Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association.

Advances in cancer therapeutics have revolutionized survival outcomes in patients with cancer. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Recent studies have uncovered excess risks of these cardiotoxic events, especially in traditionally underrepresented populations. Despite advances in strategies to limit the risks of cardiovascular events among cancer survivors, relatively limited guidance is available to address the rapidly growing problem of disparate cardiotoxic risks among women and underrepresented patient populations. Previously decentralized and sporadic evaluations have led to a lack of consensus on the definitions, investigation, and potential optimal strategies to address disparate cardiotoxicity in contemporary cancer care (eg, with immunotherapy, biologic, or cytotoxic therapies) settings. This scientific statement aims to define the current state of evidence for disparate cardiotoxicity while proposing uniform and novel methodological approaches to inform the identification and mitigation of disparate cardio-oncology outcomes in future clinical trials, registries, and daily clinical care settings. We also propose an evidence-based integrated approach to identify and mitigate disparities in the routine clinical setting. This consensus scientific statement summarizes and clarifies available evidence while providing guidance on addressing inequities in the era of emerging anticancer therapies.

MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.

mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.

Training and Career Development in Cardio-Oncology Translational and Implementation Science.

Cardiovascular disease is a leading cause of death in cancer survivors, after recurrence of the primary tumor or occurrence of a secondary malignancy. Consequently, the interdisciplinary field of cardio-oncology has grown rapidly in recent years to address the cardiovascular care needs of this unique population through clinical care and research initiatives. Here, the authors discuss the ideal infrastructure for training and career development in cardio-oncology translational and implementation science and emphasize the importance of the multidisciplinary cardiovascular team for both research and patient care. Cardio-oncology training opportunities in general cardiology, hematology/oncology, and specialized cardio-oncology clinical and research fellowships are also considered.

Lifestyle and Cardiovascular Risk Factors Associated With Heart Failure Subtypes in Postmenopausal Breast Cancer Survivors.

Background: Breast cancer (BC) survivors experience an increased burden of long-term comorbidities, including heart failure (HF). However, there is limited understanding of the risk for the development of HF subtypes, such as HF with preserved ejection fraction (HFpEF), in BC survivors. Objectives: This study sought to estimate the incidence of HFpEF and HF with reduced ejection fraction (HFrEF) in postmenopausal BC survivors and to identify lifestyle and cardiovascular risk factors associated with HF subtypes. Methods: Within the Women's Health Initiative, participants with an adjudicated diagnosis of invasive BC were followed to determine the incidence of hospitalized HF, for which adjudication procedures determined left ventricular ejection fraction. We calculated cumulative incidences of HF, HFpEF, and HFrEF. We estimated HRs for risk factors in relation to HF, HFpEF, and HFrEF using Cox proportional hazards survival models. Results: In 2,272 BC survivors (28.6% Black and 64.9% White), the cumulative incidences of hospitalized HFpEF and HFrEF were 6.68% and 3.96%, respectively, over a median of 7.2 years (IQR: 3.6-12.3 years). For HFpEF, prior myocardial infarction (HR: 2.83; 95% CI: 1.28-6.28), greater waist circumference (HR: 1.99; 95% CI: 1.14-3.49), and smoking history (HR: 1.65; 95% CI: 1.01-2.67) were the strongest risk factors in multivariable models. With the exception of waist circumference, similar patterns were observed for HFrEF, although none were significant. In relation to those without HF, the risk of overall mortality in BC survivors with hospitalized HFpEF was 5.65 (95% CI: 4.11-7.76), and in those with hospitalized HFrEF, it was 3.77 (95% CI: 2.51-5.66). Conclusions: In this population of older, racially diverse BC survivors, the incidence of HFpEF, as defined by HF hospitalizations, was higher than HFrEF. HF was also associated with an increased mortality risk. Risk factors for HF were largely similar to the general population with the exception of prior myocardial infarction for HFpEF. Notably, both waist circumference and smoking represent potentially modifiable factors.

Cardiotoxicity risk factors with immune checkpoint inhibitors.

BACKGROUND: Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors. METHODS: Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P-value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P-value. Adjusted P-values were calculated using multivariable regression adjusting for other covariates. RESULTS: Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively. CONCLUSIONS: Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.

The Role of Cardiac MRI in Animal Models of Cardiotoxicity: Hopes and Challenges.

Animal models of chemotherapy-induced cardiotoxicity have been instrumental in understanding the underlying mechanisms of the disease. The use of cardiac magnetic resonance (CMR) imaging and nuclear magnetic resonance (NMR) imaging in preclinical models allows the non-invasive study of subclinical pathophysiological processes that influence cardiac function and establish imaging parameters that can be adopted into clinical practice to predict cardiovascular outcomes. Given the rising population of cancer survivors and the current lack of effective therapies for the management of cardiotoxicity, research combining clinically relevant animal models and non-invasive cardiac imaging remains essential to improve methods to monitor, predict, and treat cardiovascular adverse events. This comprehensive review summarizes the lessons learned from animal models of cardiotoxicity employing CMR and tissue characterization techniques and discusses the ongoing challenges and hopes for the future.

Incremental risk of cardiovascular disease and/or chronic kidney disease for future ASCVD and mortality in patients with type 2 diabetes mellitus: ACCORD trial.

BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) are complications of type 2 diabetes mellitus (DM). Current cholesterol guidelines recommend the same prevention strategy for patients with DM alone as patients with DM + CKD. However, the incremental risk of these common complications for incident cardiovascular disease and mortality has not been well studied. METHODS: We compared the incremental risk of having DM + CKD, DM + CVD and DM + CVD + CKD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants for incident CVD as the primary outcome and all-cause mortality. RESULTS: After a mean (SD) follow up of 4.7(1.4) years, 1,046(10%) participants developed CVD. DM +vCKD, DM + CVD, and DM + CKD + CVD had a significantly increased risk of the primary outcome compared to DM alone [adjusted hazard ratio(95%CI): 1.41 (1.06-1.89), p = 0.02; 2.20 (1.92-2.53), p < 0.001); 2.35 (1.81-3.04), p < 0.001), respectively]. All-cause mortality had a graded increased risk compared to the reference group [adjusted hazard ratio(95%CI): 1.39 (1.01-1.90), p = 0.04; 1.29 (1.51-2.12), p < 0.0001; 2.36 (1.75-3.13), p < 0.0001), respectively]. CONCLUSION: Our post hoc analysis shows an incremental graded risk for CVD outcomes and all-cause mortality with the development of CKD and/or CVD in individuals with DM.

Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain.

Regulator of G protein signaling 14 (RGS14) is a multifunctional signaling protein primarily expressed in mouse pyramidal neurons of hippocampal area CA2 where it regulates synaptic plasticity important for learning and memory. However, very little is known about RGS14 protein expression in the primate brain. Here, we validate the specificity of a new polyclonal RGS14 antibody that recognizes not only full-length RGS14 protein in primate, but also lower molecular weight forms of RGS14 protein matching previously predicted human splice variants. These putative RGS14 variants along with full-length RGS14 are expressed in the primate striatum. By contrast, only full-length RGS14 is expressed in hippocampus, and shorter variants are completely absent in rodent brain. We report that RGS14 protein immunoreactivity is found both pre- and postsynaptically in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra, and amygdala in adult rhesus monkeys. A similar cellular expression pattern of RGS14 in the monkey striatum and hippocampus was further confirmed in humans. Our electron microscopy data show for the first time that RGS14 immunostaining localizes within nuclei of striatal neurons in monkeys. Taken together, these findings suggest new pre- and postsynaptic regulatory functions of RGS14 and RGS14 variants, specific to the primate brain, and provide evidence for unconventional roles of RGS14 in the nuclei of striatal neurons potentially important for human neurophysiology and disease.

Endogenous RGS14 is a cytoplasmic-nuclear shuttling protein that localizes to juxtanuclear membranes and chromatin-rich regions of the nucleus.

Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and H-Ras/MAPkinase signaling pathways to regulate synaptic plasticity important for hippocampal learning and memory. However, to date, little is known about the subcellular distribution and roles of endogenous RGS14 in a neuronal cell line. Most of what is known about RGS14 cellular behavior is based on studies of tagged, recombinant RGS14 ectopically overexpressed in unnatural host cells. Here, we report for the first time a comprehensive assessment of the subcellular distribution and dynamic localization of endogenous RGS14 in rat B35 neuroblastoma cells. Using confocal imaging and 3D-structured illumination microscopy, we find that endogenous RGS14 localizes to subcellular compartments not previously recognized in studies of recombinant RGS14. RGS14 localization was observed most notably at juxtanuclear membranes encircling the nucleus, at nuclear pore complexes (NPC) on both sides of the nuclear envelope and within intranuclear membrane channels, and within both chromatin-poor and chromatin-rich regions of the nucleus in a cell cycle-dependent manner. In addition, a subset of nuclear RGS14 localized adjacent to active RNA polymerase II. Endogenous RGS14 was absent from the plasma membrane in resting cells; however, the protein could be trafficked to the plasma membrane from juxtanuclear membranes in endosomes derived from ER/Golgi, following constitutive activation of endogenous RGS14 G protein binding partners using AlF4¯. Finally, our findings show that endogenous RGS14 behaves as a cytoplasmic-nuclear shuttling protein confirming what has been shown previously for recombinant RGS14. Taken together, the findings highlight possible cellular roles for RGS14 not previously recognized that are distinct from the regulation of conventional GPCR-G protein signaling, in particular undefined roles for RGS14 in the nucleus.

Integration of G protein α (Gα) signaling by the regulator of G protein signaling 14 (RGS14).

RGS14 contains distinct binding sites for both active (GTP-bound) and inactive (GDP-bound) forms of Gα subunits. The N-terminal regulator of G protein signaling (RGS) domain binds active Gαi/o-GTP, whereas the C-terminal G protein regulatory (GPR) motif binds inactive Gαi1/3-GDP. The molecular basis for how RGS14 binds different activation states of Gα proteins to integrate G protein signaling is unknown. Here we explored the intramolecular communication between the GPR motif and the RGS domain upon G protein binding and examined whether RGS14 can functionally interact with two distinct forms of Gα subunits simultaneously. Using complementary cellular and biochemical approaches, we demonstrate that RGS14 forms a stable complex with inactive Gαi1-GDP at the plasma membrane and that free cytosolic RGS14 is recruited to the plasma membrane by activated Gαo-AlF4(-). Bioluminescence resonance energy transfer studies showed that RGS14 adopts different conformations in live cells when bound to Gα in different activation states. Hydrogen/deuterium exchange mass spectrometry revealed that RGS14 is a very dynamic protein that undergoes allosteric conformational changes when inactive Gαi1-GDP binds the GPR motif. Pure RGS14 forms a ternary complex with Gαo-AlF4(-) and an AlF4(-)-insensitive mutant (G42R) of Gαi1-GDP, as observed by size exclusion chromatography and differential hydrogen/deuterium exchange. Finally, a preformed RGS14·Gαi1-GDP complex exhibits full capacity to stimulate the GTPase activity of Gαo-GTP, demonstrating that RGS14 can functionally engage two distinct forms of Gα subunits simultaneously. Based on these findings, we propose a working model for how RGS14 integrates multiple G protein signals in host CA2 hippocampal neurons to modulate synaptic plasticity.

Long-distance signals are required for morphogenesis of the regenerating Xenopus tadpole tail, as shown by femtosecond-laser ablation.

BACKGROUND: With the goal of learning to induce regeneration in human beings as a treatment for tissue loss, research is being conducted into the molecular and physiological details of the regeneration process. The tail of Xenopus laevis tadpoles has recently emerged as an important model for these studies; we explored the role of the spinal cord during tadpole tail regeneration. METHODS AND RESULTS: Using ultrafast lasers to ablate cells, and Geometric Morphometrics to quantitatively analyze regenerate morphology, we explored the influence of different cell populations. For at least twenty-four hours after amputation (hpa), laser-induced damage to the dorsal midline affected the morphology of the regenerated tail; damage induced 48 hpa or later did not. Targeting different positions along the anterior-posterior (AP) axis caused different shape changes in the regenerate. Interestingly, damaging two positions affected regenerate morphology in a qualitatively different way than did damaging either position alone. Quantitative comparison of regenerate shapes provided strong evidence against a gradient and for the existence of position-specific morphogenetic information along the entire AP axis. CONCLUSIONS: We infer that there is a conduit of morphology-influencing information that requires a continuous dorsal midline, particularly an undamaged spinal cord. Contrary to expectation, this information is not in a gradient and it is not localized to the regeneration bud. We present a model of morphogenetic information flow from tissue undamaged by amputation and conclude that studies of information coming from far outside the amputation plane and regeneration bud will be critical for understanding regeneration and for translating fundamental understanding into biomedical approaches.