Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager). METHODS: Safety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab. RESULTS: Tisagenlecleucel is associated with cardiac failure (IC025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28-5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66]. CONCLUSIONS: Tisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Chimeric antigen receptor (CAR) T-cell therapy and blinatumomab are two new types of cancer therapies used to treat blood cancers that fail to respond to conventional chemotherapy. Our goal is to study if there are major differences in how these treatments affect the heart. We analyzed a large, global database of patients who had these treatments. We find that in a blood cancer called diffuse large B-cell lymphoma, two CAR-T cell therapies are linked to heart failure and low blood pressure. In another type of cancer, acute lymphocytic leukemia, CAR-T cell therapy is associated with heart failure and cardiac arrest. The study suggests that given the frequency and severity of these side effects, clinical care should involve an interdisciplinary team experienced in managing these serious side effects.

Left atrial appendage volume as a prognostic Indicator of long-term mortality in Cancer survivors treated with thoracic radiation.

BACKGROUND: Cancer survivors with prior chest radiation therapy (CXRT) frequently present with atrial fibrillation, heart failure, and have higher overall long-term mortality. There are no data examining the utility of left atrial (LA) and LA appendage (LAA) volume-indices to predict clinical outcomes in these patients. OBJECTIVES: We examined the prognostic value of cardiac phase-dependent 3-D volume-rendered cardiac computerized tomography (CT)-derived LA and LAA volume-indices to predict mortality and major adverse cardiac events (MACE) in cancer survivors treated with thoracic irradiation. METHOD: We screened 625 consecutive patients with severe aortic stenosis who had undergone transcatheter aortic valve replacement from 2012 to 2017. Based on the gated cardiac CT image quality, we included 184 patients (CXRT:43, non-CXRT:141) for further analysis. We utilized multiplane-3D-reconstructed cardiac CT images to calculate LA and LAA volume-indices, and examined the prognostic role of CCT-derived LA and LAA volume-indices in predicting the all-cause mortality, cardiovascular (CV) mortality, and MACE. We used multivariate cox-proportional hazard analysis to identify the clinical predictors of survival. RESULTS: Overall, the CXRT group had significantly elevated LAA volume-index compared to non-CXRT group (CXRT:11.2 ± 8.9 ml/m2; non-CXRT:8.6 ± 4.5 ml/m2, p = 0.03). On multivariate cox-proportional hazard analysis, the elevated LAA volume and LAA volume-index were the strongest predictors of reduced survival in CXRT group compared to non-CXRT group (LAA volume: RR = 1.03,95% CI 1.0-1.01, p = 0.01; and LAA volume index: RR = 1.05, 95% CI 1.0-1.01, p = 0.03). LAA volume > 21.9 ml was associated with increased mortality. In contrast, LA volume was not a significant predictor of mortality. CONCLUSION: We describe a novel technique to assess LA and LAA volume using 3-D volume-rendered cardiac CT. This study shows enlarged LAA volume rather than LA volume carries a poor prognosis in cancer-survivors treated with prior CXRT. Compared to conventionally reported markers, LAA volume of > 21.9 ml was incremental to that of other risk factors.

Echocardiographic and Cardiac MRI Comparison of Longitudinal Strain and Strain Rate in Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background: Immune checkpoint inhibitor (ICI)-induced cardiac side effects in cancer patients are increasingly being recognized and can be fatal. There is no standardized cardiac imaging test to examine the effects of ICIs in myocardial morphology and function. Objective: To study the utility of echocardiography and cardiac MRI in examining regional and global changes arising from ICI-induced myocarditis and cardiomyopathy in high-risk subjects suspected to have developed ICI cardiomyopathy. Methods: We studied eight consecutive patients referred for cardiac MRI (CMR) from a comprehensive cancer center for suspected ICI-induced myocarditis and compared the data with sixteen age-matched controls. Using newly developed strain analysis algorithms, we measured myocardial strain and strain rates using echocardiography and CMR. Then, we compared the mean longitudinal strain and strain rates derived from echocardiography and CMR in the same ICI-treated cohort of patients (n = 8). They underwent both of these imaging studies with images taken 24−48 h apart and followed up prospectively within the same hospital course. Results: All our cases had preserved ejection fraction (EF) > 50%. Echocardiogram showed reduced mean systolic longitudinal strain (LS, %) (ICI: −12.381 ± 4.161; control: −19.761 ± 1.925; p < 0.001), peak systolic strain rate (SRS, s−1) (ICI: −0.597 ± 0.218; control: −0.947 ± 0.135; p = 0.002) and early diastolic strain rate (SRE, s−1) (ICI: 0.562 ± 0.295; control: 1.073 ± 0.228; p = 0.002) in ICI-treated cases. Direct comparison between the echocardiogram vs. CMR obtained within the same hospital course demonstrated strong a correlation of LS scores (r = 0.83, p = 0.012) and SRS scores (r = 0.71, p = 0.048). The Bland−Altman plots showed that 95% of the data points fitted within the ±1.96 SD of the mean difference, suggesting an agreement among these two imaging modalities. Conclusion: In this feasibility cohort study, both echocardiography- and CMR-based strain indices illustrate changes in myocardial contractility and relaxation suggestive of ICI-induced cardiomyopathy. Our data, after validation in a larger cohort, can form the basis of myocardial imaging in cancer patients treated with ICIs.

Modified GAN Augmentation Algorithms for the MRI-Classification of Myocardial Scar Tissue in Ischemic Cardiomyopathy.

Contrast-enhanced cardiac magnetic resonance imaging (MRI) is routinely used to determine myocardial scar burden and make therapeutic decisions for coronary revascularization. Currently, there are no optimized deep-learning algorithms for the automated classification of scarred vs. normal myocardium. We report a modified Generative Adversarial Network (GAN) augmentation method to improve the binary classification of myocardial scar using both pre-clinical and clinical approaches. For the initial training of the MobileNetV2 platform, we used the images generated from a high-field (9.4T) cardiac MRI of a mouse model of acute myocardial infarction (MI). Once the system showed 100% accuracy for the classification of acute MI in mice, we tested the translational significance of this approach in 91 patients with an ischemic myocardial scar, and 31 control subjects without evidence of myocardial scarring. To obtain a comparable augmentation dataset, we rotated scar images 8-times and control images 72-times, generating a total of 6,684 scar images and 7,451 control images. In humans, the use of Progressive Growing GAN (PGGAN)-based augmentation showed 93% classification accuracy, which is far superior to conventional automated modules. The use of other attention modules in our CNN further improved the classification accuracy by up to 5%. These data are of high translational significance and warrant larger multicenter studies in the future to validate the clinical implications.

Biventricular Strain Imaging with Cardiac MRI in Genotyped and Histology Validated Amyloid Cardiomyopathy.

Cardiac amyloidosis (CA) is a common and potentially fatal infiltrative cardiomyopathy. Contrast-enhanced cardiac MRI (CMR) is used as a diagnostic tool. However, utility of CMR for the comprehensive analysis of biventricular strains and strain rates is not reported as extensively as echocardiography. In addition, RV strain analysis using CMR has not been described previously. OBJECTIVES: We sought to study the global and regional indices of biventricular strain and strain rates in endomyocardial biopsy (EMB)-proven, genotyped cases of CA. METHODS: A database of 80 EMBs was curated from 2012 to 2019 based on histology. A total of 19 EMBs positive for CA were subjected to further tissue-characterization with histology, and compared with four normal biopsy specimens. Samples were genotyped for ATTR- or AL-subtypes. Five patients, with both echocardiography and contrast-enhanced CMR performed 72-h apart, were subjected to comprehensive analysis of biventricular strain and strain-rates. RESULTS: Histology confirmed that the selected samples were indeed positive for cardiac amyloid. Echocardiography showed reduced global and regional left-ventricular (LV) longitudinal strain indices. CMR with tissue-characterization of LV showed global reductions in circumferential, radial and longitudinal strains and strain-rates, following a general trend with the echocardiographic findings. The basal right-ventricular (RV) segments had reduced circumferential strains with no changes in longitudinal strain. CONCLUSIONS: In addition to providing a clinical diagnosis of CA based on contrast clearance-dynamics, CMR can be a potent tool for accurate functional assessment of global and regional changes in strain and strain-rates involving both LV and RV. Further studies are warranted to validate and curate the strain imaging capacity of CMR in CA.

Small Endogeneous Peptide Mitigates Myocardial Remodeling in a Mouse Model of Cardioselective Galectin-3 Overexpression.

BACKGROUND: Myocardial Gal3 (galectin-3) expression is associated with cardiac inflammation and fibrosis. Increased Gal3 portends susceptibility to heart failure and death. There are no data reporting the causative role of Gal3 to mediate cardiac fibro-inflammatory response and heart failure. METHODS: We developed a cardioselective Gal3 gain-of-function mouse (Gal3+/+) using α-myosin heavy chain promotor. We confirmed Gal3-transgene expression with real-time polymerase chain reaction and quantified cardiac/circulating Gal3 with Western blot and immunoassays. We used echocardiogram and cardiac magnetic resonance imaging to measure cardiac volumes, function, and myocardial velocities. Ex vivo, we studied myocardial inflammation/fibrosis and downstream TGF (transforming growth factor) ß1-mRNA expression. We examined the effects of acute myocardial ischemia in presence of excess Gal3 by inducing acute myocardial infarction in mice. Two subsets of mice including mice treated with N-acetyl-seryl-aspartyl-lysyl-proline (a Gal3-inhibitor) and mice with genetic Gal3 loss-of-function (Gal3-/-) were studied for comparative analysis of Gal3 function. RESULTS: Gal3+/+ mice had increased cardiac/circulating Gal3. Gal3+/+ mice showed excess pericardial fat pad, dilated ventricles and cardiac dysfunction, which was partly normalized by N-acetyl-seryl-aspartyl-lysyl-proline. Cardiac magnetic resonance imaging showed reduced myocardial contractile velocities in Gal3+/+. The majority of Gal3+/+ mice did not survive acute myocardial infarction, and the survivors had profound cardiac dysfunction. Myocardial histology of Gal3+/+ mice showed macrophage/mast-cell infiltration, fibrosis and higher TGFß1-mRNA expression, which were mitigated by both Gal3 gene deletion and N-acetyl-seryl-aspartyl-lysyl-proline administration. CONCLUSIONS: Our study shows that cardioselective Gal3 overexpression leads to multiple cardiac phenotypic defects including ventricular dilation and cardiac dysfunction. Pharmacological Gal3 inhibition conferred protective effects with reduction of inflammation and fibrosis. Our study highlights the importance of translational studies to counteract Gal3 function and prevent cardiac dysfunction.

Elevated myocardial wall stress after percutaneous coronary intervention in acute ST elevation myocardial infraction is associated with increased mortality.

BACKGROUND: Despite early attempts to salvage myocardium-at-risk with percutaneous coronary intervention (PCI), changes in myocardial wall stress (MWS) leads to ventricular dilatation and dysfunction after acute ST-elevation myocardial infraction (STEMI). Whether this is transient or leads to long-term adverse outcomes major adverse cardiovascular events (MACE) is not known. We studied the association between MWS and MACE in patients after a successful PCI for acute STEMI. OBJECTIVES: To study the MWS in percutaneously revascularized STEMI patients in relation to all-cause mortality and MACE. METHODS: We prospectively enrolled 142 patients who presented to our tertiary care hospital with acute STEMI requiring emergent PCI. In addition to the standard clinical biomarkers, both end-systolic and end-diastolic MWS was calculated using our recently validated Echocardiographic indices. Patients were then prospectively followed up to an average of 16.5 (± 12.0) months to assess all-cause mortality and MACE. RESULTS: During the follow-up period, 9% of the patients died and 17% developed MACE. Patients who died had significantly elevated end-systolic WS compared to those who survived (mean ESWS, 80.01 ± 36.86 vs 59.28 ± 27.68). There was no significant difference in end-diastolic WS, left ventricular systolic function and peak troponin levels among survivors versus non-survivors. Elevated ESWS (>62.5 Kpa) and age remained the significant predictors of mortality on multivariate logistic analysis (OR 7.75, CI 1.33-73.86, P = .03; OR 1.16, CI 1.06-1.31, P = .002). CONCLUSION: Elevated ESWS measured by echocardiogram is associated with increased odds of long-term mortality in STEMI patients who have undergone emergent PCI. This finding can help clinicians to risk stratify high-risk patients.

CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin.

BACKGROUND: The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts. OBJECTIVES: This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment. METHODS: We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson's biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA). RESULTS: Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups. CONCLUSIONS: CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

Tagged cine magnetic resonance imaging to quantify regional mechanical changes after acute myocardial infarction.

PURPOSE: The conventional volumetric approaches of measuring cardiac function are load-dependent, and are not able to discriminate functional changes in the infarct, transition and remote myocardium. We examined phase-dependent regional mechanical changes in the infarct, transition and remote regions after acute myocardial infarction (MI) in a preclinical mouse model using cardiovascular magnetic resonance imaging (CMR). METHODS: We induced acute MI in six mice with left anterior descending coronary artery ligation. We then examined cardiac (infarct, transition and remote-zone) morphology and function utilizing 9.4 T high field CMR before and 2 weeks after the induction of acute MI. Myocardial scar tissue was evaluated by using CMR with late gadolinium enhancement (LGE). After determining global function through volumetric analysis, regional wall motion was evaluated by measuring wall thickening and radial velocities. Strain rate imaging was performed to assess circumferential contraction and relaxation at the myocardium, endocardium, and epicardium. RESULTS: There was abnormal LGE in the anterior walls after acute MI suggesting a successful MI procedure. The transition zone consisted of a mixed signal intensity, while the remote zone contained viable myocardium. As expected, the infarct zone had demonstrated severely decreased myocardial velocities and strain rates, suggesting reduced contraction and relaxation function. Compared to pre-infarct baseline, systolic and diastolic velocities (vS and vD) were significantly reduced at the transition zone (vS: -1.86 ±â€¯0.16 cm/s vs -0.68 ±â€¯0.13 cm/s, P < 0.001; vD: 1.86 ±â€¯0.17 cm/s vs 0.53 ±â€¯0.06 cm/s, P < 0.001) and remote zone (vS: -1.86 ±â€¯0.16 cm/s vs -0.65 ±â€¯0.12 cm/s, P < 0.001; vD: 1.86 ±â€¯0.16 cm/s vs 0.51 ±â€¯0.04 cm/s, P < 0.001). Myocardial peak systolic and diastolic strain rates (SRS and SRD) were significantly lower in the transition zone (SRS: -4.2 ±â€¯0.3 s-1 vs -1.3 ±â€¯0.2 s-1, P < 0.001; SRD: 3.9 ±â€¯0.3 s-1 vs 1.3 ±â€¯0.2 s-1, P < 0.001) and remote zone (SRS: -3.8 ±â€¯0.3 s-1 vs -1.4 ±â€¯0.3 s-1, P < 0.001; SRD: 3.5 ±â€¯0.2 s-1 vs 1.5 ±â€¯0.4 s-1, P = 0.006). Endocardial and epicardial SRS and SRD were similarly reduced in the transition and remote zones compared to baseline. CONCLUSIONS: This study, for the first time, utilized state-of-the art high-field CMR algorithms in a preclinical mouse model for a comprehensive and controlled evaluation of the regional mechanical changes in the transition and remote zones, after acute MI. Our data demonstrate that CMR can quantitatively monitor dynamic post-MI remodeling in the transition and remote zones, thereby serving as a gold standard tool for therapeutic surveillance.