Checkpoint inhibitor myocarditis with preceding immunosuppression and tolerance of sequential anthracycline therapy.

A man in his 50s with no known cardiac history and diffuse large B-cell lymphoma on nivolumab presented with acute dyspnoea and swelling. Physical examination revealed volume overload. Work-up noted new elevation of B-type natriuretic peptide and troponin, with new lateral T-wave inversions on ECG. He was admitted to cardiac intensive care for decompensated heart failure. Echocardiography showed ejection fraction 51% with diffuse hypokinesis and reduction of global longitudinal strain. Cardiac MRI demonstrated diffuse myocardial fibrosis with oedema suggesting acute injury. Endomyocardial biopsy revealed lymphocytic and macrophagic infiltrate with cardiomyocyte damage, compatible with immune checkpoint inhibitor (ICI) myocarditis. Immunotherapy was discontinued and he was treated with diuresis, steroids and initiation of goal-directed medical therapy for heart failure. He required additional treatment with anthracyclines. He was monitored with cardio-oncology follow-up after every cycle of anthracycline and tolerated a cumulative 312 mg/m2 therapy. The safety of anthracycline administration after ICI-myocarditis has not been described.

Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

BACKGROUND: Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. OBJECTIVES: To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. METHODS: Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. RESULTS: Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. CONCLUSION: Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

The risk vs. benefit calculus of anticoagulation in patients with ibrutinib-related atrial fibrillation.

For ibrutinib-related atrial fibrillation (IRAF), guidelines for anticoagulation do not exist. We sought to describe stroke, bleeding, and anticoagulation rates among patients with IRAF. We performed a single-center retrospective review of 168 patients treated with ibrutinib followed from 2013 to 2022. Over a median follow-up of 6.4 years, 44 (26.0%) patients developed IRAF of which 38 (86.4%) had a CHA2DS2-VASc ≥2 and 7 (15.9%) had a HAS-BLED ≥3. Anticoagulation was initiated in 20 (45.5%) without a clear pattern in scores, risk factors, or cumulative dose, besides having another reason for anticoagulation. Few patients with IRAF developed non-hemorrhagic CVA (n = 3, 6.8%) or significant bleeding (n = 3, 6.8%). Among those with each adverse outcome, 2 in each group were anticoagulated and all were older than 65 years old. In conclusion, decisions for anticoagulation vary widely and patients who are elderly or with HTN may be most at risk for CVA or significant bleed.

Circulating Cardiovascular Biomarkers in Cancer Therapeutics-Related Cardiotoxicity: Review of Critical Challenges, Solutions, and Future Directions.

Cardiotoxicity is a growing concern in the oncology population. Transthoracic echocardiography and multigated acquisition scans have been used for surveillance but are relatively insensitive and resource intensive. Innovative imaging techniques are constrained by cost and availability. More sensitive, cost-effective cardiotoxicity surveillance strategies are needed. Circulating cardiovascular biomarkers could provide a sensitive, low-cost solution. Biomarkers such as troponins, natriuretic peptides (NPs), novel upstream signals of oxidative stress, inflammation, and fibrosis as well as panomic technologies have shown substantial promise, and guidelines recommend baseline measurement of troponins and NPs in all patients receiving potential cardiotoxins. Nonetheless, supporting evidence has been hampered by several limitations. Previous reviews have provided valuable perspectives on biomarkers in cancer populations, but important analytic aspects remain to be examined in depth. This review provides comprehensive assessment of critical challenges and solutions in this field, with focus on analytical issues relating to biomarker measurement and interpretation. Examination of evidence pertaining to common and serious forms of cardiotoxicity reveals that improved study designs incorporating larger, more diverse populations, registry-based approaches, and refinement of current definitions are key. Further efforts to harmonize biomarker methodologies including centralized biobanking and analyses, novel decision limits, and head-to-head comparisons are needed. Multimarker algorithms incorporating machine learning may allow rapid, personalized risk assessment. These improvements will not only augment the predictive value of circulating biomarkers in cardiotoxicity but may elucidate both direct and indirect relationships between cardiovascular disease and cancer, allowing biomarkers a greater role in the development and success of novel anticancer therapies.

Social Risk Factors That Increase Cardiovascular and Breast Cancer Risk.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) and breast cancer (BC) are significant causes of mortality globally, imposing a substantial health burden. This review article aims to examine the shared risk factors and social determinants that contribute to the high prevalence of both diseases, with a focus on social risk factors. RECENT FINDINGS: The common risk factors for CVD and BC, such as hypertension, diabetes, obesity, aging, and physical inactivity, are discussed, emphasizing their modifiability. Adhering to ideal cardiovascular health behaviors has shown a trend toward lower BC incidence. Increased risk of CVD-related mortality is significantly impacted by age and race in BC patients, especially those over 45 years old. Additionally, racial disparities in both diseases highlight the need for targeted interventions. Social determinants of health, including socioeconomic status, education, employment, and neighborhood context, significantly impact outcomes for both CVD and BC. Addressing social factors is vital in reducing the burden of both CVD and BC and improving overall health equity.

Global Cardio Oncology Registry (G-COR): Registry Design, Primary Objectives, and Future Perspectives of a Multicenter Global Initiative.

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Challenges in Cardiovascular Imaging in Women with Breast Cancer.

Cardiovascular imaging in breast cancer patients is paramount for the surveillance of cancer therapy-related cardiac dysfunction (CTRCD); however, it comes with specific limitations. PURPOSE OF REVIEW: This review aims to describe the unique challenges faced in cardiovascular imaging of breast cancer patients, discuss evidence to support the utility of various imaging modalities, and provide solutions for improvement in imaging this unique population. RECENT FINDINGS: Updated clinical society guidelines have introduced more unifying surveillance of CTRCD, although there remains a lack of a universally accepted definition. Traditional and novel multi-modality imaging can be used to detect CTRCD and myocarditis in breast cancer patients. Cardiovascular imaging in breast cancer patients is difficult due to reconstructive surgery. Although echocardiography with myocardial strain is the cornerstone, multi-modality imaging can be used to evaluate for CTRCD and myocarditis. Novel imaging techniques to improve the diagnosis of cardiotoxicities in breast cancer patients are needed.

COVID-19 severity and cardiovascular outcomes in SARS-CoV-2-infected patients with cancer and cardiovascular disease.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p<0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], pinteraction <0.001). Conclusions: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701).

Cancer Treatment-Related Cardiovascular Toxicity in Gynecologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Improvements in early detection and treatment of gynecologic malignancies have led to an increasing number of survivors who are at risk of long-term cardiac complications from cancer treatment. Multimodality therapies for gynecologic malignancies, including conventional chemotherapy, targeted therapeutics, and hormonal agents, place patients at risk of cancer therapy-related cardiovascular toxicity during and following treatment. Although the cardiotoxicity associated with some female predominant cancers (eg, breast cancer) have been well recognized, there has been less recognition of the potential adverse cardiovascular effects of anticancer therapies used to treat gynecologic malignancies. In this review, the authors provide a comprehensive overview of the cancer therapeutic agents used in gynecologic malignancies, associated cardiovascular toxicities, risk factors for cardiotoxicity, cardiac imaging, and prevention strategies.

Echocardiographic correlates of major adverse cardiac events at 1 year in patients with apical ballooning takotsubo syndrome.

INTRODUCTION: Takotsubo syndrome (TTS) is characterized by transient left ventricular dysfunction and associated with considerable morbidity and mortality. We sought to evaluate the association between change in cardiac mechanics after diagnosis of TTS with 1-year incidence of major adverse cardiovascular events (MACE). METHODS: We retrospectively identified 85 patients with apical TTS based on ICD 9/10 codes and chart adjudication, who had a follow-up echocardiogram within 6 months of diagnosis. Echocardiograms were analyzed for left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), GLS ratio, global circumferential strain (GCS), and global radial strain (GRS). Multivariable logistic regression was performed to identify parameters associated with MACE (all-cause mortality, heart failure, stroke, and coronary artery disease [CAD] requiring percutaneous coronary intervention [PCI]) at 1 year. Event-free survival was assessed in patients with GLS (≤-18% vs. >18%) and LVEF (≥53% vs. <53%). RESULTS: Within 1 year of diagnosis, MACE occurred in 15 (18%) patients. Between baseline and follow-up echocardiogram (median 15 [range 1-151] days), there were significant differences in change in LVEF and GLS in patients with versus without incident MACE. In multivariate analysis, change in LVEF (odds ratio [OR] = .93 [.87, .98], p = .013) and change in GLS (OR = 1.32 [1.04, 1.67], p = .022) were independently associated with MACE; however, the association with change in GLS was attenuated (odds ratio [OR] = 1.13 [.94, 1.36], p = .21) after adjustment for baseline and change in LVEF. Among patients with normalized LVEF at follow-up, there were five (14.7%) MACE; whereas, there were no events among patients with normalized GLS. CONCLUSIONS: In patients with apical TTS, recovery in GLS and LVEF at follow-up was associated with significantly lower MACE at 1 year. Normalization of GLS at follow-up was better able to discriminate event-free survival than normalization of LVEF.

External validation of a heart failure risk score in patients with acute myeloid leukemia.

A 21-point risk score for heart failure (HF) has been developed for patients with acute myeloid leukemia (AML), stratifying patients into three groups: low, moderate, and high-risk. In this study, 193 patients with AML treated with anthracycline-based therapy were stratified using the risk score, and its prognostic utility for HF events and all-cause mortality at one year of follow-up were evaluated. HF occurred in 18% (34/193) of anthracycline-treated patients. Global longitudinal strain (GLS) was more negative among patients without HF events (-19 ± 3 vs. -17 ± 4%). One year incidence of HF was increased in the higher risk groups: 12% of low-risk, 24% of moderate-risk, and 50% of high-risk (p < 0.001). However, a higher risk score was not associated with an increased risk of all-cause mortality. This study provides external validation of a 21-point risk score for HF events but not all-cause mortality at one year in patients with AML.

Adverse Cardiac Effects of CAR T-Cell Therapy: Characteristics, Surveillance, Management, and Future Research Directions.

This review summarizes the current literature on the adverse cardiac effects of CAR T-cell therapy. Case reports and series suggest that major adverse cardiovascular events are not uncommon after CAR T-cell therapy; however, limited data exist regarding incidence, pathophysiology, and prevention strategies related to CAR T-associated cardiovascular events. As cellular therapy advances and the indications for its use continue to expand, it is essential to better understand its associated cardiovascular toxicities. Biomarkers, cardiac imaging, longitudinal data from larger populations, and translational research are all essential areas for further research. Interestingly, CAR T-cell therapy can also be used to reverse cardiac fibrosis in murine models. Altogether this underscores the need to broadly understand how T-cells, endogenous and engineered, may impact cardiovascular diseases.

Real-World Persistence and Time to Next Treatment With Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Including Patients at High Risk for Atrial Fibrillation or Stroke.

BACKGROUND: Atrial fibrillation (AF) is a recognized adverse consequence associated with all Bruton's tyrosine kinase inhibitors used to treat chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); however, real-world time to discontinuation (TTD) and time to next treatment (TTNT) of CLL/SLL patients with a high baseline AF/stroke risk remain unknown. MATERIALS AND METHODS: Patients with CLL/SLL from a nationwide electronic health record-derived database (February 12, 2013-January 31, 2021) initiating first-line (1L) or second or later-line (2L+) treatment with ibrutinib or other regimens on or after February 12, 2014 (index date) were analyzed. Kaplan-Meier survival analysis was used to assess TTD and TTNT among all patients, patients with high AF risk (CHARGE-AF risk score ≥10.0%), and patients at high risk of stroke (CHA2DS2-VASc risk score ≥3 [females] or ≥2 [males]). RESULTS: In 1L/2L+, 2190/1851 patients received ibrutinib and 4388/4135, were treated with other regimens. Median TTD for ibrutinib was similar regardless of AF/stroke-related risk (1L: all patients, 15.7 months; high AF risk, 11.7 months; high stroke risk, 13.7 months; similar results in 2L+). Median TTNT was significantly longer for ibrutinib vs. other regimens (1L: not reached vs. 45.9 months; 2L+: not reached vs. 23.6 months; both P < .05), including among those with high AF/stroke risk. TTNT was similar between all patients and high-risk cohorts in 1L and 2L+ (all P > .05). CONCLUSION: This study highlights that elevated baseline AF/stroke-related risk does not adversely impact TTD and TTNT outcomes associated with ibrutinib use. Additionally, TTNT was significantly longer for patients treated with ibrutinib vs. other regimens.

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057). CONCLUSION: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.