Cardioprotective Potential of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Cancer Treated With Anthracyclines: An Observational Study.

Anthracyclines are pivotal in cancer treatment, yet their clinical utility is hindered by the risk of cardiotoxicity. Preclinical studies highlight the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in mitigating anthracycline-induced cardiotoxicity. Nonetheless, the translation of these findings to clinical practice remains uncertain. This study aims to evaluate the safety and potential of SGLT2i for preventing cardiotoxicity in patients with cancer, without preexisting heart failure (HF), receiving anthracyclines therapy. Using the TriNetX Global Research Network, patients with cancer, without previous HF diagnosis, receiving anthracycline therapy were identified and classified into 2 groups based on SGLT2i usage. A 1:1 propensity score matching was used to control for baseline characteristics between the 2 groups. Patients were followed for 2 years. The primary end point was new-onset HF, and the secondary end points were HF exacerbation, new-onset arrhythmia, myocardial infarction, all-cause mortality, and all-cause hospitalization. Safety outcomes included acute renal failure and creatinine levels. A total of 79,074 patients were identified, and 1,412 were included post-matching (706 in each group). They comprised 53% females, 62% White, with a mean age of 62.5 ± 11.4 years. Over the 2-year follow-up period, patients on SGLT2i had lower rates of new-onset HF (hazard ratio 0.147, 95% confidence interval 0.073 to 0.294) and arrhythmia (hazard ratio 0.397, 95% confidence interval 0.227 to 0.692) compared with those not on SGLT2i. The incidence of all-cause mortality, myocardial infarction, all-cause hospitalization, and safety outcomes were similar between both groups. In conclusion, among patients with cancer receiving anthracycline therapy without preexisting HF, SGLT2i use demonstrates both safety and effectiveness in reducing anthracycline-induced cardiotoxicity, with a decreased incidence of new-onset HF, HF exacerbation, and arrhythmias.

Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

Incidental Coronary Arterial Calcification for Cardiovascular Risk Assessment in Men With Prostate Cancer Undergoing PET/CT Imaging.

BACKGROUND: Cardiovascular (CV) disease is common among men with prostate cancer and the leading cause of death in this population. There is a need for CV risk assessment tools that can be easily implemented in the prostate cancer treatment setting. METHODS: Consecutive patients who underwent positron emission tomography/computed tomography (PET/CT) for recurrent prostate cancer at a single institution from 2012 to 2017 were identified retrospectively. Clinical data and coronary calcification on nongated CT imaging were obtained. The primary outcome was major adverse CV event (MACE; myocardial infarction, coronary or peripheral revascularization, stroke, heart failure hospitalization, or all-cause mortality) occurring within 5 years of PET/CT. RESULTS: Among 354 patients included in the study, there were 98 MACE events that occurred in 74 patients (21%). All-cause mortality was the most common MACE event (35%), followed by coronary revascularization/myocardial infarction (26%) and stroke (19%). Coronary calcification was predictive of MACE (HR = 1.9, 95% CI: 1.1-3.4, P = .03) using adjusted Kaplan-Meier analysis. As a comparator, the Framingham risk score was calculated for 198 patients (56%) with complete clinical and laboratory data available. In this subgroup, high baseline Framingham risk (corresponding to 10-year risk of CV disease > 20%) was not predictive of MACE. CONCLUSIONS: MACE was common (21%) in men with recurrent prostate cancer undergoing PET/CT over 5 years of follow-up. Incidental coronary calcification on PET/CT was associated with increased risk of MACE and may have utility as a CV risk predictor that is feasible to implement among all prostate cancer providers.

Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

SGLT2 Inhibitor Use and Risk of Clinical Events in Patients With Cancer Therapy-Related Cardiac Dysfunction.

BACKGROUND: Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF. OBJECTIVES: This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF. METHODS: The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period. RESULTS: The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors. CONCLUSIONS: SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma.

Background: Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis. Methods: Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis. Results: The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9-22.3, p = 5.42*10-7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10-6). Conclusions: We identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.

Clinicopathological classification of immune checkpoint inhibitor-associated myocarditis: possible refinement by measuring macrophage abundance.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with high morbidity and mortality. While endomyocardial biopsy (EMB) is considered a gold standard for diagnosis, the sensitivity of EMB is not well defined. Additionally, the pathological features that correlate with the clinical diagnosis of ICI-associated myocarditis remain incompletely understood. METHODS: We retrospectively identified and reviewed the clinicopathological features of 26 patients with suspected ICI-associated myocarditis based on institutional major and minor criteria. Seventeen of these patients underwent EMB, and the histopathological features were assessed by routine hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for CD68, a macrophage marker. RESULTS: Only 2/17 EMBs obtained from patients with suspected ICI myocarditis satisfied the Dallas criteria. Supplemental IHC staining and quantification of CD68+ macrophages identified an additional 7 patients with pathological features of myocardial inflammation (> 50 CD68+ cells/HPF). Macrophage abundance positively correlated with serum Troponin I (P = 0.010) and NT-proBNP (N-terminal pro-brain natriuretic peptide, P = 0.047) concentration. Inclusion of CD68 IHC could have potentially changed the certainty of the diagnosis of ICI-associated myocarditis to definite in 6/17 cases. CONCLUSIONS: While the Dallas criteria can identify a subset of ICI-associated myocarditis patients, quantification of macrophage abundance may expand the diagnostic role of EMB. Failure to meet the traditional Dallas Criteria should not exclude the diagnosis of myocarditis.

Real-World Efficacy of Tafamidis in Patients With Transthyretin Amyloidosis and Heart Failure.

Tafamidis was associated with a reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. We conducted a retrospective, observational cohort study using the TriNetX research network. Patients with wild-type TTR amyloidosis and heart failure (HF) were divided into 2 groups based on treatment with tafamidis. Propensity score matching (PSM) was performed, and rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared. After PSM, 421 patients were in each group (tafamidis vs nontafamidis). During the 12-month follow-up period, patients treated with tafamidis experienced significantly less HFE and all-cause mortality. A higher probability of event-free survival for HFE and all-cause mortality was noted with tafamidis. This real-world analysis supports that tafamidis use is associated with reduced HFE and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer-term follow-up is needed to better understand the utility of tafamidis, given the increasing recognition of ATTR-CM and the high cost of tafamidis.

Safety and efficacy of transcatheter edge-to-edge repair (TEER) in patients with history of cancer.

Background: Surgical therapy has been a long-standing option for valvular heart disease, in patients with history of cancer, it carries an increased risk of complications. Objectives: Transcatheter edge-to-edge repair (TEER) for mitral regurgitation, represents a less invasive option. However, patients with history of cancer have generally been excluded from trials. Methods: A retrospective cohort analysis was performed on de-identified, aggregate patient data from the TriNetX research network. Patients 18 ≥ years of age, who had undergone TEER between January 1, 2013 and May 19, 2021, were identified using the CPT codes and divided into two cohorts based on a history of cancer. Subgroup analysis was performed based on history of systemic antineoplastic therapy. Odds ratio and log-rank test were used to compare the outcomes over 1 and 12-months. Results: In matched cohorts (503 patients in each, mean age 77.7 years, men 55 vs 58 %, white 84 vs 87 % in non-cancer and cancer cohorts respectively), the risk of heart failure exacerbation, all-cause mortality and all-cause hospitalizations were similar at 1 and 12 months among patients undergoing TEER. Risk of major complications (ischemic stroke, blood product transfusion and cardiac tamponade) were also similar. In the cancer cohort, hematologic/lymphoid malignancies were the most common (28.0 %) and 12.5 % patients had a history of metastatic cancer. There was no significant difference in heart failure exacerbation or all-cause mortality based on history of systemic antineoplastic therapy. Conclusions: Overall outcomes following TEER are similar in patients with a history of cancer and should be considered in selected patients in this population.

Late cardiac events after allogeneic stem cell transplant: incidence, risk factors, and impact on overall survival.

BACKGROUND: There is limited data on the impact of cardiac disease on long term outcomes of allogeneic stem cell transplant (alloSCT). Our study aims to describe the incidence of late cardiac events after alloSCT, identify risk factors for developing a late cardiac event, and illustrate the impact of late cardiac events on overall survival. METHODS: Patients who underwent alloSCT from 2007 to 2017 and survived more than 1 year after transplant (N = 804) were included. Gray's sub-distribution methods, while accounting for death as a competing risk, were used to calculate the cumulative incidence of late cardiac events. Univariate regression models based on Gray's sub-distribution were fitted to assess the potential predictive effects of baseline characteristics on the risk of developing any late cardiac events. Univariate Cox proportional hazard regression models were used to evaluate the association between late cardiac events and overall survival. RESULTS: The cumulative incidence of a late cardiac event at 5 years after transplant was 22% (95% CI 19-25%). The most frequent cardiac event was a decline in LVEF to < 45% with a cumulative incidence of 9% (95% CI 7-11%). Patients were at significantly increased hazard of developing a late cardiac event if they had a history of congestive heart failure prior to alloSCT (HR 4.53, 95% CI 2.57-7.97, p-value < 0.001), a decline in LVEF to < 45% (HR 3.95, 95% CI 2.09-7.47, p-value < 0.001) or cerebral vascular accident (HR 3.13, 95% CI 1.38-7.06, p-value 0.004). Transplant characteristics such as primary disease, donor type, use of TBI, myeloablative conditioning regimen or tyrosine kinase inhibitor had no significant association with late cardiac events. Almost all cardiac events demonstrated a significantly increased risk of death. This hazard was the highest in patients who experienced an atrial arrhythmia (HR 10.6, 95% CI 7.7-14.6). CONCLUSION: Adverse cardiac events are relatively common late after alloSCT with identifiable risk factors such as medical comorbidities prior to transplant and are associated with a negative impact on overall survival.

Long-term survival in people with transthyretin amyloid cardiomyopathy who took tafamidis: A Plain Language Summary.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. WHAT DID RESEARCHERS FIND OUT?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. WHAT DO THE RESULTS MEAN?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration: NCT02791230 (ClinicalTrials.gov).

Implementing a Machine-Learning-Adapted Algorithm to Identify Possible Transthyretin Amyloid Cardiomyopathy at an Academic Medical Center.

Background: Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is a frequently under-recognized cause of heart failure (HF) in older patients. To improve identification of patients at risk for the disease, we initiated a pilot program in which 9 cardiac/non-cardiac phenotypes and 20 high-performing phenotype combinations predictive of wild-type ATTR-CM were operationalized in electronic health record (EHR) configurations at a large academic medical center. Methods: Inclusion criteria were age >50 years and HF; exclusion criteria were end-stage renal disease and prior amyloidosis diagnoses. The different Epic EHR configurations investigated were a clinical decision support tool (Best Practice Advisory) and operational/analytical reports (Clarity™, Reporting Workbench™, and SlicerDicer); the different data sources employed were problem list, visit diagnosis, medical history, and billing transactions. Results: With Clarity, among 45 051 patients with HF, 4006 patients (8.9%) had ⩾1 phenotype combination associated with increased risk of wild-type ATTR-CM. Across all data sources, 2 phenotypes (cardiomegaly; osteoarthrosis) and 2 combinations (carpal tunnel syndrome + HF; atrial fibrillation + heart block + cardiomegaly + osteoarthrosis) generated the highest proportions of patients for wild-type ATTR-CM screening. Conclusion: All EHR configurations tested were capable of operationalizing phenotypes or phenotype combinations to identify at-risk patients; the Clarity report was the most comprehensive.

Global pattern of cardiovascular disease management in patients with cancer and impact of COVID-19 on drug selection: IRAQ-IC-OS survey-based study.

Background: Regional variations in cardiovascular disease (CVD) and CVD management are well known. However, there is limited information on geographical variations in the discipline of Cardio-Oncology, including both the nature of CVD in patients with cancer and its management. Furthermore, during the recent COVID-19 pandemic, CV care for patients was disrupted resulting in an unknown impact on cardio-oncology services. Objective: The aim of this study was to identify the regional variations in the management of CVD among patients with cancer and the impact of the COVID-19 pandemic on the selection of cardiovascular drugs in cardio-oncology. Methods: An online survey was conducted by the Iraq Chapter of the International Cardio-Oncology Society (IC-OS). The survey was shared with cardiologists and oncologists in all seven continents to identify whether regional variations exist in cardio-oncology daily practice. Results: From April to July 2021, 140 participants responded to the survey, including cardiologists (72.9%) and oncologists (27.1%). Most of the respondents were from the Middle East (26.4%), North America (25%), Latin America and the Caribbean (25%), and Europe (20.7%). Baseline CV risk assessment in patients with cancer using the HFA/IC-OS score was reported in 75.7% of respondents (78.4% cardiologists and 68.4% oncologists). Hypertension was the most common CVD treated by the survey respondents globally (52.1%) unlike in Europe where heart failure was the most prominent CVD (51.7%). The blood pressure cutoff value to initiate hypertension management is >140/90 mmHg globally (72.9%), but in North America (48.6%) it was >130/80 mmHg. In the Middle East, 43.2% of respondents do not use cardioprotective medication. During the COVID-19 pandemic, 10.7% of respondents changed their practice, such as switching from prescribing ACEI to ARB. Apixaban is the main anticoagulant used in patients with cancer (32.9%); however, in cancer patients with COVID-19 infection, the majority used enoxaparin (31.4%). Conclusion: More than three-quarters of cardiologists and oncologists responding to the survey are using HFA/IC-OS proformas. The survey showed regional variations in the management of CVD on different continents. The use of cardioprotective agents was limited in some regions including the Middle East. COVID-19 pandemic impacted daily practice on the selection and switching of cardiovascular drugs including ACEI/ARB and the choice of anticoagulants.

Permissive Cardiotoxicity: The Clinical Crucible of Cardio-Oncology.

The field of cardio-oncology was born from the necessity for recognition and management of cardiovascular diseases among patients with cancer. This need for this specialty continues to grow as patients with cancer live longer as a result of lifesaving targeted and immunologic cancer therapies beyond the usual chemotherapy and/or radiation therapy. Often, potentially cardiotoxic anticancer treatment is necessary in patients with baseline cardiovascular disease. Moreover, patients may need to continue therapy in the setting of incident cancer therapy-associated cardiotoxicity. Herein, we present and discuss the concept of permissive cardiotoxicity as a novel term that represents an essential concept in the field of cardio-oncology and among practicing cardio-oncology specialists. It emphasizes a proactive rather than reactive approach to continuation of lifesaving cancer therapies in order to achieve the best oncologic outcome while mitigating associated and potentially off-target cardiotoxicities.

Clinical Practice Guidelines in Cardio-Oncology.

Consensus statements on recommended definitions and practice in cardio-oncology have been developed. There is recognition of the potential for anthracyclines, trastuzumab, pertuzumab, immune checkpoint inhibitors, tyrosine kinase inhibitors, cyclophosphamide, and radiotherapy to cause left ventricular dysfunction and heart failure with heterogeneous natural histories. Cardiac function should be evaluated by echocardiography before the initiation of these therapies. For the prevention of cardiotoxicity, there is evidence to support the use of dexrazoxane under specific circumstances; existing research does not support the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or ß-blockers in unselected individuals but should be considered in specific instances.