHF prior to treatment; however, only one received CHOP therapy. Of our initial 50 patients, 31 (62%) are alive and 2 (4%) were lost to follow-up. CHF was listed as a major contributor of death in 3 patients (6%). The median number of CHF risk factors did not differ significantly between patients who did develop CHF post-treatment and those who did not (4 vs. 2, P = 0.133).Our preliminary results suggest that the decision to administer an anthracycline-based chemotherapy regimen was not directly affected by echocardiogram or MUGA scan results. If these findings are reinforced at completion of our chart review, it may challenge the existing policy of routinely screening patients with DLBCL with echocardiograms or MUGA scans prior to initiation of treatment. Disclosures:No relevant conflicts of interest to declare.

Fibroblast Growth Factor-23 and Cardiovascular Events in CKD

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Trastuzumab-Related Cardiotoxicity Among Older Patients With Breast Cancer

The use of trastuzumab in the adjuvant setting improves outcomes but is associated with cardiotoxicity manifested as congestive heart failure (CHF). The rates and risk factors associated with trastuzumab-related CHF among older patients are unknown. Breast cancer patients at least 66 years old with full Medicare coverage, diagnosed with stage I-III breast cancer between 2005 and 2009, and treated with chemotherapy were identified in the SEER-Medicare and in the Texas Cancer Registry-Medicare databases. The rates and risk factors associated with CHF were evaluated. Chemotherapy, trastuzumab use, comorbidities, and CHF were identified using International Classification of Diseases, version 9, and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics and Cox proportional hazards models. In total, 9,535 patients were included, of whom 2,203 (23.1%) received trastuzumab. Median age of the entire cohort was 71 years old. Among trastuzumab users, the rate of CHF was 29.4% compared with 18.9% in nontrastuzumab users (P < .001). Trastuzumab users were more likely to develop CHF than nontrastuzumab users (hazard ratio [HR], 1.95; 95% CI, 1.75 to 2.17). Among trastuzumab-treated patients, older age (age > 80 years; HR, 1.53; 95% CI, 1.16 to 2.10), coronary artery disease (HR, 1.82; 95% CI, 1.34 to 2.48), hypertension (HR, 1.24; 95% CI, 1.02 to 1.50), and weekly trastuzumab administration (HR, 1.33; 95% CI, 1.05 to 1.68) increased the risk of CHF. In this large cohort of older breast cancer patients, the rates of trastuzumb-related CHF are higher than those reported in clinical trials. Among patients treated with trastuzumab, those with cardiac comorbidities and older age may be at higher risk. Further studies need to confirm the role that the frequency of administration plays in the development of trastuzumab-related CHF.

Diabetic Cardiomyopathy in the Elderly

Diabetic cardiomyopathy is a microvascular disorder that occurs in diabetics that may lead to congestive heart failure (CHF) in the absence of hypertension, coronary artery disease, or valvular heart disease. In a large study of elderly subjects with 865 men and 1872 women, mean age 81 ± 9 years, CHF developed in 272 of 690 diabetics (39 %) and in 467 of 2047 nondiabetics (23 %) (P < 0.0001) at 43-month follow-up. Cox regression analysis showed that diabetes mellitus (risk ratio = 1.34, P = 0.0003) was an independent significant predictor of time to development of CHF. For each 1 % increase in hemoglobin A1c, in 25,958 men and 22,900 women with diabetes, there was an 8 % increased risk of CHF (95 % CI, 5 %–12 %). The pathologic substrate of diabetic cardiomyopathy is characterized by myocardial damage, left ventricular hypertrophy, interstitial fibrosis, structural and functional changes of the coronary vessels, metabolic abnormalities, and autonomic cardiac neuropathy.

Longer-term cardiac safety and outcomes of dose dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) with and without lapatinib (L) in patients (pts) with early breast cancer (BC).

167 Background: The addition of H to chemotherapy has improved outcomes in HER2-positive early BC. This approach is associated with (w/) an increased risk (&lt;4%) of congestive heart failure (CHF). Dose-dense (every 2 weeks) anthracycline-taxane therapy (Rx) improves survival compared to the every 3 week schedule and can be combined w/ anti-HER2 Rx w/ no increased risk of cardiotoxicity up to 36 months. Here we report the incidence of NYHA Class III/IV CHF in 2 phase II studies with longer follow-up. Methods: We conducted a retrospective review of pts w/ HER2 + early stage BC treated at MSKCC and DFCI on two trials: In trial A - pts received dd AC (60/600 mg/m2) x 4 → T (175mg/m2) x 4 (w/ pegfilgrastim) w/ H x 1 year. Trial B differed w/ use of weekly T (80mg/m2) x 12 and the addition of L (1000mg orally daily) x 1 year. Left ventricular ejection fraction (LVEF) was prospectively assessed by a multi-gated acquisition scan serially throughout Rx. Results: Trial A enrolled 70 pts and Trial B enrolled 95 pts w/ the median age of 46 years (range 27-73 years). Overall, the 5-year distant disease-free survival (DDFS) for trials A and B is 92% (95%Cl; 83-97%) and 89% (95%CI; 81-94%), respectively. The baseline median LVEF was 68% (range 52-81%). In total, 28 of 165 (17%) pts had pre-existing hypertension. Now at a median follow-up of 84 and 57 months respectively, only one (1.4%, 95%CI; 1.36-7.7%) and 4 (4.2%, 95%CI; 4.2-10.4%) pts developed CHF. Since our earlier report, 1 additional CHF event occurred (Trial B) at month 44. Conclusions: Longer follow-up of these 2 studies demonstrate that dd AC → TH with or without L is associated w/ a low risk of CHF. This is consistent w/ the long-term cardiac toxicity reported from the randomized phase III studies of H w/ conventionally scheduled anthracycline-based regimens (with or without taxanes). DDFS outcomes are also encouraging. Clinical trial information: NCT00591851 and NCT00482391.

Effect of pill burden on dosing preferences, willingness to pay, and likely adherence among patients with type 2 diabetes

PurposeTo quantify willingness-to-pay (WTP) for reducing pill burden and dosing frequency among patients with type 2 diabetes mellitus (T2DM), and to examine the effect of dosing frequency and pill burden on likely medication adherence.Patients and methodsParticipants were US adults with T2DM on oral antihyperglycemic therapy. Each patient completed an online discrete-choice experiment (DCE) with eight choice questions, each including a pair of hypothetical medication profiles. Each profile was defined by reduction in average glucose (AG), daily dosing, chance of mild-to-moderate stomach problems, frequency of hypoglycemia, weight change, incremental risk of congestive heart failure (CHF), and cost. Patients were asked to rate their likely adherence to the profiles presented in each question. Choice questions were based on a predetermined experimental design. Choice data were analyzed using random-parameters logit. Likely treatment adherence was analyzed using a Heckman two-stage model.ResultsOf the 1,114 patients who completed the survey, 90 had lower dosing burden (<5 pills/day taken once/day or as needed) for all medications, and 1,024 had higher dosing burden (≥5 pills/day or more than once/day). Reduction in AG was valued most highly by patients. Hypoglycemia, chance of mild-to-moderate stomach problems, weight change, incremental risk of CHF, and daily dosing were less valued. Patients with higher current dosing burden had lower WTP for more convenient dosing schedules than patients with lower current dosing burden. Changes in dosing and cost impacted likely adherence. The magnitude of the impact of dosing on likely adherence was higher for patients with lower current dosing burden than for patients with higher current dosing burden.ConclusionPatients with T2DM were willing to pay for improvements in efficacy, side effects, and dosing. Patients’ WTP for more convenient dosing depended on current dosing burden, as did the effect of these attributes on likely adherence.

Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes

Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; α1-microglobulin, Kim-1, and TFF-3 predicted all-cause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to <0.001), whereas α1-microglobulin, β2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values<0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of α1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.

Long‐term cardiac safety and outcomes of dose‐dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab with and without lapatinib in patients with early breast cancer

The authors have previously reported 2 consecutive phase 2 trials in patients with early breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2) to assess the feasibility of incorporating anti-HER2 therapies into dose-dense (dd) chemotherapy regimens. The incidence of congestive heart failure (CHF) at a median follow-up of 2 years was 1.4% and 3.2%, respectively. In trial A, patients received dd doxorubicin and cyclophosphamide (AC)→paclitaxel (T) (each given every 2 weeks) × 4 with trastuzumab (H) given × 1 year. In trial B, weekly T (weekly × 12) was substituted for ddT and lapatinib × 1 year was added. Herein, the authors report the longer-term incidence of CHF and distant disease-free survival (DDFS). From January 2005 to May 2008, 165 patients enrolled (median age, 46 years, with a median left ventricular ejection fraction of 68% [range, 52%-81%]), 17%of whom had previous hypertension. With a median follow-up of 84 months (trial A) and 57 months (trial B), 1 additional patient developed CHF. Therefore, the cumulative incidence of CHF was 1.4% (95% confidence interval [95% CI], 1.36%-7.7%) for trial A and 4.2% (95% CI, 4.2%-10.4%) for trial B. The 5-year DDFS for trials A and B was 92% (95% CI, 83%-97%) and 89% (95% CI, 81%-94%), respectively. Longer follow-up of these 2 studies has demonstrated that ddAC→TH only or with lapatinib is associated with a low risk of CHF and promising DDFS in patients with early breast cancer.

Abstract 320: Roles of Estrogen, AMPK and Micro RNAs in the Progression of Cardiac Hypertrophy

In industrialized countries, the prevalence of congestive heart failure (CHF) is increasing steadily and has become one of the leading causes of hospitalization. In addition, the risk of cardiovascular disease increases in post-menopausal women. Yet, the association between estrogen and the risk of CHF has not been adequately studied. Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. Our on-going studies indicate differential AMPK regulation through two miR species (miR195 and miR451) in a mouse model harboring a missense mutation (R403Q) in alpha-myosin heavy chain (αMHC) causing hypertrophic cardiomyopathy (HCM). Using bioinformatic algorithms (TargetScanMouse, 5.2), we were able to predict miR candidates that potentially target the AMPK axis. In addition, Altered expression of miRs that target AMPK axis was found in phenylephrine induced hypertrophic neonatal rat cardiomyocytes (NRCM). However, Estradiol treatment of NRCM blocked the hypertrophic changes induced by phenylephrine treatment. It was known that the activation of AMPK pathway inhibits cardiomyocyte hypertrophy. Our data showed that AMPK pathway was activated by Estradiol treatment, which can be blocked by estrogen receptor (ER) β antagonist. Therefore, estradiol increase AMPK pathway activation which in turn attenuate phenylephrine induced increase in cardiomyocyte cell size. Further studies are need to further explore the role of estrogen in the regulation of miR expression in hypertrophic cardiomyocytes, and the role of the expression changes of miRs regulated by estrogen in the development of hypertrophic phenotype.

Longer-term cardiac safety and outcomes of dose dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) with and without lapatinib (L) in patients (pts) with early breast cancer (BC).

630 Background: The addition of H to chemotherapy has improved outcomes in HER2-positive early BC. This approach is associated with (w/) an increased risk (&lt;4%) of congestive heart failure (CHF). At a median f/u of 36 months, the addition of anti-HER2 Rx to dose-dense (every 2 weeks) anthracycline-taxane therapy (Rx) was not associated with excess cardiotoxicity. Here we report the incidence of NYHA Class III/IV CHF in 2 phase II studies with longer follow-up. Methods: We conducted a retrospective review of pts w/ HER2 + early stage BC treated at MSKCC and DF/HCC on two trials: In trial A - pts received dd AC (60/600 mg/m2) x 4 → T (175mg/m2) x 4 (w/ pegfilgrastim) w/ H x 1 year. Trial B differed w/ use of weekly T (80mg/m2) x 12 and the addition of L (1000mg orally daily) x 1 year. In both trials, H was begun after completion of AC and concurrent with T. Left ventricular ejection fraction (LVEF) was prospectively assessed by multi-gated acquisition scan serially throughout Rx. Results: Trial A enrolled 70 pts and Trial B enrolled 95 pts w/ the median age of 46 years (range 27-73 years). Overall, the 5-year distant disease-free survival (DDFS) for trials A and B is 92% (95%Cl; 83-97%) and 89% (95%CI; 81-94%), respectively. The baseline median LVEF was 68% (range 52-81%). In total, 28 of 165 (17%) pts had pre-existing hypertension. Now at a median follow-up of 84 and 57 months respectively, only one (1.4%, 95%CI; 1.36-7.7%) and 4 (4.2%, 95%CI; 4.2-10.4%) pts developed CHF. Since our earlier report, 1 additional CHF event occurred (Trial B) at month 44. Conclusions: Longer follow-up of these 2 studies demonstrate that dd AC → TH with or without L is associated w/ a low risk of CHF. This is consistent w/ the long-term cardiac toxicity reported from the randomized phase III studies of H w/ conventionally scheduled anthracycline-based regimens (with or without taxanes). DDFS outcomes are also encouraging. Clinical trial information: NCT00482391.

Congestive heart failure (CHF) in acute myeloid leukemia patients during induction.

7105 Background: Leukemia induction treatment is associated with significant morbidity and mortality. Myocardial stunning may be a result of chemotherapy as well as cytokines released from lysis of tumor cells leading to drop in ejection fraction (EF). When CHF is associated with sepsis, it may result in increased mortality. We report the incidence of CHF in leukemia patients undergoing induction. Methods: We performed a retrospective chart review on patients diagnosed with AML including acute promyelocytic leukemia (APL), who received chemotherapy between December 1, 2004 and December 31, 2012 at Georgia Regents University. Baseline and follow up EFs were recorded by echocardiogram or nuclear medicine scan. We evaluated patients who had a drop in EF after the first or subsequent inductions. We excluded patients who had a delayed drop in EF. Results: 217 consecutive patients with AML with normal ejection fraction at diagnosis were evaluated. 18 patients (8.2%) demonstrated a decrease in EF. This included 14 patients with AML and 4 with APL. 15 patients received one cycle of induction, 2 received re-induction and 1 was treated for relapsed disease. 2 patients did not receive anthracyclines(ACs). Median age of patients with CHF was 57 years (range 29-75). The median drop in EF was 23% (10-45%). Median days from the start of treatment to the observed drop were 25 (5-109). 6 patients are alive with median survival of 175 days. Overall, 5 out of 18 patients recovered their cardiac function with a median survival in these patients of 1,173 days. In 13 patients without recovery in EF survival was only 71 days. Conclusions: Chemotherapy by itself and cytokines released from treatment may result in reversible drop in EF in some patients and a persistent drop in the others. Re-induction is essential in a significant proportion of patients and ACs are commonly used that puts them at an increased risk for CHF. We propose that repeat cardiac evaluation, especially in patients getting re-induced, is necessary for identifying patients with cardiac abnormalities to prevent further cardiac injury and increased mortality.

Comprehensive profiling of cardiac dysfunction in asymptomatic childhood cancer survivors (CCS) treated with anthracyclines.

10020 Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m2 (high-risk [HR]: n=100) compared with: i) CCS exposed to &lt;300 mg/m2 (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P&lt;0.01) as well as increased LV wall stress ([ESWS] HR: 66 g/cm2, LR: 58 g/cm2, Con: 55 g/cm2, p&lt;0.01) and higher myocardial performance index ([MPI] HR: 0.51, LR: 0.46, Con: 0.46; P&lt;0.01). Blood biomarkers: HR had higher plasma NT-pro BNP (HR: 71 pg/dL, LR: 37 pg/dL, Con: 26 pg/dL; P&lt;0.01); there were no differences in troponins, Galectin-3 or ST-2. Metabolomics:Individuals with LV dysfunction (&gt;2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p&lt;0.01) contributing to altered fatty acid β-oxidation and accumulation of cardiotoxic long-chain (docosadienoate [RR=1.26], adrenate [RR=1.29]; p&lt;0.05) and essential fatty acid intermediates (dihomo-linolenate [RR=1.27], eicosapentaenoate [RR=1.23], docosapentaenoate [RR=1.46]; p&lt;0.05). Conclusions: Comprehensive profiling of anthracycline-exposed CCS with preserved EF revealed dose-dependent echo (LV ESWS, T-D ratio, MPI) and blood (NT-ProBNP) abnormalities 10+years from dx; metabolomic studies demonstrated the role of carnitine in the pathogenesis of LV dysfunction. Taken together, these findings may facilitate early detection and targeted interventions in CCS at highest risk for CHF.

Circulating levels of persistent organic pollutants (POPs) are associated with left ventricular systolic and diastolic dysfunction in the elderly

Background and objectiveMajor risk factors for congestive heart failure (CHF) are myocardial infarction, hypertension, diabetes, atrial fibrillation, smoking, left ventricular hypertrophy (LVH) and obesity. However, since these risk factors only explain part of the risk of CHF, we investigated whether persistent organic pollutants (POPs) might also play a role. MethodsIn the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular ejection fraction, (EF), E/A-ratio and isovolumic relaxation time (IVRT), were determined by echocardiography and serum samples of 21 POPs were analyzed in serum measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 998 subjects all aged 70 years. ResultsIn this cross-sectional analysis, high levels of several of the polychlorinated biphenyls (PCB congeners 99, 118, 105, 138, 153, and 180) and octachlorodibenzo-p-dioxin (OCDD) were significantly related to a decreased EF. Some POPs were also related to a decreased E/A-ratio (PCBs 206 and 209). All the results were adjusted for gender, hypertension, diabetes, smoking, LVH and BMI, and subjects with myocardial infarction or atrial fibrillation were excluded from the analysis. ConclusionsCirculating levels of POPs were related to impairments in both left ventricular systolic and diastolic function independently of major congestive heart failure risk factors, suggesting a possible role of POPs in heart failure.

Abstract MP14: Long-chain Monounsaturated Fatty Acids and Incidence of Coronary Heart Disease: The Cardiovascular Health Study

Background: Decades-old animal experiments demonstrated that consumption of large amounts of long-chain monounsaturated fatty acids (LCMUFA, 22:1 and 24:1 fatty acids) caused cardiotoxicity. We recently found that plasma phospholipid 22:1 and 24:1 were associated with higher incidence of congestive heart failure (CHF) in two independent cohorts: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities Study. However, their association with incident CHD is unknown. Aim: to investigate association of plasma phospholipid 22:1 and 24:1 levels with incident CHD. Methods: The study included 3,221 adults free of CHD (age=74.9±5.2) in CHS in whom plasma phospholipid LCMUFA were measured in 1992. Incident CHD events from 1992 to 2006 were centrally adjudicated, and we assessed total CHD, including fatal CHD (fatal MI and other CHD deaths) and non-fatal MI. We examined prospective associations of LCMUFA with incident CHD using Cox proportional hazards. We further evaluated potential confounding or mediation by baseline risk factors and incident CHF. Results: Mean±SD phospholipid levels of 22:1 and 24:1 were 0.03±0.01 and 1.96±0.44 percent of total fatty acids. During 34,776 person-years, 628 incident CHD events occurred, including 309 fatal CHD and 401 non-fatal MIs. After multivariable adjustment, higher levels of both 22:1 and 24:1 were associated with higher risk of total incident CHD. Hazard ratios (95% CI) for quintiles 5 vs. 1 of 22:1 and 24:1 levels were 1.48 (1.07-2.06, p trend=0.005) and 1.65 (1.16-2.34, p trend=0.001). The associations with CHD were largely specific to fatal CHD rather than non-fatal MI (Figure). These associations did not change after adjustment for incident CHF and baseline risk factors including circulating lipids, blood pressure, and inflammatory markers. Conclusions: Higher levels of circulating 22:1 and 24:1 LCMUFA were associated with higher incidence of CHD, in particular fatal CHD, supporting the possibility of cardiotoxicity by current levels of LCMUFA exposure.

Abstract MP13: Circulating Long-chain Monounsaturated Fatty Acids and Cardiac Structure and Function

Background: We previously observed a prospective association of higher levels of plasma phospholipid long-chain monounsaturated fatty acids (LCMUFA, 22:1 and 24:1 fatty acids) with higher risk of incident congestive heart failure (CHF) in two independent cohorts: the Cardiovascular Health Study (CHS) and Atherosclerosis Risk in Communities Study. This is consistent with decades-old animal experiments demonstrating cardiotoxicity of LCMUFA, including cardiac lipid accumulation and dysfunction. However, relationships of LCMUFA to cardiac structure and function in humans are unknown. Aim: to evaluate associations of circulating LCMUFA with indices of cardiac structure and function including left-ventricular mass (LVM), LV hypertrophy (LVH), LV wall thickness, and systolic and diastolic function. Methods: We evaluated 2,220 CHS participants (age=74.6±5.0) in whom plasma phospholipid LCMUFA were measured in 1992 and M-mode echocardiography was performed in 1996. Primary outcomes were LVM index (LVM / height to the 2.7th power), LVH (LVM / height, &gt;143 g/m for men and &gt;102 g/m for women), LV wall thickness (average of posterior and septal wall thickness), systolic function (% fractional shortening), and diastolic function (ratio of early to atrial ventricular filling velocities, E/A ratio). Adjusting for sociodemographics, lifestyle factors, dietary factors, and prevalent cardiovascular diseases, we performed linear regression analyses to examine associations of 22:1 and 24:1 levels with each continuous outcome. For LVH (a common binary outcome), Poisson regression analysis was performed. Results: Mean±SD plasma phospholipid levels of 22:1 and 24:1 were 0.03±0.01 and 1.96±0.44 percent of total fatty acids. Across the interdecile range, higher levels of 22:1 and 24:1 were each associated with lower fractional shortening by 1.2% (95% confidence interval=0.1-2.3%, p=0.03) and 1.4% (0.2-2.7%, p=0.02), respectively. Higher levels of 22:1 and 24:1 were also associated with higher risk of LVH by 27% (0-62%, p=0.05) and 40% (5-86%, p=0.02), respectively. LCMUFA were not associated with LVM index, LV wall thickness, or E/A ratio (p&gt;0.1 each). Findings were similar after excluding 410 adults with prevalent coronary heart disease or CHF. Conclusions: Higher circulating levels of plasma phospholipid 22:1 and 24:1 were associated with two indices of lower systolic function and greater risk of LVH, but not with other indices. These findings, if replicated, suggest mechanistic pathways whereby LCMFUA exposure may increase CHF risk and potentially inform future prevention efforts.

Association between glycated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta‐analysis

Clinical trials to date have not provided definitive evidence regarding the effects of glucose lowering on the incidence of congestive heart failure (CHF). We synthesized available prospective epidemiological data on the association between glycaemia measured by haemoglobin A(1c) (HbA(1c)) and incident CHF in individuals with diabetes. We searched electronic databases and reference lists of selected articles for relevant prospective epidemiological studies. We abstracted data from relevant studies using standardized forms and obtained additional data from investigators when required. We pooled study-specific relative risk estimates using random-effects model meta-analysis. Of the 1044 citations identified, we included 10 studies comprising 178 929 participants with diabetes and 14 176 incident CHF cases. Five studies included only patients with type 2 diabetes, four studies had predominantly patients with type 2 diabetes, and one study included only patients with type 1 diabetes. All studies except one showed an increased risk of CHF with higher HbA(1c). The overall adjusted risk ratio (RR) for CHF was 1.15 [95% confidence interval (CI) 1.10-1.21] for each percentage point higher HbA(1c). There was substantial heterogeneity across the 10 studies (I(2): 83%; 95% CI 69-91%; P < 0.001) not explained by available study-level characteristics such as study design or average HbA(1c) level. In seven studies reporting RRs with more than one degree of adjustment, the association was minimally altered after adjustment for several cardiovascular risk factors. In observational studies of individuals with diabetes, a higher HbA(1c) level was associated with a significantly increased incidence of CHF.

Intraoperative use of dextran is associated with cardiac complications after carotid endarterectomy

Although dextran has been theorized to diminish the risk of stroke associated with carotid endarterectomy (CEA), variation exists in its use. We evaluated outcomes of dextran use in patients undergoing CEA to clarify its utility. We studied all primary CEAs performed by 89 surgeons within the Vascular Study Group of New England database (2003-2010). Patients were stratified by intraoperative dextran use. Outcomes included perioperative death, stroke, myocardial infarction (MI), and congestive heart failure (CHF). Group and propensity score matching was performed for risk-adjusted comparisons, and multivariable logistic and gamma regressions were used to examine associations between dextran use and outcomes. There were 6641 CEAs performed, with dextran used in 334 procedures (5%). Dextran-treated and untreated patients were similar in age (70 years) and symptomatic status (25%). Clinical differences between the cohorts were eliminated by statistical adjustment. In crude, group-matched, and propensity-matched analyses, the stroke/death rate was similar for the two cohorts (1.2%). Dextran-treated patients were more likely to suffer postoperative MI (crude: 2.4% vs 1.0%; P = .03; group-matched: 2.4% vs 0.6%; P = .01; propensity-matched: 2.4% vs 0.5%; P = .003) and CHF (2.1% vs 0.6%; P = .01; 2.1% vs 0.5%; P = .01; 2.1% vs 0.2%; P < .001). In multivariable analysis of the crude sample, dextran was associated with a higher risk of postoperative MI (odds ratio, 3.52; 95% confidence interval, 1.62-7.64) and CHF (odds ratio, 5.71; 95% confidence interval, 2.35-13.89). Dextran use was not associated with lower perioperative stroke but was associated with higher rates of MI and CHF. Taken together, our findings suggest limited clinical utility for routine use of intraoperative dextran during CEA.

Serum β-carotene concentrations and the risk of congestive heart failure in men: A population-based study

Fruit and vegetable intake has been associated with lower risk for cardiovascular diseases, but data on congestive heart failure (CHF) are inconsistent. The association of serum carotenoids, biomarkers reflecting fruit and vegetable intake, with the risk of CHF has not been well documented in previous studies. We therefore examined the association between carotenoid levels and the risk of CHF. Data were available for 1031 males aged 46 to 65 years participating in the Kuopio Ischaemic Heart Disease Risk Factor Study (Finland). Baseline data for the present study were collected between 1991 and 1993. The association between serum concentrations of carotenoids and the risk of CHF was examined by using Cox proportional hazard models. During the median of 17.8 follow-up years, CHF occurred in 72 patients. Age and examination year adjusted risk (hazard ratio, HR) for CHF among men within the lowest quartile of serum β-carotene was 4.08 (95% CI, 1.90-8.78, p<0.001) as compared to men in the highest quartile of serum β-carotene. After further adjustment for many potential confounders, men with the lowest quartile of β-carotene had almost 3-fold increased risk of CHF (HR=2.78, 95% CI, 1.23-6.25, p=0.014). However, serum concentrations of lycopene and α-carotene were not related to the risk of CHF. The present study suggests that low concentrations of serum β-carotene may be associated with an increased risk of CHF.

Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF) in Survivors of Hematopoietic Cell Transplantation (HCT)

AbstractAbstract ▪589▪This icon denotes a clinically relevant abstract Background:HCT survivors are at increased risk for developing cardiovascular disease, including CHF. We have demonstrated that the risk of post-HCT CHF is primarily ascribed to pre-HCT exposure to anthracyclines. The anthracycline-related cardiotoxicity is dose-dependent, with well-established factors that modify this association, such as young age at exposure to anthracyclines, female gender, chest irradiation, and presence of conventional cardiovascular risk factors (CVRFs: hypertension, diabetes mellitus, and dyslipidemia). However, these modifiers fail to explain the wide inter-individual variability in the risk of anthracycline-related CHF. Proposed pathogenesis of anthracycline-related CHF includes oxidative stress and intracardiac metabolic derangements induced by anthracycline toxic metabolites. Inherent susceptibility in these pathways could explain the inter-individual variability in risk – an area that is unstudied in this population. Methods:A nested case-control approach was used to evaluate the impact of functional SNPs in candidate genes hypothesized to be associated with anthracycline-related CHF. Cases were defined per the American Heart Association criteria for clinical CHF. Individuals with CHF and with pre-HCT germline DNA were identified from 2950 patients transplanted at City of Hope between 1988 and 2007. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age at HCT, type of HCT (allo, auto), race/ethnicity confirmed by genetic ancestry, anthracycline dose, and length of follow-up. We studied genes involved in free radical metabolism (NAD[P]H oxidase: subunits NCF4, RAC2, CYBA; Hemochromatosis: HFE; Superoxide dismutase: SOD; Apolipoprotein E: ApoE), genes involved in regulation of the renin-angiotensin and beta-adrenergic systems (AGT, AGTR1, ACE, ADRB1, ADRB2) as well as those impacting the pharmacodynamics of anthracyclines (carbonyl reductase: CBR1 and CBR3; Multidrug resistant protein: MRP1 and MRP2). Results:The cumulative incidence of CHF was 6% at 15 years after transplantation; Pre-HCT germline DNA was available for 77 patients with CHF; median age at HCT was 47.5 yrs (16.0–68.6); 82% underwent autologous HCT; 60% were non-Hispanic white; median anthracycline dose was 300 mg/m2 (60–650); median time to CHF: 2.8 yrs (0.1–12.7). One-hundred and seventy eight matched controls with available germline DNA were identified. There was no difference in underlying diagnosis, conditioning regimen, and body mass index (BMI) at HCT between cases and controls. Cases were more likely to be female (55.8% vs. 34%, p<0.01), to have received chest radiation prior to HCT (14.3% vs. 5.1%, p=0.01), and have hypertension following HCT (28.6% vs. 14.6%, p<0.01) when compared to controls. Multivariate conditional logistic regression revealed an increased risk of CHF in individuals with variants of genes coding for the NAD(P)H oxidase subunit RAC2 (rs13058338, 7508T→A; Odds Ratio [OR]: 2.8, p<0.01), HFE (rs17999945, 63C→G; OR: 2.5, p=0.01) or the doxorubicin efflux transporter MRP2 (rs8187710, Cys1515Tyr; OR: 4.3, p<0.01). Compared to males with one or no at-risk alleles, female HCT survivors with ≥2 at-risk alleles were at highest risk of CHF (Table; OR=17.1, p<0.01). Conclusion:Our findings support the “unifying hypothesis” that the risk of anthracycline-related cardiotoxicity is significantly modified by high-risk variants of RAC2 (free radical generation), HFE (dysregulation of iron homeostasis and free radical generation), and MRP2 (intracellular accumulation of cardiotoxic anthracyclines). These data could facilitate the development of novel approaches for targeted surveillance as well as early intervention strategies in HCT survivors at highest risk for CHF.OR95% CIP-ValueMale, <2 SNPs1.0____Male, ≥2 SNPs5.01.10–22.530.04Female, <2 SNPs2.41.11–5.160.03Female, ≥2 SNPs17.14.63–63.36<0.01Model adjusted for: chest radiation exposure, BMI, underlying diagnosis, post-HCT CVRFs (hypertension, diabetes, dyslipidemia).Case-Control matching criteria: age at HCT, race/ethnicity, lifetime anthracycline dose, type of HCT, length of follow-up. Disclosures:No relevant conflicts of interest to declare.

Deferasirox Is Associated with Reduced Mortality Risk in a Medicare Population with Myelodysplastic Syndromes

AbstractAbstract 426 Background:While there is extensive evidence of the impact of iron chelation therapy (ICT) on clinical outcomes in thalassemia patients (pts), there is a paucity of data relevant to myelodysplastic syndromes (MDS). In this study, we examined the association between oral deferasirox (DFX) therapy and conditions potentially associated with iron overload [congestive heart failure (CHF) and endocrine disease (diabetes or thyroid)], drug side effects (renal disease), and overall mortality, among MDS pts in a U.S. Medicare cohort. Methods:MDS pts from 2005–2008 were identified using ICD-9 CM codes (1 inpatient or 2 outpatient) from the 100% Medicare claims database. Pts meeting a minimum transfusion threshold of 20 units packed RBC were considered “eligible” for ICT. The study cohort consisted of ICT-eligible pts enrolled in Medicare Part D, under which oral drug prescriptions are reimbursed. The observation period began the week (wk) after the RBC threshold was met and ended at incident diagnosis of a condition of interest, death, or end of study. Patients receiving parenteral ICT (deferoxamine) during the observation period were excluded. Patients with a history of the specific condition (CHF, endocrine disease, renal disease) were excluded from the outcome-specific sample, but were included in overall survival analysis. Onset of CHF or renal disease was based on the presence of 1 inpatient or 2 outpatient Medicare claims with ICD-9-CM diagnoses of each condition. Onset of diabetes or thyroid disease was measured based on new use of oral anti-diabetic or thyroid medications, respectively. Covariates in the outcome models included demographics (age, sex, race), ICD-9 coded MDS risk category at diagnosis, baseline indicators for co-morbid conditions, and time-varying exposure to RBC, erythropoiesis-stimulating agents (ESA), lenalidomide and hypomethylating agents (HMA). Marginal structural models (MSM) estimated the effects of cumulative DFX, controlling for anemia management and patient characteristics. The analysis adjusted for effects of time-varying health status on the probability of receiving DFX. Results:The cohort of 4,226 beneficiaries with MDS was 54% female, 90% white, with mean age of 77.7 years. MDS risk status was 16% lower/del5q, 5% higher, & 79% not otherwise specified. Common baseline comorbidities included CHF (46%), diabetes (18%), thyroid disease (21%), and renal disease (29%). Drug exposures prior to cohort entry included ESA (84%), HMA (19%) and lenalidomide (7%). Prior ICT was noted for 4.5% of patients. Patients were observed for a median of 35 weeks. Death occurred in 2496 (59%) of the cohort. DFX was used during the observation period by 544 (12%) patients, with mean duration of 29.2 weeks (median 20.5). Estimates from MSM indicate that each incremental week of DFX was associated with a decreased risk of death [hazard ratio (HR) 0.987; 95%CI 0.981–0.993]. The magnitude of risk reduction increased from HR 0.77 (95%CI 0.536–1.02) for patients receiving 14–26 weeks of DFX to HR 0.342 (95%CI 0.179–0.651) for patients with 53 or more weeks. Cumulative RBC units were associated with increased risk of death (HR 1.01, 95%CI 1.007–1.013 per unit), as were a baseline solid tumor diagnosis, renal and cardiac disease, and poor predicted performance status. After controlling for time-varying incidence of sepsis, bleeds, and cytopenias in MSM treatment propensity model, DFX use was not found to be associated with altered risk of CHF, endocrine or renal disease. Conclusions:This is the first large population-based Medicare study evaluating the association between DFX use in older MDS patients and sequelae of iron overload and mortality. The decrease in risk of death was proportional to the duration of therapy. Application of MSM addresses the role of observed time-varying confounders between treatment and outcomes, while permitting us to assess the duration-outcome relationships. The MSM analysis cannot address potential confounding by unobserved factors that may influence physician selection of patients for ICT. Nonetheless, this retrospective analysis controls for bias associated with observed patient health status, and lends significant support to a positive association of oral iron chelation therapy with decreased mortality in MDS patients with a minimum transfusion threshold, and ongoing transfusion needs. Disclosures:Gore:Celgene Corporation: Consultancy, Research Funding. Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis: Employment. Davidoff:GlaskoSmithKline: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Novartis: Research Funding.