Navigating cancer therapy induced cardiotoxicity: From pathophysiology to treatment innovations.

Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an instrumental tool for treating cancer, it also causes severe adverse effects. The more commonly acknowledged adverse effects include hair loss, fatigue, and nausea, but a more severe and longer lasting side effect is cardiotoxicity. Cardiotoxicity, or heart damage, is a common complication of cancer treatments. It can range from mild to severe, and it can affect some patients temporarily or others permanently, even after they are cured of cancer. Dexrazoxane is the only FDA-approved drug for treating anthracycline induced cardiotoxicity, but it also has drawbacks and adverse effects. There is no other type of chemotherapy induced cardiotoxicity that has an approved treatment option. In this review, we discuss the pathophysiology of chemotherapeutic-induced cardiotoxicity, methods and guidelines of diagnosis, methods of treatment and mitigation, and current drug delivery approaches in therapeutic development.

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

AIMS: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. METHODS AND RESULTS: One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R = -0.30, P < 0.001) and fewer daily steps (R = -0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). CONCLUSIONS: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

In Situ-Crosslinked Zippersomes Enhance Cardiac Repair by Increasing Accumulation and Retention.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are a promising treatment for myocardial infarction, but their therapeutic efficacy is limited by inefficient accumulation at the target site. A non-invasive MSC EV therapy that enhances EV accumulation at the disease site and extends EV retention could significantly improve post-infarct cardiac regeneration. Here we show that EVs decorated with the next-generation of high-affinity heterodimerizing leucine zippers, termed high-affinity (HiA) Zippersomes, amplify targetable surface areas through in situ crosslinking and exhibited ∼7-fold enhanced accumulation within the infarcted myocardium in mice after three days and continued to be retained up to day 21, surpassing the performance of unmodified EVs. After myocardial infarction in mice, high-affinity Zippersomes increase the ejection fraction by 53% and 100% compared with unmodified EVs and PBS, respectively. This notable improvement in cardiac function played a crucial role in restoring healthy heart performance. High-affinity Zippersomes also robustly decrease infarct size by 52% and 60% compared with unmodified EVs and PBS, respectively, thus representing a promising platform for non-invasive vesicle delivery to the infarcted heart. Translational Impact Statement: Therapeutic delivery to the heart remains inefficient and poses a bottleneck in modern drug delivery. Surgical application and intramyocardial injection of therapeutics carry high risks for most heart attack patients. To address these limitations, we have developed a non-invasive strategy for efficient cardiac accumulation of therapeutics using in situ crosslinking. Our approach achieves high cardiac deposition of therapeutics without invasive intramyocardial injections. Patients admitted with myocardial infarction typically receive intravenous access, which would allow painless administration of Zippersomes alongside standard of care.

The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart.

AIMS: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic ß-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. METHODS: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and α1A-AR knockout mice and defined the effects of chronic ß-AR activation and myocardial infarction on selected mitochondrial functions. RESULTS: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The ß-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. CONCLUSIONS: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Cardiomyocyte Alpha-1A Adrenergic Receptors Mitigate Postinfarct Remodeling and Mortality by Constraining Necroptosis.

Clinical studies have shown that α1-adrenergic receptor antagonists (α-blockers) are associated with increased heart failure risk. The mechanism underlying that hazard and whether it arises from direct inhibition of cardiomyocyte α1-ARs or from systemic effects remain unclear. To address these issues, we created a mouse with cardiomyocyte-specific deletion of the α1A-AR subtype and found that it experienced 70% mortality within 7 days of myocardial infarction driven, in part, by excessive activation of necroptosis. We also found that patients taking α-blockers at our center were at increased risk of death after myocardial infarction, providing clinical correlation for our translational animal models.

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

Cardiovascular Outcomes of α-Blockers vs 5-α Reductase Inhibitors for Benign Prostatic Hyperplasia.

Importance: The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood. Objective: To compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes. Design, Setting, and Participants: This active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019. Exposures: Exposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes. Main Outcomes and Measures: Follow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome. Results: Among 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone. Conclusions and Relevance: These results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications' widespread use.

Carbon-infiltrated carbon nanotubes inhibit the development of Staphylococcus aureus biofilms.

Staphylococcus aureus forms biofilms that cause considerable morbidity and mortality in patients who receive implanted devices such as prosthetics or fixator pins. An ideal surface for such medical devices would inhibit biofilm growth. Recently, it was reported that surface modification of stainless steel materials with carbon-infiltrated carbon nanotubes (CICNT) inhibits the growth of S. aureus biofilms. The purpose of this study was to investigate this antimicrobial effect on titanium materials with CICNT coated surfaces in a variety of surface morphologies and across a broader spectrum of S. aureus isolates. Study samples of CICNT-coated titanium, and control samples of bare titanium, a common implant material, were exposed to S. aureus. Viable bacteria were removed from adhered biofilms and quantified as colony forming units. Scanning electron microscopy was used to qualitatively analyze biofilms both before and after removal of cells. The CICNT surface was found to have significantly fewer adherent bacteria than bare titanium control surfaces, both via colony forming unit and microscopic analyses. This effect was most pronounced on CICNT surfaces with an average nanotube diameter of 150 nm, showing a 2.5-fold reduction in adherent bacteria. Since S. aureus forms different biofilm structures by isolate and by growth conditions, we tested 7 total isolates and found a significant reduction in the biofilm load in six out of seven S. aureus isolates tested. To examine whether the anti-biofilm effect was due to the structure of the nanotubes, we generated an unstructured carbon surface. Significantly more bacteria adhered to a nonstructured carbon surface than to the 150 nm CICNT surface, suggesting that the topography of the nanotube structure itself has anti-biofilm properties. The CICNT surface possesses anti-biofilm properties that result in fewer adherent S. aureus bacteria. These anti-biofilm properties are consistent across multiple isolates of S. aureus and are affected by nanotube diameter. The experiments performed in this study suggest that this effect is due to the nanostructure of the CICNT surface.

Association of Depression Symptoms and Biomarkers of Risk on Clinical Outcomes in HFrEF.

BACKGROUND: Prior studies have demonstrated an association of depression with adverse clinical outcomes in patients with HFrEF, but the possible mechanisms responsible for the association are not unserstood. METHODS: 142 men and women with HFrEF were enrolled through HF clinics and followed over time. At baseline and 6-months, depression was assessed by the Beck Depression Inventory (BDI-II) and disease activity by B-type natriuretic peptide (BNP). Proportional Hazards Regression Models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. RESULTS: Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% higher hazard of death or cardiovascular hospitalization. Greater baseline BDI-II scores were associated with poorer HF self-care maintenance (R=-0.30, p<0.001) and fewer daily steps (R=-0.19, p=0.04), suggesting that depression may adversely affect important health behaviors. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II score and plasma BNP over 6 months were positively correlated (R=0.25, p=0.004). CONCLUSIONS: This study underscores the importance of elevated depression symptoms and their association with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Health behaviors may play a greater role than direct biobehavioral pathways in the adverse effects of depression on the HF disease trajectory and resultant clinical outcomes.

Clonal Hematopoiesis and the Heart: a Toxic Relationship.

PURPOSE OF REVIEW: Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes. RECENT FINDINGS: A combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1ß and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1ß or JAK2 signaling are potential avenues for preventing CH-caused cardiovascular morbidity and mortality.

ZipperCells Exhibit Enhanced Accumulation and Retention at the Site of Myocardial Infarction.

There has been extensive interest in cellular therapies for the treatment of myocardial infarction, but bottlenecks concerning cellular accumulation and retention remain. Here, a novel system of in situ crosslinking mesenchymal stem cells (MSCs) for the formation of a living depot at the infarct site is reported. Bone marrow-derived mesenchymal stem cells that are surface decorated with heterodimerizing leucine zippers, termed ZipperCells, are engineered. When delivered intravenously in sequential doses, it is demonstrated that ZipperCells can migrate to the infarct site, crosslink, and show ≈500% enhanced accumulation and ≈600% improvement in prolonged retention at 10 days after injection compared to unmodified MSCs. This study introduces an advanced approach to creating noninvasive therapeutics depots using cellular crosslinking and provides the framework for future scaffold-free delivery methods for cardiac repair.

Association of QTc Formula With the Clinical Management of Patients With Cancer.

Importance: Monitoring of the corrected QT interval (QTc) for patients with cancer receiving chemotherapy is not standardized. Selection of QTc formula may be associated with adverse event grading and chemotherapy delivery. Objective: To describe the association of QTc formula selection with adverse event grading and chemotherapy delivery. Design, Setting, and Participants: This retrospective observational cohort study used data from January 2010 to April 2020 and included adult patients seen at the University of North Carolina Cancer Hospital who had an electrocardiogram (ECG) performed. Exposures: Adjusted QTc using the Bazett, Fridericia, and Framingham formulae. Main Outcomes and Measures: The main outcome was QTc prolongation using the Common Terminology Criteria for Adverse Events (CTCAE). Consistency between formulae was evaluated. Subsequently, appropriateness of clinical management due to prolonged QTc was assessed for a subset of patients being treated with chemotherapy agents associated with a prolonged QT interval. We hypothesized that use of the Bazett formula would be associated with higher rates of QTc prolongation and inappropriate modifications to chemotherapy. Results: A total of 19 955 ECGs from 6881 adult patients (3055 [44.4%] women, 3826 [55.6%] men; median [IQR] age at first ECG, 60 [47-68] years) were analyzed. The percentage of ECGs with grade 3 QTc prolongation differed by formula (all patients: Framingham, 1.8%; Fridericia, 2.8%; and Bazett, 9.0%; patients receiving QT-prolonging chemotherapy [2340 ECGs]: Framingham, 2.7%; Fridericia, 4.5%; and Bazett, 12.5%). The Bazett formula resulted in a median QTc value 26.4 milliseconds higher than Fridericia and 27.8 milliseconds higher than Framingham. Of the 1786 ECGs classified as grade 3 by Bazett, 1446 (81.0%) were grade 2 or less by either Fridericia or Framingham. A total of 5 of 28 (17.9%) evaluated clinical changes associated with prolonged QTc were deemed inappropriate when using either Fridericia or Framingham formula. Conclusions and Relevance: Findings of this cohort study suggest that the Bazett formula resulted in higher QTc values associated with a 3-fold increase in grade 3 CTCAE toxic effects compared with other common formulae. Use of the Bazett formula likely was associated with inappropriate changes in clinical management. These data support the use of a standard QTc formula (such as Fridericia or Framingham) for QTc correction in oncology.

Design and performance of a dedicated coherent X-ray scanning diffraction instrument at beamline NanoMAX of MAX IV.

The diffraction endstation of the NanoMAX beamline is designed to provide high-flux coherent X-ray nano-beams for experiments requiring many degrees of freedom for sample and detector. The endstation is equipped with high-efficiency Kirkpatrick-Baez mirror focusing optics and a two-circle goniometer supporting a positioning and scanning device, designed to carry a compact sample environment. A robot is used as a detector arm. The endstation, in continued development, has been in user operation since summer 2017.

Curvature-induced defects on carbon-infiltrated carbon nanotube forests.

A morphological study of the micro-scale defects induced by growing a carbon-infiltrated carbon nanotube (CICNT) forest on concave substrates was conducted. Two CICNT heights (roughly 60 µm and 400 µm) and 4 curvatures (1-4 mm ID) were studied in order to test the geometric limitations. Defects were categorized and quantified by scanning electron microscopy (SEM) of the tops and cross-sections. These deformities were categorized as increased roughness on the top surface, a corrugated (also called wavy or rippled) forest, a curved forest, an inside crevice where the forest separates, and increased forest density on the top surface. Roughness increased nearly 3-fold with the taller forest heights no matter the substrate curvature. Due to the geometric limitations of CICNT height and substrate curvature, all other microscale defects were significantly more present on samples with a small radius of curvature and a tall CICNT forest (p < 0.05). These buckling and warping types of defects were attributed to the increase in circumferential compression as the forest grows as well as the van der Waals interactions between the nanotubes. Because the fabrication process for CICNT involves growing a CNT forest and then infiltrating it with pyrolytic carbon, this work may be applicable to other CNT forests on concave substrates within these forest heights and substrate curvatures.

Adrenergic Receptor Regulation of Mitochondrial Function in Cardiomyocytes.

ABSTRACT: Adrenergic receptors (ARs) are G protein-coupled receptors that are stimulated by catecholamines to induce a wide array of physiological effects across tissue types. Both α1- and ß-ARs are found on cardiomyocytes and regulate cardiac contractility and hypertrophy through diverse molecular pathways. Acute activation of cardiomyocyte ß-ARs increases heart rate and contractility as an adaptive stress response. However, chronic ß-AR stimulation contributes to the pathobiology of heart failure. By contrast, mounting evidence suggests that α1-ARs serve protective functions that may mitigate the deleterious effects of chronic ß-AR activation. Here, we will review recent studies demonstrating that α1- and ß-ARs differentially regulate mitochondrial biogenesis and dynamics, mitochondrial calcium handling, and oxidative phosphorylation in cardiomyocytes. We will identify potential mechanisms of these actions and focus on the implications of these findings for the modulation of contractile function in the uninjured and failing heart. Collectively, we hope to elucidate important physiological processes through which these well-studied and clinically relevant receptors stimulate and fuel cardiac contraction to contribute to myocardial health and disease.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. CONCLUSION: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.