Cancer therapy-induced cardiomyopathy: can human induced pluripotent stem cell modelling help prevent it?

Cardiotoxic effects from cancer therapy are a major cause of morbidity during cancer treatment. Unexpected toxicity can occur during treatment and/or after completion of therapy, into the time of cancer survivorship. While older drugs such as anthracyclines have well-known cardiotoxic effects, newer drugs such as tyrosine kinase inhibitors, proteasome inhibitors, and immunotherapies also can cause diverse cardiovascular and metabolic complications. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly being used as instruments for disease modelling, drug discovery, and mechanistic toxicity studies. Promising results with hiPSC-CM chemotherapy studies are raising hopes for improving cancer therapies through personalized medicine and safer drug development. Here, we review the cardiotoxicity profiles of common chemotherapeutic agents as well as efforts to model them in vitro using hiPSC-CMs.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Cats With Hypertrophic Cardiomyopathy.

Objective: To assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) for cardiac death in cats with hypertrophic cardiomyopathy. Study Design: Prospective observation study. Animals: Ninety-six client-owned cats. Methods: Complete blood count samples were collected from 38 healthy and 58 cats with hypertrophic cardiomyopathy (HCM), and the NLR ratios were analyzed. All cats had echocardiographic measurements performed on the same day as blood collection. Spearman rank correlation was used to assess the relationship between echocardiographic measurements and NLR. Long-term outcome data were obtained, and time to cardiac death and variables associated with cardiac death were analyzed using Kaplan-Meier survival curves and Cox proportional hazards models, respectively. Results: The NLR was significantly higher in cats with confirmed congestive heart failure. When evaluating HCM patients, cats in the third NLR tertile had a significantly higher risk of cardiac death with a hazard ratio of 10.26 (95% CI: 1.84-57.14; p = 0.0001) when compared with that of patients in the first tertile. NLR was significantly associated with echocardiographic measures of left atrial size, left auricular function, the presence of left atrial spontaneous echo contrast (SEC), and thrombus formation. Conclusions and Clinical Relevance: Increased NLR is a negative prognostic indicator in cats with HCM.

Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV). HYPOTHESIS/OBJECTIVES: To quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats. ANIMALS: Seventeen healthy and 12 preclinical HCM, age-matched, client-owned cats. METHODS: Prospective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography. RESULTS: There were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P < .0001), native T1 mapping (healthy = 1122 ms, HCM = 1209 ms, P = .004), and ECV (healthy = 26.0%, HCM = 32.6%, P < .0001). Variables of diastolic function including deceleration time of early diastolic transmitral flow (DTE), ratio between peak velocity of early diastolic transmitral flow and peak velocity of late diastolic transmitral flow (E : A), and peak velocity of late diastolic transmitral flow (A wave) were significantly correlated with ECV (DTE; r = 0.73 P = .007, E : A; r = -0.75 P = .004, A wave; r = 0.76 P = .004). CONCLUSIONS AND CLINICAL IMPORTANCE: Quantitative assessment of cardiac ECV is feasible and can provide additional information not available using echocardiography.

Quantitative assessment of left ventricular volume and function by transthoracic and transesophageal echocardiography, ultrasound velocity dilution, and gated magnetic resonance imaging in healthy foals.

OBJECTIVE: To compare measurements of left ventricular volume and function derived from 2-D transthoracic echocardiography (2DE), transesophageal echocardiography (TEE), and the ultrasound velocity dilution cardiac output method (UDCO) with those derived from cardiac MRI (cMRI) in healthy neonatal foals. ANIMALS: 6 healthy 1-week-old Standardbred foals. PROCEDURES: Foals were anesthetized and underwent 2DE, TEE, and cMRI; UDCO was performed simultaneously with 2DE. Images acquired by 2DE included the right parasternal 4-chamber (R4CH), left apical 4- and 2-chamber (biplane), and right parasternal short-axis M-mode (M-mode) views. The longitudinal 4-chamber view was obtained by TEE. Measurements assessed included left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), ejection fraction, stroke volume (LVSV), cardiac output (CO), and cardiac index (CI). Bland-Altman analyses were used to compare measurements derived from biplane, R4CH, and M-mode images and UDCO with cMRI-derived measurements. Repeatability of measurements calculated by 3 independent reviewers was assessed by the intraclass correlation coefficient. RESULTS: Compared with cMRI, all 2DE and TEE modalities underestimated LVEDV and LVESV and overestimated ejection fraction, CO, and CI. The LVSV was underestimated by the biplane, R4CH, and TEE modalities and overestimated by UDCO and M-mode methods. However, the R4CH-derived LVSV, CO, and CI were clinically comparable to cMRI-derived measures. Repeatability was good to excellent for measures derived from the biplane, R4CH, M-mode, UDCO, and cMRI methods and poor for TEE-derived measures. CONCLUSIONS AND CLINICAL RELEVANCE: All assessed modalities yielded clinically acceptable measurements of LVEDV, LVESV, and function, but those measurements should not be used interchangeably when monitoring patient progress.

Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics.

There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.