Absolute Left Ventricular Ejection Fraction Research Articles

High fat mass associates with occurrence of targeted therapy-induced left ventricular ejection fraction reduction in patients with renal cell carcinoma

Recent research suggests that variations of skeletal muscle (SM) and fat predict the severity of chemotherapy-induced toxicities in patients with renal cell carcinoma (RCC). Cardio-toxicity has not been evaluated in this context. In this study we considered 47 RCC patients who participated in randomized clinical trials of sorafenib or sunitinib (i.e., targeted therapy). To capture cardio-toxicity, multi gated acquisition (MUGA) scan-defined left ventricular ejection fraction (LVEF) tests (at least 3 tests over 1 year of treatment) were abstracted. Computed tomography (CT) cross-sectional images were analyzed before start of targeted therapy and at 1 year to define SM and fat at baseline and changes over time concurrent with MUGA-defined LVEF measurement. MUGA-defined cardio-toxicity (usually fall in LVEF >10% to an absolute LVEF<55%) occurred in 8/47 (17%) patients over 1 year of targeted therapy (all were male). Percentage of patients with high fat mass (baseline CT-defined total adipose tissue/indexed by height2 greater than the gender-specific median value) was higher among patients with cardio-toxicity versus patients without cardio-toxicity [7 (87.5%) versus 16 (41.0%); p=0.02]. The percentage of SM loss in patients with cardio-toxicity was higher than the patients without cardio-toxicity [median of loss (%) -7 versus 0 respectively; p=0.04]. Cardio-toxicity in RCC patients might be associated with high fat mass. This finding is distinct from prior observations that low body weight and sarcopenia associated with non-cardiac toxicities of targeted therapies. Concurrence of SM loss over time and development of cardio-toxicity is reported for the first time.

Abstract P4-21-05: Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study

Abstract INTRODUCTION Targeting HER2 by dual blockade with trastuzumab (T) and pertuzumab (P) in a taxane-based regimen is an active neoadjuvant treatment (NAT) of HER2+ early breast cancer (EBC). Addition of an anthracycline could further enhance this response, but potential cardiac toxicity is a concern. The Opti-HER HEART trial (NCT01669239) aims to optimize neoadjuvant treatment while minimizing cardiac risk, by combining T+P with a taxane and non-pegylated liposomal doxorubicin (NPLD). MATERIAL AND METHODS Phase II open-label, single-arm study of six 21-day cycles of NPLD (50mg/m2 D1), paclitaxel (80mg/m2 D1,8,15), T (4mg/kg C1D1, followed by 2mg/kg weekly), and P (840mg C1D1, followed by 420mg C2-6D1) as NAT for patients (pts) with stage II-IIIB HER2+ BC. Primary objective was to evaluate cardiac safety of the combination, measured by the incidence of type A (symptomatic congestive heart failure ) or type B [asymptomatic reduction of Left Ventricular Ejection Fraction (LVEF) value: ≥10% absolute decrease and LVEF&amp;lt;50%, LVEF&amp;lt;40% or any absolute decrease ≥20%] events, during NAT. Eighty-three pts were required to reject with 80% confidence the null hypothesis that the combination increases the incidence of cardiac events above the historical control of 18% (3% type A; 15% type B). RESULTS Between June 2013 and January 2015, 83 pts with HER2+ EBC (stage II 78%, stage III 22%) and adequate cardiac function (LVEF≥55%) were enrolled. Mean age was 50 years, N+ 47%, hormone receptor (HR) positive 71% and median baseline LVEF 66%. Eighty-five percent of pts completed 6 cycles of NAT, whereas 15% discontinued NAT due to toxicity. Adverse events (AEs) leading to dose adjustments/temporary interruptions and discontinuation of at least 1 drug occurred in 70% and 21% of pts, respectively. Primary objective was met with an incidence of cardiac events during NAT of 4% (95%CI 1-10, 3pts, all type B). Cardiac events until study completion (1 year) were 8% (all type B). All (but 2 cases with no follow-up data) were reversible and only 1 pt presented an asymptomatic LVEF&amp;lt;40%. Neutropenia (45%) was the most frequent hematological toxicity (G3/4 34%; febrile neutropenia 6%), less frequent in the 71% of pts that received primary G-CSF prophylaxis (G3/4 25% vs. 67%). Common non-hematological toxicities were diarrhea (74%; G3 7%), asthenia (78%; G3 11%) and neurotoxicity (52%; G3/4 10%). Pathological complete response (pCR) in breast+axilla (ypT0/is ypN0) was 60% (87% in HR-) and 69% in breast (91% in HR-). TOTALHR-HR+% ypT0/is (95% CI)69 (58-79)91 (72-99)61 (47-74)% ypT0/is ypN0 (95% CI)60 (46-71)87 (66-97)50 (36-64) CONCLUSIONS The neoadjuvant combination of T+P, paclitaxel and NPLD does not increase the risk for cardiac events in HER2+ BC pts. Since cardiac toxicities may present later, long-term cardiac monitoring is essential. Efficacy in terms of pCR was remarkable, being higher to historical values of combinations with dual anti-HER2 blockade and one of the highest reported among HR-HER2+ BC. This regimen administered with primary G-CSF prophylaxis and cardiac function monitoring may be an effective and secure option for early and locally advanced HER2+ pts with good cardiac function. Citation Format: Gavilá J, Perez-Garcia J, Calvo I, Ciruelos E, Muñoz M, Virizuela JA, Ruiz I, Andrés R, Morales S, Perelló A, Sánchez P, Garcia-Saenz JA, Quero Guillen JC, González-Santiago S, Garau Llinas I, González-Martín A, Cantos Sánchez de Ibargüen B, Zaragoza K, de la Peña L, Llombart-Cussac A, Oliveira M. Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-05.

Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7–14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.

Association between High Endocardial Unipolar Voltage and Improved Left Ventricular Function in Patients with Ischemic Cardiomyopathy.

We know that endocardial mapping reports left ventricular electrical activity (voltage) and that these data can predict outcomes in patients undergoing traditional revascularization. Because the mapping data from experimental models have also been linked with myocardial viability, we hypothesized an association between increased unipolar voltage in patients undergoing intramyocardial injections and their subsequent improvement in left ventricular performance. For this exploratory analysis, we evaluated 86 patients with left ventricular dysfunction, heart-failure symptoms, possible angina, and no revascularization options, who were undergoing endocardial mapping. Fifty-seven patients received bone marrow mononuclear cell (BMC) injections and 29 patients received cell-free injections of a placebo. The average mapping site voltage was 9.7 ± 2 mV, and sites with voltage of ≥6.9 mV were engaged by needle and injected (with BMC or placebo). For all patients, at 6 months, left ventricular ejection fraction (LVEF) improved, and after covariate adjustment this improvement was best predicted by injection-site voltage. For every 2-mV increase in baseline voltage, we detected a 1.3 increase in absolute LVEF units for all patients (P=0.038). Multiple linear regression analyses confirmed that voltage and the CD34(+) count present in bone marrow (but not treatment assignment) were associated with improved LVEF (P=0.03 and P=0.014, respectively). In an exploratory analysis, higher endocardial voltage and bone marrow CD34(+) levels were associated with improved left ventricular function among ischemic cardiomyopathy patients. Intramyocardial needle injections, possibly through stimulation of angiogenesis, might serve as a future therapy in patients with reduced left ventricular function and warrants investigation.

Association of apical rocking with super-response to cardiac resynchronisation therapy.

BackgroundSuper-responders to cardiac resynchronisation therapy (CRT) show an exceptional improvement in left ventricular ejection fraction (LVEF). Previous studies showed that apical rocking was independently associated with echocardiographic response to CRT. However, little is known about the association between apical rocking and super-response to CRT.ObjectivesTo determine the independent association of LV apical rocking with super-response to CRT in a large cohort.MethodsA cohort of 297 consecutive heart failure patients treated with primary indication for CRT-D were included in an observational registry. Apical rocking was defined as motion of the left ventricular (LV) apical myocardium perpendicular to the LV long axis. ‘Super-response’ was defined by the top quartile of LVEF response based on change from baseline to follow-up echocardiogram. Best-subset regression analysis identified predictors of LVEF super-response to CRT.ResultsApical rocking was present in 45 % of patients. Super-responders had an absolute mean LVEF increase of 27 % (LVEF 22.0 % ± 5.7 at baseline and 49.0 % ± 7.5 at follow-up). Apical rocking was significantly more common in super-responders compared with non-super-responders (76 and 34 %, P < 0.001). In univariate analysis, female gender (OR 2.39, 95 % CI 1.38–4.11), lower LVEF at baseline (OR 0.91 95 % CI 0.87–0.95), non-ischaemic aetiology (OR 4.15, 95 % CI 2.33–7.39) and apical rocking (OR 6.19, 95 % CI 3.40–11.25) were associated with super-response. In multivariate analysis, apical rocking was still strongly associated with super-response (OR 5.82, 95 % CI 2.68–12.61). Super-responders showed an excellent clinical prognosis with a very low incidence of heart failure admission, cardiac mortality and appropriate ICD therapy.ConclusionApical rocking is independently associated with super-response to CRT.Electronic supplementary materialThe online version of this article (doi:10.1007/s12471-015-0768-4) contains supplementary material, which is available to authorized users.

Meta-analysis on the impact of percutaneous coronary intervention of chronic total occlusions on left ventricular function and clinical outcome

BackgroundPercutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) may have a beneficial effect on survival through a better-preserved or improved LVEF. Current literature consists of small observational studies therefore we performed a weighted meta-analysis on the impact of revascularization of CTOs on left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and long-term mortality. MethodsWe conducted a meta-analysis evaluating LVEF before and after CTO PCI and long-term mortality. No language or time restrictions were applied. References from the identified articles and reviews were examined to find additional relevant manuscripts. ResultsOf the 812 citations, 34 studies performed between 1987–2014 in 2243 patients were eligible for LVEF and 27 studies performed between 1990–2013 in 11,085 patients with success and 4347 patients that failed CTO PCI were eligible for long-term mortality. After successful CTO PCI, LVEF increased with 4.44% (95% CI: 3.52–5.35, p<0.01) compared to baseline. In a small cohort of ~70 patients, no significant difference in LVEF was observed after non-successful CTO PCI or reocclusion. Additionally, 8 studies reported the change in left ventricular end-diastolic volume (LVEDV) in a total of 412 patients. LVEDV decreased with 6.14ml/m2 (95% CI: −9.31 to −2.97, p<0.01). Successful CTO PCI was also associated with reduced mortality in comparison with failed CTO PCI (OR: 0.52, 95% CI: 0.43–0.62, p-value<0.01). ConclusionsThe current meta-analysis revealed that successful recanalization of a CTO resulted in an overall improvement of 4.44% absolute LVEF points, reduced adverse remodeling and an improvement of survival (OR: 0.52).

Elevated High Sensitivity Troponin T (HsTnT) during Front-Line Therapy with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone +/- Rituximab (CHOP+/-R) or Cyclophosphamide, Epirubicin, Vincristine and Prednisone +/- Rituximab (CEpOP+/-R) Correlates with a Decline in Left Ventricular Ejection Fraction (LVEF) in Patients with Aggressive B-Cell Lymphoma: Results from a Randomized Prospective Clinical Trial NCT00854568

Anthracycline associated cardiomyopathy (AAC) is a rare but real complication that negatively influence the clinical outcome and quality of life in B-cell lymphoma patients. Guidelines for cardiac monitoring during chemotherapy had been formulated but are primarily based on cardiac imaging. On the other hand, current available cardiac imaging studies only detect changes once significant myocardial damage has occurred. Thus, there is a need to identify, test and validate novel biomarkers that may predict early cardiac injury in cancer patients receiving cardio-toxic agents.Recently introduced into the clinical practice, high sensitivity troponin T (HsTnT) assay has allowed unparalleled sensitivity and precision to detect early myocardial injury. To this end, we prospectively evaluated changes in HsTnT levels during chemotherapy and correlated it with changes in left ventricular ejection fraction (LVEF) and/or incidence of AAC in previously untreated diffuse large B-cell lymphoma (DLBCL) patients enrolled in a phase III clinical trial comparing two chemotherapy regimens CHOP+/-R vs. CEpOP+/-R, (NCT00854568). A total of 348 DLBCL (N=315) or follicular lymphoma grade 3 (FLG3) (N=33) were randomized to receive either 6 cycles of CHOP+/-R or CEpOP+/-R administered on a 21 day cycles. Demographic, clinical and pathological characteristics were collected for each patient. In addition, baseline and after 4 cycles of the planned therapy were completed, cardiac multi gated acquisition [MUGA] scan and HsTnT using one-step electrochemiluminescence immunoassay (Roche cobase 411) were performed. Treatment groups were well balanced in terms of clinical and demographic characteristics.After 27.1 month follow up, there was no difference in terms of overall response rate (ORR) and progression free survival (PFS) between CHOP+/-R or CEpOP+/-R (Estimated 3-year PFS: 79.7±3.3 % vs. 80.0±3.4%, P = 0.958). Cardiac biomarkers were collected in 324 patients. Elevated HsTnT values after 4 cycles of therapy were observed in 30.9% and changes in LVEF were detected only in 16.0 % of the patients. In detail, elevated levels of HsTnT were observed in 100/324 patients, 66/157 in the CHOP+/-R group and 34/167 in the CEpOP+/-R group (42.0% vs. 20.4%, P = 0.001) (Figure 1). All these patients were asymptomatic, clinically and hemodynamically stable. Moreover, there was no difference between these two groups in terms of incidence of decreased LVEF (27/168, 16.1% vs. 27/180, 15.0%, P = 0.783). Patients with an elevated HsTnT after 4 cycles of their planned treatment exhibited a more pronounced decrease in the absolute LVEF than patients with stable HsTnT levels (P = 0.009) (Figure 2).Our data suggest that while CHOP+/-R or CEpOP+/-R are equivalent in terms of clinical activity; CEpOP+/-R is associated with a lower incidence of HsTnT elevation. Subclinical decrease in LVEF was associated with elevations on HsTnT in the patient population studied suggesting that HsTnT can potentially be applied as a serum biomarker to identify patients at risk for AAC. Longer follow up is required to further define if the differences observed on HsTnT changes between CHOP+/-R and CEpOP+/-R treated patients will translate in differences in the incidence of clinically relevant AAC. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure: Results of the ANTHEM-HF Trial

ObjectiveANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Methods and ResultsSixty subjects (New York Heart Association [NYHA] functional class II–III, left ventricular ejection fraction (LVEF) ≤40%, left ventricular end-diastolic diameter ≥50 mm to <80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar for left- and right-side VNS. After 6 months of ART, the adjusted left-right differences in LVEF, left ventricular end-systolic volume (LVESV), and left ventricular end-systolic diameter (LVESD) were 0.2% (95% CI -4.4 to 4.7), 3.7 mL (95% CI -7.0 to 14.4), and 1.3 mm (95% CI -0.9 to 3.6), respectively. In the combined population, absolute LVEF improved by 4.5% (95% CI 2.4–6.6), LVESV improved by -4.1 mL (95% CI -9.0 to 0.8), and LVESD improved by -1.7 mm (95% CI -2.8 to -0.7). Heart rate variability improved by 17 ms (95% CI 6.5–28) with minimal left-right difference. Six-minute walk distance improved an average of 56 m (95% CI 37–75); however, improvement was greater for right-side ART (77 m [95% CI 49-105]). NYHA functional class improved in 77% of patients (baseline to 6 months). ConclusionsChronic open-loop ART via left- or right-side VNS is feasible and well tolerated in HFrEF patients. Safety and efficacy measures are encouraging and warrant further study.

Abstract 189: Surveillance and Management of Lymphoma Patients Receiving Anthracycline Based Chemotherapy

Background: Cardiotoxicity is one of the most common and devastating complications of anthracyline-based chemotherapy (AC). The AHA recommends routine surveillance, early diagnosis and treatment of AC induced cardiomyopathy (CMP). We assessed the pattern of surveillance of left ventricular ejection fraction (LVEF) and management of AC-CMP. Methods: We performed a retrospective analysis of a cohort of Non-Hodgkin lymphoma (NHL) patients evaluated by the Emory Lymphoma program who received AC between 1992 and 2013. We assessed cardiac function by echocardiogram or equilibrium radionuclide imaging. We also examined the prevalence of AC-CMP (defined as an absolute decrease in LVEF &gt; 10% with a decline &lt;50%, or an LVEF reduction of at least 15% with absolute LVEF &gt; 50%) and quality of care of AC-CMP based on AHA heart failure guidelines including treatment with beta-blockers and ACE-inhibitors. Finally, we reviewed echocardiograms to assess echocardiographic measures of diastolic function. Results: Of 218 patients who received AC (median dose 300 mg/m2), 41% (89 of 218) had imaging surveillance before and after AC (Table 1). LVEF was evaluated by limited echo in 52% (46 of 89), comprehensive echo in 32% (29 of 89) and MUGA in 16% (14 of 89) of patients. Diastolic function was evaluated in only 20% (15 of 75) of patients. Twenty seven percent of patients (24 of 89) had AC-CMP, out of which 17% (15 of 89) had moderate-severe decrease in LVEF &lt; 45%. Of patients with LVEF &lt; 45%, only 47% (7 of 15) received ACE Inhibitors, 40% (6 of 15) received beta-blockers and 40% (6 of 15) had repeat assessment of LVEF. Notably, 46% (11 of 24) of patients with AC-CMP were asymptomatic and 42% (10 of 24) were symptomatic. Conclusions: Less than half of NHL patients treated with AC receive surveillance and treatment according to AHA guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving AC .

Relationship between Two-Dimensional Speckle-Tracking Septal Strain and Response to Cardiac Resynchronization Therapy in Patients with Left Ventricular Dysfunction and Left Bundle Branch Block: A Prospective Pilot Study

Previous studies have demonstrated variable patterns of longitudinal septal deformation in patients with left ventricular (LV) dysfunction and left bundle branch block. This prospective single center study was designed to assess the relationship between septal deformation patterns obtained by two-dimensional speckle-tracking echocardiography and response to cardiac resynchronization therapy (CRT). One hundred one patients with New York Heart Association class II to IV heart failure, LV ejection fractions ≤ 35%, and left bundle branch block underwent echocardiography before CRT. Longitudinal two-dimensional speckle-tracking strain analysis in the apical four-chamber view identified three patterns: double-peaked systolic shortening (pattern 1), early pre-ejection shortening peak followed by prominent systolic stretch (pattern 2), and pseudonormal shortening with a late systolic shortening peak and less pronounced end-systolic stretch (pattern 3). CRT response was defined as a relative reduction in LV end-systolic volume of ≥ 15% at 9-month follow-up. CRT super-response was defined as an absolute LV ejection fraction of ≥ 50% associated with a relative reduction in LV end-systolic volume of ≥ 15% and an improvement in New York Heart Association functional class. Cardiac death or hospitalization for heart failure during follow-up was systematically investigated. Ninety-two percent of patients with pattern 1 or 2 were responders to CRT compared with 59% with pattern 3 (P < .0001). Thirty-six percent of patients with pattern 1 were super-responders compared with 15% of those with pattern 2 and 12% of those with pattern 3 (P = .037). The improvement in LV volumes, LV ejection fraction, and global longitudinal strain after CRT was better in patients with pattern 1 or 2 compared with those with pattern 3 (P < .0001 for all). Eighteen-month outcomes were excellent in patients with pattern 1 or 2, with event-free survival of 95 ± 3% compared with 75 ± 7% in patients with pattern 3 (P = .010). Septal deformation strain pattern 1 or 2 is highly predictive of CRT response. Further studies are needed to identify predictors of "nonresponse" in patients with a pattern 3.

Factors Affecting Long-Term Safety of Trastuzumab in Patients with Early HER2-Positive Breast Cancer

Background: Trastuzumab treatment is associated with cardiac dysfunction. We evaluated the incidence of cardiotoxicity during and long-term after trastuzumab treatment in an unselected early breast cancer population. Methods: This study included a retrospective part, the chemotherapy- and trastuzumab treatment period and a prospective part, the period of data collection long-term after trastuzumab treatment. Cardiac evaluation included left ventricular ejection fraction (LVEF) changes and an evaluation of symptomatic cardiotoxicity. Cardiac events were defined as a decrease of 10 percentage points in LVEF compared with baseline and to an absolute LVEF of below 50%. Secondary outcomes included the evaluation of cardiac markers (B-type natriuretic peptide and troponins) and single nucleotide polymorphisms (SNPs) in the HER2 gene as parameters to detect or predict trastuzumab-related cardiotoxicity. Results: Overall, 105 patients were evaluable for the primary endpoint. The 3-year cumulative incidence of cardiac events was 12% (95 CI, 4%-19%). All 8 patients with a cardiac event were pre-treated with anthracyclines and cyclophosphamide and 7 of them recovered partially or completely. Four patients experienced symptomatic cardiotoxicity, of who 2 recovered completely and the other 2 recovered partially. No statistically significant association was observed between cardiac events and cardiac markers or SNPs. Conclusion: Trastuzumab treatment in combination with anthracy cline-based chemotherapy is associated with significant and only partly reversible cardiac dysfunction. Baseline LVEF value is a prominent predictor for long-term LVEF especially, in patients who are not treated with anthracycline-based chemotherapy. These findings can be used to establish optimal monitoring strategies in trastuzumab treatment.

ENOS Overexpressing Bone Marrow Cells are Safe and Effective in a Porcine Model of Myocardial Regeneration Following Acute Myocardial Infarction

Cell therapy has been shown to be effective in improving LV function postmyocardial infarction (MI). We hypothesized that eNOS-transfected bone marrow cells (BMCs) are safe in a swine model of myocardial infarction (MI). We also hypothesized that endothelial nitric oxide synthase (eNOS) transfection would enhance cell function, as assessed by myocardial functional recovery post-MI. Fifteen female Yorkshire pigs underwent bone marrow aspiration and creation of MI. Bone marrow cells were cultured for 7days, and each pig received either autologous BMCs transiently transfected with eNOS plasmid (eNOS-BMC, n=5), nontransfected BMCs (nt-BMC, n=4), or phosphate-buffered saline (PBS) control (n=6). Cardiac MRI was performed at baseline (1week post-MI) and 6weeks post-MI. There was no difference in safety outcomes between groups. Absolute left ventricular ejection fraction (LVEF) at 6weeks showed a trend toward improvement in both cell therapy groups compared with baseline but worsened in the PBS control group. The absolute improvement in LVEF was significantly greater in both cell therapy groups compared with PBS control. Infarct mass was significantly lower in the eNOS-BMC group between baseline and 6weeks, but the absolute change in infarct mass was not different between groups. Finally, there was a trend toward reduced LV mass in the eNOS-BMC group. Bone marrow cell delivery, with and without eNOS overexpression, is safe and leads to improvement in LVEF when administered in the coronary circulation 7days following acute MI in swine. Transfection of healthy BMCs with eNOS resulted in some improvement in left ventricular remodeling. Further study is warranted in a preclinical model that approximates the impact of cardiovascular risk factors on BMC function.

Outcomes of Transcatheter and Surgical Aortic Valve Replacement in High-Risk Patients With Aortic Stenosis and Left Ventricular Dysfunction

The Placement of Aortic Transcatheter Valves (PARTNER) trial demonstrated similar survival after transcatheter and surgical aortic valve replacement (TAVR and SAVR, respectively) in high-risk patients with symptomatic, severe aortic stenosis. The aim of this study was to evaluate the effect of left ventricular (LV) dysfunction on clinical outcomes after TAVR and SAVR and the impact of aortic valve replacement technique on LV function. The PARTNER trial randomized high-risk patients with severe aortic stenosis to TAVR or SAVR. Patients were stratified by the presence of LV ejection fraction (LVEF) <50%. All-cause mortality was similar for TAVR and SAVR at 30-days and 1 year regardless of baseline LV function and valve replacement technique. In patients with LV dysfunction, mean LVEF increased from 35.7±8.5% to 48.6±11.3% (P<0.0001) 1 year after TAVR and from 38.0±8.0% to 50.1±10.8% after SAVR (P<0.0001). Higher baseline LVEF (odds ratio, 0.90 [95% confidence interval, 0.86, 0.95]; P<0.0001) and previous permanent pacemaker (odds ratio, 0.34 [95% confidence interval, 0.15, 0.81]) were independently associated with reduced likelihood of ≥10% absolute LVEF improvement by 30 days; higher mean aortic valve gradient was associated with increased odds of LVEF improvement (odds ratio, 1.04 per 1 mm Hg [95% confidence interval, 1.01, 1.08]). Failure to improve LVEF by 30 days was associated with adverse 1-year outcomes after TAVR but not SAVR. In high-risk patients with severe aortic stenosis and LV dysfunction, mortality rates and LV functional recovery were comparable between valve replacement techniques. TAVR is a feasible alternative for patients with symptomatic severe aortic stenosis and LV dysfunction who are at high risk for SAVR. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.

Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors

ObjectiveAlthough adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of...

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Trastuzumab-induced cardiotoxicity in early breast cancer: Evaluation of possible risk and protective factors.

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF &lt;50%. The term heart failure (HF) referred to the New York Heart Association classification III or IV. Logistic regression was used to assess relative risks. Results: A total of 179 HER2-positive EBC pts (median 54 years, range 30-84) were evaluated. 154 (86%) were treated with anthracycline-based adjuvant chemotherapy. 78 (44%) did not show any risk factors, whereas 101 (56%) had at least one: hypertension (24%), smoking habit (16%), dysthyroidism (18%), obesity (12%), hypercholesterolemia (9%) and diabetes mellitus (4%). Among the 179 EBC pts, 78 (44%, 95% confidence intervals (CI) 37-51%) experienced TIC during their 12-month trastuzumab treatment and only 4 (2%, 95% CI 0-4%) developed HF. 14 pts stopped trastuzumab due to TIC. None of the risk factors described above was correlated with TIC development. A previous anthracycline cumulative dose &gt; 240 mg/m2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.

Circadian Dependence of Infarct Size and Left Ventricular Function After ST Elevation Myocardial Infarction

In rodents, infarct size after ischemia/reperfusion exhibits a circadian dependence on the time of coronary occlusion. It is not known if a similar circadian dependence of infarct size occurs in humans. To determine if humans exhibit a circadian dependence of infarct size in the setting of ST elevation myocardial infarction (STEMI). A retrospective analysis of 1031 patients with STEMI referred for primary percutaneous coronary intervention with known ischemic times between 1 and 6 hours identified 165 patients with occluded arteries on presentation without evidence of preinfarction angina or collateral blood flow. Both ischemic duration and angiographic area at risk were not dependent on time of infarct onset. We observed that the extent of infarct size measured by creatine kinase release was significantly associated with time of day onset of infarction (P<0.0001). The greatest myocardial injury occurred at 1:00 am onset of ischemia and 5:00 am onset of reperfusion, with the peak creatine kinase measured at the peak of the curve being 82% higher than that recorded at the trough. Similarly, left ventricular ejection fraction measured within 2 days of infarction was also dependent on time of onset of STEMI with the absolute left ventricular ejection fraction at peak >7% higher than at trough (43% vs 51%; P<0.03). These findings were supported by a subgroup of patients (n = 45) who underwent cardiac MRI measurements of infarct size and area-at-risk measurements. The results of this study demonstrate for the first time in humans that myocardial infarct size and left ventricular function after STEMI have a circadian dependence on the time of day onset of ischemia.

Abstract P105: Clinical Factors Associated With Left Ventricular Ejection Fraction Disparity in Patients With Left Ventricular Dysfunction Undergoing Multimodality Imaging

Background: Drug and device therapy of heart failure is increasingly determined based on left ventricular ejection fraction (LVEF) partition values. Many patients undergo both single photon emission computed tomography (SPECT) and echocardiographic assessment of LVEF. Significant disparity frequently exists between these 2 techniques, even when testing is performed near simultaneously in clinically stable patients. Objective: We aimed to determine clinical predictors of LVEF disparity in patients undergoing multimodality testing. Methods: Between January 2006 and July 2007, 2937 patients underwent both echo and SPECT testing within a 7 day period. Of these, 119 patients had an LVEF &lt;50% by 1 or both techniques, and an absolute LVEF difference between the 2 techniques of at least 10%. A control group comprising of 118 patients had an LVEF &lt;50% by 1 or both techniques, and an absolute LVEF difference between the 2 techniques of less than 10%. In a logistic model with a stepwise selection method 30 candidate clinical variables were available to be selected in the model. Results: The predictive model resulted in five variables: Atrial Fibrillation, Severe mitral regurgitation, Left ventricular hypertrophy, high basal heart rate during echocardiogram and Paced rhythm. The model obtained good predictability(c=0.82) and fit (Hosmer-Lemeshow p=0.51). The point estimates and odds ratios are shown in the figure below. Conclusions: In patients with LVEF &lt; 50%, atrial fibrillation, severe mitral regurgitation, left ventricular hypertrophy, high basal heart rate during echocardiogram and paced rhythm are associated with a &gt;10% LVEF disparity between the two imaging techniques.

Multicenter Phase III Randomized Trial Comparing Docetaxel and Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens

Docetaxel-trastuzumab (TH) is effective therapy for HER2-amplified metastatic breast cancer (MBC). Preclinical findings of synergy between docetaxel, carboplatin, and trastuzumab (TCH) prompted a phase III randomized trial comparing TCH with TH in patients with HER2-amplified MBC. Two hundred sixty-three patients were randomly assigned to receive eight 3-week cycles of TH (trastuzumab plus docetaxel 100 mg/m(2)) or TCH (trastuzumab plus carboplatin at area under the serum concentration-time curve 6 and docetaxel 75 mg/m(2)). Trastuzumab was given at 4 mg/kg loading dose followed by a 2 mg/kg dose once per week during chemotherapy, and then 6 mg/kg once every 3 weeks until progression. Patient characteristics were balanced between groups. There was no significant difference between TH and TCH in terms of the primary end point, time to progression (medians of 11.1 and 10.4 months, respectively; hazard ratio, 0.914; 95% CI, 0.694 to 1.203; P = .57), response rate (72% for both groups), or overall survival (medians of 37.1 and 37.4 months, respectively; P = .99). Rates of grades 3 or 4 adverse effects for TH and TCH, respectively, were neutropenic-related complications, 29% and 23%; thrombocytopenia, 2% and 15%; anemia, 5% and 11%; sensory neuropathy, 3% and 0.8%; fatigue, 5% and 12%; peripheral edema, 3.8% and 1.5%; and diarrhea, 2% and 10%. Two patients given TCH died of sepsis, and one patient given TH experienced sudden cardiac death. Absolute left ventricular ejection fraction decline > 15% was seen in 5.5% of patients on the TH arm and 6.7% of patients on the TCH arm. Adding carboplatin did not enhance TH antitumor activity.TH (docetaxel, 100 mg/m(2)) and TCH (docetaxel, 75 mg/m(2)) demonstrated efficacy with acceptable toxicity in women with HER2-amplified MBC.

Characterization of super-response to cardiac resynchronization therapy

In patients with chronic systolic heart failure who undergo cardiac resynchronization therapy (CRT), improvements in left ventricular ejection fraction (LVEF) and reductions in left ventricular volume are generally modest. A minority of patients experience a dramatic response to CRT (super-responders), but the attributes associated with these patients have not been fully characterized. The purpose of this study was to identify baseline clinical attributes of super-responders and to assess the survival benefit associated with this response. We reviewed clinical, echocardiographic, and ECG data from a cohort of 233 patients undergoing new implantation of a CRT device between December 2001 and November 2006. All patients had a baseline LVEF < or =40% and New York Heart Association class II to IV symptoms on standard medical therapy. Patients whose absolute LVEF improved by > or =20% were termed super-responders. A multivariate model was constructed to determine factors predictive of super-response, and an assessment of mortality was made. In this cohort of 233 patients, 32 (13.7%) met criteria for super-response. In univariate analysis, super-responders were more likely to be female and have a native left bundle branch block, lower preimplant brain natriuretic peptide and red cell distribution width levels, and smaller baseline left ventricular volumes with trends toward having more nonischemic cardiomyopathy and midventricular lead positions. In multivariate analysis, only left bundle branch block remained significantly associated with super-response. Super-responders had a considerably lower incidence of mortality compared to non-super-responders (9.4% vs 43.2%, P = .006) at mean follow-up of 5.5 +/- 1.2 years. Baseline left bundle branch block is strongly associated with super-response to CRT. Super-responders derive better long-term outcomes with CRT than do non-super-responders.