Anthracycline-Induced Atrial Structural and Electrical Remodeling Characterizes Early Cardiotoxicity and Contributes to Atrial Conductive Instability and Dysfunction

Tan, Ruopeng; Cong, Tao; Xu, Guojun; Hao, Zhujing; Liao, Jiaowei; Xie, Yuanfang; Lin, Yajuan; Yang, Xiaolei; Li, Qingsong; Liu, Yang; Xia, Yunlong

doi:10.1089/ars.2021.0002

Cited by 13 publications

(12 citation statements)

References 62 publications

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“…Hemichannels regulate extracellular communications, especially allowing for the dissemination of disease, since gap junctions and connexins have been reported to conduct both cell survival and cell death signals [ 19 ]. Many studies showed that Doxo administration induces alterations in Cx43 localization and activity in cardiac cells [ 20 , 21 ], and similar results have been recently reported for other chemotherapeutic drugs such as Ponatinib [ 22 ] and Tzb [ 17 ].…”

Section: Introductionsupporting

confidence: 65%

Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Pecoraro

Marzocco

Franceschelli

et al. 2022

IJMS

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Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities.

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Section: Introductionsupporting

confidence: 65%

Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Pecoraro

Marzocco

Franceschelli

et al. 2022

IJMS

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“…It is conceivable that compared to the left ventricle, the left atrium is structured with a thinner wall, which may bear larger cardiotoxic stress from anthracycline. Translational studies have found LA pathological changes in animal models induced by anthracycline, including cardiomyocyte death, hypotrophy, vacuolization, and increased atrial fibrosis 34 . In addition, electrophysiological alterations characterized by changes in gap junction protein, slowed/heterogeneous atrial conduction, and increased effective refractory period have also been reported 35 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, electrophysiological alterations characterized by changes in gap junction protein, slowed/heterogeneous atrial conduction, and increased effective refractory period have also been reported 35 . The anthracycline‐induced electrical remodeling has been suggested to predispose the left atrium to AF even before the onset of ventricular dysfunction 34 . The combination of LA structural and electrical remodeling secondary to anthracycline toxicity directly impairs the LA phasic function and serves as the substrate for the development and maintenance of AF.…”

Section: Discussionmentioning

confidence: 99%

“…Translational studies have found LA pathological changes in animal models induced by anthracycline, including cardiomyocyte death, hypotrophy, vacuolization, and increased atrial fibrosis. 34 In addition, electrophysiological alterations characterized by changes in gap junction protein, slowed/heterogeneous atrial conduction, and increased effective refractory period have also been reported. 35 The anthracycline-induced electrical remodeling has been suggested to predispose the left atrium to AF even before the onset of ventricular dysfunction.…”

Section: Lasr Is a Promising Index For The Early Diagnosis Of Anthrac...mentioning

confidence: 99%

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Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline‐induced cardiotoxicity

Li,

Zhao,

Zhang

et al. 2024

Echocardiography

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BackgroundLeft ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline‐induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three‐dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline.MethodsA total of 80 patients with diffuse large B‐cell lymphoma who received six cycles of anthracycline‐based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS = LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%.ResultsFourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35 ± 5.03 vs. 25.04 ± 4.10, p < .001), LVGLS (–22.77 ± 2.45 vs. –20.44 ± 2.62, p < .001), and LAVGLS (51.12 ± 5.63 vs. 45.61 ± 5.22, p < .001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30 ± 4.73 vs. 57.08 ± 5.83, p < .001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of >19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC), .842; p < .001), a ΔLVGLS of >13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC, .763; p < .001), and a ΔLAVGLS of >16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC, .905; p < .001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905 vs. .763, p = .027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9% vs. 74.2%, p = .002) and maintained sensitivity in predicting LV cardiotoxicity.ConclusionsLASr could predict anthracycline‐induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.

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“…[19] A recent study conducted on mice showed that doxorubicin induced structural and electrical remodeling, leading to increased susceptibility to atrial fibrillation. [20] As such, further studies are warranted to explore the potential benefit of prophylactic anti-fibrotic and anti-arrhythmic drugs in the prevention of arrhythmias among patients receiving anthracyclines.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis

Dean,

Dahshan,

Motawea

et al. 2023

Medicine

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Background: There have been controversial findings from recent studies regarding anthracyclines use and the subsequent risk of arrhythmias. This study aimed to evaluate the existing evidence of the risk of arrhythmias in patients treated with anthracyclines. Methods: PubMed, Scopus, and Web of Science databases were searched up to April 2022 using keywords such as “anthracycline” and “arrhythmia.” Dichotomous data were presented as relative risk (RR) and confidence interval (CI), while continuous data were presented as mean difference (MD) and CI. Revman software version 5.4 was used for the analysis. Results: Thirteen studies were included with a total of 26891 subjects. Pooled analysis showed that anthracyclines therapy was significantly associated with a higher risk of arrhythmia (RR: 1.58; 95% CI: 1.41–1.76; P < .00001), ST segment and T wave abnormalities (RR: 1.73, 95% CI: 1.18–2.55, P = .005), conduction abnormalities and AV block (RR = 1.86, 95% CI = 1.06–3.25, P = .03), and tachycardia (RR: 1.736, 95% CI: 1.11–2.69, P = .02). Further analyses of the associations between anthracyclines and atrial flutter (RR = 1.30, 95% CI = 0.29–5.89, P = .74), atrial ectopic beats (RR: 1.27, 95% CI: 0.78–2.05, P = .34), and ventricular ectopic beats (RR: 0.93, 95% CI: 0.53–1.65, P = .81) showed no statistically significant results. Higher doses of anthracycline were associated with a higher risk of arrhythmias (RR: 1.49; 95% CI: 1.08–2.05; P = .02) compared to the lower doses (RR: 1.36; 95% CI: 1.00–1.85; P = .05). Newer generations of Anthracycline maintained the arrhythmogenic properties of previous generations, such as Doxorubicin. Conclusion: Anthracyclines therapy was significantly associated with an increased risk of arrhythmias. Accordingly, Patients treated with anthracyclines should be screened for ECG abnormalities and these drugs should be avoided in patients susceptible to arrhythmia. The potential benefit of the administration of prophylactic anti-fibrotic and anti-arrhythmic drugs should also be explored.

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Anthracycline-Induced Atrial Structural and Electrical Remodeling Characterizes Early Cardiotoxicity and Contributes to Atrial Conductive Instability and Dysfunction

Cited by 13 publications

References 62 publications

Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline‐induced cardiotoxicity

Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis

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