Artificial intelligence applications in cardio-oncology: Leveraging high dimensional cardiovascular data

Growing evidence suggests a wide spectrum of potential cardiovascular complications following cancer therapies, leading to an urgent need for better risk-stratifying and disease screening in patients undergoing oncological treatment. As many cancer patients undergo frequent surveillance through imaging as well as other diagnostic testing, there is a wealth of information that can be utilized to assess one's risk for cardiovascular complications of cancer therapies. Over the past decade, there have been remarkable advances in applying artificial intelligence (AI) to analyze cardiovascular data obtained from electrocardiograms, echocardiograms, computed tomography, and cardiac magnetic resonance imaging to detect early signs or future risk of cardiovascular diseases. Studies have shown AI-guided cardiovascular image analysis can accurately, reliably and inexpensively identify and quantify cardiovascular risk, leading to better detection of at-risk or disease features, which may open preventive and therapeutic opportunities in cardio-oncology. In this perspective, we discuss the potential for the use of AI in analyzing cardiovascular data to identify cancer patients at risk for cardiovascular complications early in treatment which would allow for rapid intervention to prevent adverse cardiovascular outcomes

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies

The effect of age on outcomes of coronary artery bypass surgery compared with balloon angioplasty or bare-metal stent implantation among patients with multivessel coronary disease. A collaborative analysis of individual patient data from 10 randomized trials.

OBJECTIVES: This study sought to assess whether patient age modifies the comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI). BACKGROUND: Increasingly, CABG and PCI are performed in older patients to treat multivessel disease, but their comparative effectiveness is uncertain. METHODS: Individual data from 7,812 patients randomized in 1 of 10 clinical trials of CABG or PCI were pooled. Age was analyzed as a continuous variable in the primary analysis and was divided into tertiles for descriptive purposes (≤56.2 years, 56.3 to 65.1 years, ≥65.2 years). The outcomes assessed were death, myocardial infarction and repeat revascularization over complete follow-up, and angina at 1 year. RESULTS: Older patients were more likely to have hypertension, diabetes, and 3-vessel disease compared with younger patients (p < 0.001 for trend). Over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age (interaction p < 0.01), with adjusted CABG-to-PCI hazard ratios and 95% confidence intervals (CI) of 1.23 (95% CI: 0.95 to 1.59) in the youngest tertile; 0.89 (95% CI: 0.73 to 1.10) in the middle tertile; and 0.79 (95% CI: 0.67 to 0.94) in the oldest tertile. The CABG-to-PCI hazard ratio of less than 1 for patients 59 years of age and older. A similar interaction of age with treatment was present for the composite outcome of death or myocardial infarction. In contrast, patient age did not alter the comparative effectiveness of CABG and PCI on the outcomes of repeat revascularization or angina. CONCLUSIONS: Patient age modifies the comparative effectiveness of CABG and PCI on hard cardiac events, with CABG favored at older ages and PCI favored at younger ages

Spatiotemporal controlled delivery of nanoparticles to injured vasculature

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.Complex multimodal nanoparticles (NP) that target and deliver therapeutic agents to a site of disease are a promising direction in modem medicine. As a starting point for innovation, we designed a hybrid NP system combining the benefits of liposomes and polymeric NPs. These particles have a polymeric surface which displays targeting ligands while avoiding macrophage uptake. A liposome-like layer provides in vivo biocompatibility and a hydrophobic core allows for high-capacity small molecule drug delivery. Targeting ligands that bind injured vasculature were discovered and optimized by screening an M13 bacteriophage library (109 independent clones) against collagen IV, the major component of the basement membrane. Relative binding affinities using ELISA identified the lead targeting candidate, which bound with 900-fold greater relative affinity to collagen IV when compared with the unselected library. The selected peptide sequence was synthesized and tested for its ability to actively target the hybrid NP system. Paclitaxel, an anti-proliferative drug, was chosen as the delivered pharmaceutical. Drug release was modified through a slow-eluting paclitaxel conjugate using controlled ester hydrolysis (drug release -10-12 days in vitro). To test these targeted NPs, injured vasculature was approximated using an aortic smooth muscle culture embedded on a collagen IV matrix. In this setting, the hybrid NPs showed clear evidence of increased potency using the selected ligands. In experimental animal models of surgery-induced vascular injury, targeted NPs showed a four-fold improved retention at angioplastied aortas over intact aortas ex vivo. Targeted NPs were tested as intraarterially delivered therapy to angioplastied carotid arteries in vivo and showed a two-fold better localization at injury sites versus scrambled-peptide and non-targeted NPs. Targeted NPs were also tested using a systemic, intravenous infusion administered postprocedure on Day I and 6 and resulted in lower neointima-to-media (N/M) scores at two weeks compared to FDA-approved Taxol@ and injury-only groups (N/Msham= -249 + 0.046, vs. N/MTaxol=0.837 ± 0.087, N/MNP=0.749 ± 0.136 and N/MPep-NP=0.662 ± 0.169, all P < 0.01 vs. injury-only, mean ± SEM, n=5). These findings indicate that complex, multilayered NPs can functionally target and treat injured vasculature, a clinical problem of primary importance.by Juliana Maria Chan.Ph.D

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid–polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.National Cancer Institute (U.S.) (grant CA151884)National Institute for Biomedical Imaging and Bioengineering (U.S.) (grant EB003647)National Heart, Lung, and Blood Institute. Program of Excellence in Nanotechnology (contract HHSN268201000045C)David H. Koch Cancer Research Fund (Prostate Cancer Foundation Award in Nanotherapeutics