Left ventricular global longitudinal systolic strain (GLS) has been shown to be superior to ejection fraction in detecting subclinical dysfunction in patients with cancer and predicting mortality in ...patients with cardiovascular disease. Cancer-related fatigue is common in the later stages of neoplastic malignancies and may be indicative of nonovert heart failure. The aim of this study was to determine whether reduced strain by echocardiography was associated with all-cause mortality in a cancer cohort.
In this retrospective study, 120 patients with cancer undergoing or scheduled to undergo chemotherapy and with normal ejection fractions (>50%) underwent assessments of GLS. GLS was derived by averaging all speckle-tracking strain segments of the left ventricle.
Over an average follow-up period of 21.6 ± 13.9 months, 57 of 120 patients died. Univariate predictors of all-cause mortality (P < .10) were Eastern Cooperative Oncology Group performance status, male sex, hematologic malignancy, β-blocker use, and GLS. Multivariate analysis of all significant univariate variables showed that Eastern Cooperative Oncology Group performance status (hazard ratio, 2.12; 95% confidence interval, 1.54-2.92; P < .001), male sex (hazard ratio, 1.93; 95% confidence interval, 1.14-3.27; P = .014), and GLS (hazard ratio, 0.89; 95% confidence interval, 0.81-0.97; P = .012) were significantly and independently associated with mortality. Stepwise analysis of the multivariate associations showed an increase in the global χ(2) value after adding GLS (P = .011) to significant clinical variables.
Eastern Cooperative Oncology Group performance status, male sex, and GLS were significantly associated with all-cause mortality in patients with cancer with normal ejection fractions receiving chemotherapy. Adding GLS to significant clinical variables provided incremental prognostic information.
Purpose of Review
The anticoagulation strategies for various cardiac-specific pathologies including atrial fibrillation are changing. Applying these strategies in patients with concomitant active ...cancer requires additional considerations. Here, we review the most recent changes in the anticoagulation management of common cardiac diseases and their application in cancer patients.
Recent Findings
There are a range of indications for therapeutic anticoagulation in cancer patients including venous thromboembolism (VTE), atrial fibrillation/flutter (AF/AFL), prosthetic heart valves, and intracardiac thrombi. Certain cancer therapeutics such as ibrutinib and anthracycline chemotherapy increase the risk of developing AF/AFL and pose unique challenges in anticoagulation management. Anticoagulation decisions for AF/AFL often utilize the CHADS2 or the CHA2DS2-VASc score with annualized stroke risk; however, these risk stratification models may be inadequate in cancer patients. Cancer type, stage, prognosis, and bleeding risk are all relevant when considering whether to initiate therapeutic anticoagulation. Moreover, thrombocytopenia may limit the ability to provide anticoagulation. Subsequent analyses of direct oral anticoagulants (DOACs) show fewer bleeding complications and thromboembolic events compared to warfarin in AF/AFL with apixaban and edoxaban particularly promising in this population for VTE, pulmonary embolism, and AF/AFL. There is a lack of data regarding ablation therapy and left atrial occlusion devices in this population. There is a growing experience of DOACs for intracardiac thrombi. Warfarin is still appropriate for patients with prosthetic heart valves and left ventricular assist devices.
Summary
Anticoagulation management in the cancer patient can be challenging. DOACs are often a safe alternative to warfarin in cancer-associated DVT/PE and AF/AFL, and may be preferable in certain circumstances. Other cardiac indications for anticoagulation including the presence of a mechanical heart valve remain unchanged and dependent on warfarin or heparin-based products.
The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been ...assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors.
This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing.
9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0–31·4) from the date of primary cancer diagnosis (4311 44.9% were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9–19·5) compared with 0·9% (0·0–2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23–0·29) events per survivor compared with 0·009 (0·000–0·021) events per community control participant. Increasing cumulative burden of grade 1–4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1–6·0; p<0·0001; two conditions: 6·6, 4·6–9·5; p<0·0001; and three conditions: 7·7, 5·1–11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias RR 1·5, 95% CI 1·2–2·0; p=0·0017), grade 2 left ventricular systolic dysfunction (2·2, 1·6–3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2–4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1–2 hypertriglyceridaemia, or grade 1–2 vascular stenosis.
Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events.
The US National Cancer Institute and the American Lebanese Syrian Associated Charities.
To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction ...(LVEF) at highest risk of future treatment-related cardiomyopathy.
St Jude Lifetime Cohort participants ≥5 years from diagnosis, at increased risk for cardiomyopathy per the International Guideline Harmonization Group (IGHG), with an LVEF ≥50% on baseline echocardiography (n = 1,483) underwent measurement of GLS (n = 1,483) and NT-proBNP (n = 1,052; 71%). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for postbaseline cardiomyopathy (modified Common Terminology Criteria for Adverse Events ≥grade 2) incidence in association with echocardiogram-based GLS (≥-18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles). Prediction performance was assessed using AUC in models with and without GLS and NT-proBNP and compared using DeLong's test for IGHG moderate- and high-risk individuals treated with anthracyclines.
Among survivors (median age, 37.6; range, 10.2-70.4 years), 162 (11.1%) developed ≥grade 2 cardiomyopathy 5.1 (0.7-10.0) years from baseline assessment. The 5-year cumulative incidence of cardiomyopathy for survivors with and without abnormal GLS was, respectively, 7.3% (95% CI, 4.7 to 9.9) versus 4.4% (95% CI, 3.0 to 5.7) and abnormal NT-proBNP was 9.9% (95% CI, 5.8 to 14.1) versus 4.7% (95% CI, 3.2 to 6.2). Among survivors with a normal LVEF, abnormal baseline GLS and NT-proBNP identified anthracycline-exposed, IGHG-defined moderate-/high-risk survivors at a four-fold increased hazard of postbaseline cardiomyopathy (HR, 4.39 95% CI, 2.46 to 7.83;
< .001), increasing to a HR of 14.16 (95% CI, 6.45 to 31.08;
< .001) among survivors who received ≥250 mg/m
of anthracyclines. Six years after baseline, AUCs for individual risk prediction were 0.70 for models with and 0.63 for models without GLS and NT-proBNP (
= .022).
GLS and NT-proBNP should be considered for improved identification of survivors at high risk for future cardiomyopathy.
Ibrutinib is a tyrosine kinase inhibitor most commonly associated with atrial fibrillation. However, additional cardiotoxicities have been identified, including accelerated hypertension. The ...incidence and risk factors of new or worsening hypertension following ibrutinib treatment are not as well known.
We conducted a retrospective study of 144 patients diagnosed with B cell malignancies treated with ibrutinib (n=93) versus conventional chemoimmunotherapy (n=51) and evaluated their effects on blood pressure at 1, 2, 3 and 6 months after treatment initiation. Descriptive statistics were used to compare baseline characteristics for each treatment group. Fisher's exact test was used to identify covariates significantly associated with the development of hypertension. Repeated measures analyses were conducted to analyse longitudinal blood pressure changes.
Both treatments had similar prevalence of baseline hypertension at 63.4% and 66.7%, respectively. There were no differences between treatments by age, sex and baseline cardiac comorbidities. Both systolic and diastolic blood pressure significantly increased over time with ibrutinib compared with baseline, whereas conventional chemoimmunotherapy was not associated with significant changes in blood pressure. Baseline hypertensive status did not affect the degree of blood pressure change over time. A significant increase in systolic blood pressure (defined as more than 10 mm Hg) was noted for ibrutinib (36.6%) compared with conventional chemoimmunotherapy (7.9%) at 1 month after treatment initiation. Despite being hypertensive at follow-up, 61.2% of patients who were treated with ibrutinib did not receive adequate blood pressure management (increase or addition of blood pressure medications). Within the ibrutinib group, of patients who developed more than 20 mm Hg increase in systolic blood pressure, only 52.9% had hypertension management changes.
Ibrutinib is associated with the development of hypertension and worsening of blood pressure. Cardiologists and oncologists must be aware of this cardiotoxicity to allow timely management of blood pressure elevations.
Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular ...risks of specific lipid abnormalities among childhood cancer survivors.
Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls.
Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non-high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk RR = 2.2, 95% confidence interval CI = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio HR = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy.
Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population.
The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear.
We optically mapped left ventricular wedge ...preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval CI, 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes.
SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.
Atrial fibrillation (AF) is a common cardiovascular complication affecting patients with cancer, but management strategies are not well established.
The purpose of this retrospective cohort study was ...to evaluate cross-sectional patterns of anticoagulation (AC) use in patients with cancer with AF or atrial flutter (AFL) on the basis of their risk for stroke and bleeding.
Patients with cancer and electrocardiograms showing AF or AFL performed at Moffitt Cancer Center in either the inpatient or outpatient setting were included in this retrospective analysis. We described percentages of AC prescription by stroke and bleeding risk, as determined by individual CHA2DS2-VASc and HAS-BLED scores, respectively. Multivariable logistic regression evaluated clinical variables independently associated with anticoagulant prescription.
The prevalence of electrocardiography-documented AF or AFL was 4.8% (n = 472). The mean CHA2DS2-VASc score was 2.8 ± 1.4. Among patients with CHA2DS2-VASc scores ≥2 and HAS-BLED scores <3, 44.3% did not receive AC, and of these, only 18.3% had platelet values <50,000/μl. In multivariable analysis, older age, hypertension, prior stroke, and history of venous thromboembolism were each directly associated with AC use, while current chemotherapy use, prior bleeding, renal disease, and thrombocytopenia were each inversely associated with AC use.
Nearly one-half of patients with cancer, the majority with normal platelet counts, had an elevated risk for stroke but did not receive AC. In addition to known predictors, current chemotherapy use was independently associated with a lower odds of AC use. This study highlights the need to improve the application of AF treatment algorithms to cancer populations.
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Aims
Reduced global longitudinal systolic strain (GLS) is a common finding in end‐stage renal disease (ESRD) patients with normal ejection fraction (EF), and GLS is a stronger predictor of mortality ...than EF. We sought to determine what factors may be responsible for the decreased strain in this population.
Methods and Results
The study group was comprised of 139 renal transplant candidates with a normal EF who had echocardiography with assessment of GLS and basal longitudinal systolic strain (BLS). A GLS of less than −18 and a BLS less than −17 were defined as abnormal. Logistic regression was used to determine variables associated with abnormal GLS and BLS. Of the 139 patients, 49% had abnormal GLS and 70% had abnormal BLS. The univariate predictors of abnormal GLS (P<.05) were low‐normal EF, increased interventricular septal thickness (IVS), diabetes, and dihydropyridine calcium channel blocker use. The univariate predictors of abnormal BLS (P<.05) were elevated systolic blood pressure, elevated diastolic blood pressure, elevated heart rate, decreased EF, increased IVS, increased left ventricular posterior wall thickness (LVPW), increased left ventricular mass index, regular dialysis, and clonidine use. On multivariate analysis, low‐normal EF (P<.001), increased IVS (P=.024), and diabetes (P=.042) were independent predictors of abnormal GLS, while increased DBP (P=.018), increased LVPW (P=.001), and regular dialysis (P=.006) were independent predictors of abnormal BLS.
Conclusions
Clinical variables and co‐findings beyond EF are associated with abnormal strain measurements and may partially explain the large incidence of abnormal strain in renal transplant candidates.
Purpose of review
With the continuing development of newer targeted therapies in oncology, it is necessary to understand their potential cardiovascular side effects. In this review, we discuss the ...association of novel targeted agents and left ventricular systolic dysfunction.
Recent findings
Within the last 5 years, multiple new agents have been developed to target specific cancer pathways and found to have off-targeted cardiotoxicity. The most recent example is the recognition of myocarditis caused by immune checkpoint inhibitors.
Summary
The development of targeted cancer therapies has revolutionized oncology, but many of these agents are inherently toxic to the cardiovascular system. Nearly all vascular endothelial growth factor (VEGF) inhibitors cause cardiotoxicity to varying degrees. Epidermal growth factor receptor (EGFR) inhibitors developed since the discovery of trastuzumab are significantly less cardiotoxic than their predecessor, but still convene risk. BCR-ABL tyrosine kinase inhibitors (TKI), once thought to pose significant risk as a class effect, appear to only be cardiotoxic if they have anti-VEGF activity. The newer generation of proteasome inhibitors such as carfilzomib appears to have significant cardiotoxicity, with almost 5% of patients developing symptomatic heart failure (HF). Immune checkpoint inhibitors can very rarely cause rapidly fatal myocarditis. As of now, there are no sufficient guidelines to direct clinical care for patients on these new classes of agents, but this is likely to change as more data and clinical experience accumulate.
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