Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly ...proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.
The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized.
Using administrative databases, women diagnosed with ...HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death.
A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% 95% CI, 12.0%-21.7%) as controls (17.1% 95% CI, 14.4%-20.1%); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% 95% CI, 4.7%-16.9%; controls 16.4% 95% CI, 12.1%-21.3%;
=0.03) and sequential-HF cohorts (2.7% 95% CI, 1.4%-4.8%; controls 10.8% 95% CI, 8.9%-13.0%;
<0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%-5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%-12.6%) in controls, and 1.7% (0.6%-3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1-5.8%) for controls.
Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.
Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization ...or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline- and/or trastuzumab-containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin-exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab-treated women were also matched on anthracycline exposure. We matched 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women (median age, 69 and 71 years, respectively). The 5-year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%-2.6%) in statin-exposed women and 2.9% (95% CI, 1.7%-4.6%) in unexposed women (
value, 0.01). The cause-specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24-0.85;
value, 0.01). After trastuzumab, the 5-year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%-5.2%) in statin-exposed women and 3.7% (95% CI, 2.0%-6.2%) in unexposed women (
value 0.09). The cause-specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20-1.07;
value, 0.07). Conclusions Statin-exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non-significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.
OSA conveys worse clinical outcomes in patients with coronary artery disease. The STOP-BANG score is a simple tool that evaluates the risk of OSA and can be added to the large number of clinical ...variables and scores that are obtained during the management of patients with myocardial infarction (MI). Currently, machine learning (ML) is able to select and integrate numerous variables to optimize prediction tasks.
Can the integration of STOP-BANG score with clinical data and scores through ML better identify patients who experienced an in-hospital cardiovascular event after acute MI?
This is a prospective observational cohort study of 124 patients with acute MI of whom the STOP-BANG score classified 34 as low (27.4%), 30 as intermediate (24.2%), and 60 as high (48.4%) OSA-risk patients who were followed during hospitalization. ML implemented feature selection and integration across 47 variables (including STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction) to identify those patients who experienced an in-hospital cardiovascular event (ie, death, ventricular arrhythmias, atrial fibrillation, recurrent angina, reinfarction, stroke, worsening heart failure, or cardiogenic shock) after definitive MI treatment. Receiver operating characteristic curves were used to compare ML performance against STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction, independently.
There were an increasing proportion of cardiovascular events across the low, intermediate, and high OSA risk groups (P = .005). ML selected 7 accessible variables (ie, Killip class, leukocytes, GRACE score, c reactive protein, oxygen saturation, STOP-BANG score, and N-terminal prohormone of B-type natriuretic peptide); their integration outperformed all comparators (area under the curve, 0.83 95% CI, 0.74-0.90; P < .01).
The integration of the STOP-BANG score into clinical evaluation (considering Killip class, GRACE score, and simple laboratory values) of subjects who were admitted for an acute MI because of ML can significantly optimize the identification of patients who will experience an in-hospital cardiovascular event.
Calvillo-Argüelles and Ross discuss the cardiac considerations in patients with COVID-19. Among the cardiac considerations include the importance of cardiac biomarkers for risk stratification, the ...occurrence of myocardial infarction (MI) without obstructive coronary artery disease (CAD) and the association of cardiac complications with poor outcomes. Also cited are the need for treatment to be directed at specific causes of myocardial injury and occurrence of cardiac injury in about a-quarter of patients with COVID-19 who are admitted to hospitals.
Novel risk stratification and non‐invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post‐transplant. Clonal hematopoiesis (CH) refers to ...the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes. The purpose of this study was to investigate the association between CH and OHT. Blood samples were collected from 127 OHT recipients. Error‐corrected sequencing was used to detect CH‐associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 42% vs. 15 15%, p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4–6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than previously reported for the general population of the same age group, with an associated higher prevalence of CAV and mortality.
Examining specific gene mutations in hematopoietic stem cells, we have demonstrated that clonal hematopoiesis is a novel non‐invasive test that can risk stratify adverse outcomes such as mortality and cardiac allograft vasculopathy in heart transplant recipients.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To investigate the role of right ventricular free wall strain (RVFWSL) to predict low functional capacity in repaired tetralogy of Fallot (rTOF). We prospectively enrolled 33 patients with rTOF with ...moderate to severe PR who underwent rest and peak exercise echocardiography on a semisupine cycloergometer. Conventional function and strain imaging parameters of both ventricles were measured. Patients performing < 7 METS were defined to have low functional capacity. Logistic regression was used to identify parameters associated with low functional capacity. Eleven patients (33.3%) had low functional capacity. These patients were shorter (height 155 ± 7 vs 163 ± 9 cm, p = 0.023), more frequently female (27.3 vs 72.7%, p = 0.024) and had history of Blalock–Taussig shunt (45.5 vs 9.1%, p = 0.027). On multivariate analysis RVFWSL was the only predictor of low functional capacity OR 1.39 (CI 95%, 1.06–1.83., p = 0.018) per % change. A RVFWSL < 17% (absolute value) had an AUC of 0.785, sensitivity of 81.8% and specificity of 77.3% to predict low functional capacity. Right ventricular free wall strain is an independent predictor of low functional capacity in repaired tetralogy of Fallot with moderate to severe PR. A value < 17% might be useful in deciding when to perform pulmonary valve replacement, when functional capacity cannot be objectively measured.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous ...system ischemic events. The magnitude of these risks remains poorly quantified.
Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate.
We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI.
Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.
Statins can reduce the risk of anthracycline-induced cardiotoxicity. Whether such cardioprotective effects can be seen in trastuzumab-treated patients has not been explored.
Consecutive women with ...HER2+ breast cancer who received trastuzumab with or without anthracyclines were identified retrospectively. Patients receiving statins before and during cancer treatment were matched with 2 patients of the same age (± 2 years) and anthracycline exposure status but without statin treatment. The primary outcome was final left ventricular ejection fraction (LVEF). Analysis of covariance (ANCOVA) was used to assess the relationship between statin exposure and the final LVEF. A logistic regression model was constructed to assess the relationship between statin exposure and cardiotoxicity (secondary outcome).
Included were 129 patients (62 ± 9 years). Forty-three received statins during cancer treatment. The median trastuzumab exposure time was 11.8 (interquartile range IQR 11 to 12) months. Seventy-two (56%) patients received anthracyclines. Compared with controls, patients treated with statins were more likely to have diabetes (37.2% vs 4.7%, P < 0.001), hypertension (58.1% vs 22.1%, P < 0.001), and coronary artery disease (11.6% vs 2.3%, P = 0.04). Within a median cardiac follow-up duration of 11 (IQR 9 to 18) months, the adjusted final LVEF was lower in the control group (61.2% vs 64.6%, P = 0.034). A significant change in LVEF was observed in the control group (median –6%, IQR –10% to –1% P < 0.001) but not in the statin group (median 0%, IQR –5% to +3%, P = 0.27). Upon adjusted analysis, statin treatment was independently associated with a lower risk of cardiotoxicity (odds ratio OR 0.32, 95% confidence interval CI, 0.10-0.99, P = 0.049).
In women with HER2+ breast cancer receiving trastuzumab-based therapy with or without anthracyclines, concomitant use of statins was associated with a lower risk of cardiotoxicity.
Les statines peuvent réduire le risque de cardiotoxicité des anthracyclines. La question de savoir si de tels effets cardioprotecteurs peuvent être observés chez les patients traités par le trastuzumab n’avait pas encore été explorée.
Des patientes consécutives atteintes de cancer du sein HER2+ qui avaient été traitées par le trastuzumab avec ou sans anthracyclines ont été repérées rétrospectivement. Les patientes qui recevaient une statine avant ou pendant le traitement de leur cancer ont été appariées à 2 patientes ayant le même âge (± 2 ans) et le même statut quant à l’exposition à l’anthracycline, mais ne prenant pas de statine. Le critère d’évaluation principal était la fraction d’éjection ventriculaire gauche (FEVG) finale. L’analyse de la covariance (ANCOVA) a été utilisée pour évaluer la relation entre l’exposition à la statine et la FEVG finale. Un modèle de régression logistique a été élaboré pour évaluer la relation entre l’exposition à la statine et la cardiotoxicité (critère d’évaluation secondaire).
L’étude portait sur 129 patientes (62 ± 9 ans). Quarante-trois patientes ont reçu des statines durant le traitement de leur cancer. La durée médiane d’exposition au trastuzumab était de 11,8 (écart interquartile EIQ de 11 à 12) mois. Soixante-douze (56 %) patientes avaient reçu des anthracyclines. Comparativement aux témoins, les patientes traitées par une statine étaient plus susceptibles de souffrir de diabète (37,2 % vs 4,7 %, p < 0,001), d’hypertension (58,1 % vs 22,1 %, p < 0,001) et de coronaropathie (11,6 % vs 2,3 %, p = 0,04). À l’intérieur d’une période de suivi cardiaque d’une durée médiane de 11 (EIQ de 9 à 18) mois, la FEVG finale ajustée était moins élevée dans le groupe témoin (61,2 % vs 64,6 %, p = 0,034). Une variation significative de la FEVG a été observée dans le groupe témoin (médian -6 %, EIQ de -10 % à -1 %, p < 0,001), mais pas dans le groupe ayant reçu une statine (médian 0 %, EIQ de -5 % à +3 %, p = 0,27). Après l’analyse ajustée, le traitement par la statine était associé de façon indépendante à un risque de cardiotoxicité plus faible (rapport des cotes RC 0,32, intervalle de confiance IC à 95 %, 0,10-0,99, p = 0,049).
Chez les femmes atteintes de cancer du sein HER2+ ayant reçu un traitement à base de trastuzumab avec ou sans anthracyclines, la prise concomitante d’une statine était associée à un risque de cardiotoxicité plus faible.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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