Abstract Background Functional mitral regurgitation results from interacting mechanisms whose contributions vary between atrial and ventricular subtypes and shift within each heartbeat, producing temporal patterns static analyses cannot capture. Objectives To identify which structural determinants predict mitral regurgitation variability beat to beat using Granger causality within vector autoregression, focusing on papillary muscle dynamics across subtypes. Methods Frame-level echocardiographic time series from 41 patients (21 atrial, 20 ventricular; 1,959 frames) were z-score standardised within patient. Individual (lag 3) and pooled panel vector autoregression models, with supplementary full-cycle analysis across lags 1–20, tested whether LV volume, left atrial volume, papillary muscle length, and annulus diameter Granger-predict mitral regurgitation area. Results Individual models revealed marked heterogeneity. In pooled analysis, LV volume was the strongest Granger predictor at the shortest lag (atrial p=0.011; ventricular p=0.006), while left atrial volume reached significance at longer lags (lag 6 atrial p=0.033, ventricular p=0.004). Systolic papillary muscle length was not predictive at any lag. Full-cycle analysis revealed an asymmetric subtype dissociation: papillary muscle length Granger-predicted regurgitation only in the ventricular subtype (lag 1 p<0.001) whereas regurgitation predicted papillary muscle deformation at every lag in the atrial subtype (20/20) but at none in the ventricular subtype. Cross-sectional comparisons of the four determinants did not distinguish MR severity within subtypes. Conclusions Beat-to-beat vector autoregression and Granger modelling reveals heterogeneous, subtype-specific temporal patterns and a strong directional asymmetry between regurgitation and papillary muscle dynamics across subtypes. This disease-agnostic framework may support patient-specific temporal phenotyping of functional mitral regurgitation. Graphical Abstract

Background: Functional mitral regurgitation (FMR), both atrial (AFMR) and ventricular (VFMR), results from multiple interacting mechanisms including atrial and ventricular remodeling, changes in mitral annular geometry, leaflet tethering, and heart rate variability. The relative contribution of each factor to FMR severity remains unclear. Purpose: We aimed to assess the short-term effect of a one-time change (shock) in each FMR determinant on the evolution of MR severity and other variables. Additionally, we quantified how much of the variance in MR severity is explained by shocks to its known etiological factors. Methods: Transthoracic echocardiography was used to evaluate FMR in 26 patients, yielding 810 systolic timestamps (583 for the AFMR group and 227 for the VFMR group, 30 fps). For each frame, we recorded RR interval, MR jet area, LA and LV volumes, MV annular diameter, and tenting height. We estimated vector autoregression (VAR) models separately in AFMR and VFMR groups, followed by Forecast Error Variance Decomposition (FEVD) up to step 8 (~264 msec). The FEVD at step 8 quantified the percent of MR variance attributable to each variable. To assess statistical significance, we repeated VARs for each variable pair and visually evaluated impulse response function (IRF) plots: a variable was considered significant if its IRF 95% CI excluded 0. Results: FEVD revealed high self-persistence: most variables primarily explained their own future values. LV volume emerged as a key upstream influencer across the network, while MR area had limited predictive power (Figure 1A, C). In AFMR, MR area was largely self-driven (92.7%) with modest contributions from LV volume (3.2%) and tenting height (2.4%) (Figure 1B). IRF plots showed that only MR area, LA volume, and LV volume had statistically significant effects on MR area (Figure 2). In VFMR, MR area remained self-driven (83.9%), but external contributions were stronger: RR (6.3%), tenting height (3.6%), and MV annulus (3.1%) (Figure 1D). Only MR area, tenting height, and LV volume showed significant IRF effects (Figure 3). Conclusions: In AFMR, short-term MR variability appears driven by LA and LV volume, though LV volume shows a stronger effect, possibly due to transient ventricular changes being more detectable than slow atrial remodeling. In VFMR, MR variability is shaped primarily by tenting height and LV volume, reinforcing the role of subvalvular tethering and dynamic loading in VFMR pathophysiology.

Background: Reduction in R-wave amplitude in lead aVL (RaVL) is often noted after cardiac resynchronization therapy (CRT), together with a shorter QRS duration and reduced mitral regurgitation (MR). Given that lead aVL reflects electrical activity in the anterolateral left ventricular wall, where the anterolateral papillary muscle (PM) resides, opposing the posteromedial one, we hypothesized that these electrocardiographic changes may reflect improved electrical resynchronization of the PMs, contributing to MR reduction. Objective: This study aimed to evaluate the relationship between post-CRT changes in RaVL and MR severity and assess whether RaVL can serve as a surface electrocardiographic marker of PM dyssynchrony and a predictor of clinical response and long-term survival. Methods: We analyzed 231 patients who underwent CRT implantation and were followed for a median of 41 months (interquartile range 29–55); 88 patients died during this period. Results: Baseline RaVL correlated with QRS duration (r = 0.20, P = .0018) and aVL–aVF intrinsicoid deflection difference (r = 0.36, P < .0001), supporting its role as a marker of electrical dyssynchrony. RaVL significantly decreased after CRT (0.66 ± 0.42 mV to 0.41 ± 0.41 mV, P < .0001) and independently predicted MR response in multivariable logistic regression. Patients who experienced a reduction in RaVL or a decrease in QRS duration after CRT had significantly better survival than those whose corresponding parameters remained unchanged or increased. Both variables independently predicted survival in multivariable Cox regression. Conclusion: A decrease in RaVL after CRT predicts MR improvement and survival, likely reflecting improved PM synchronization and mechanical resynchronization.

Background/Objectives: The complement system (particularly C5b-9) is an instrumental part of the induction and progression of atherosclerosis. The fluid phase C5b-9, also known as soluble C5b-9 (sC5b-9), is a reliable indicator of terminal complement pathway activation. Response Gene to Complement (RGC)-32 is a C5b-9 effector involved in cell cycle regulation and differentiation, immunity, tumorigenesis, obesity, and vascular lesion formation. RGC-32 regulates the expression of Sirtuin1 (SIRT1), known to delay vascular aging. The aim of this study was to assess the levels of sC5b-9, RGC-32, and SIRT1 in patients with atherosclerotic chronic and acute ischemic coronary syndromes. Methods: We determined the levels of sC5b-9, serum RGC-32, and SIRT1 by enzyme-linked immunosorbent assays (ELISAs) in 41 patients with chronic atherosclerotic coronary syndromes, 36 patients with acute ischemic coronary syndromes, and 21 asymptomatic controls with no history of ischemic heart disease. Results: sC5b-9 was significantly higher in patients with acute coronary syndrome as compared to the control group (p = 0.020, AUC = 0.702). In chronic coronary ischemia patients, serum RGC-32 was correlated with the extension of coronagraphically visualized atherosclerotic lesions (r = 0.352, p = 0.035) as well as with sC5b-9 levels (r = 0.350, p = 0.025). RGC-32 concentration was significantly lower in patients with acute coronary syndrome than in the control group (p = 0.020). We also observed significantly lower serum SIRT1 concentrations in patients with chronic ischemic heart disease than in the control group (p = 0.025). Conclusions: sC5b-9 may function as a possible biomarker for myocardial tissue damage in acute coronary syndrome. In acute coronary syndrome settings, low levels of RGC-32 may indicate a protective, antifibrotic function of RGC-32 in the ischemia-damaged myocardium; however, in stable chronic disease, RGC-32 serum values appear to correlate with the extent of atherosclerotic lesions, suggesting a pro-atherogenic role for RGC-32. Chronic myocardial ischemia decreases SIRT1 protein levels in serum, which underscores the use of SIRT1-modulating drugs in these patients.

This review aims to synthesize current knowledge on the angiographic anatomy of the coronary sinus and its tributaries veins, with focus on venous branches other than classical ones used in cardiac resynchronization therapy. It also presents common anatomical aspects that could impact the clinical outcome. Recent advancements in the electrophysiology field, like epicardial arrhythmia mapping and ablation through coronary sinus or cardiac pacing from atypical veins requires a detailed angiographic assessment of cardiac veins. There is an increased interest for the veins coursing in the left ventricular summit (LVS) area and could potentially provide a pathway to reach the LVS arrhythmogenic foci. However, there is no consensus regarding the nomenclature and classification of these veins. This review could offer a better understanding of the coronary sinus and its tributary veins distribution, dimensions and relationship with nearby structures that could help the development of new ablation and pacing tools and strategies, with higher success rates.

Abstract Introduction Intracardiac echocardiography (ICE) is frequently performed during catheter ablation procedures in order to guide the transseptal puncture and has been recently used to evaluate the morphology of the LAA. Purpose The objective of this study was to evaluate the feasibility of using an ICE catheter placed in the coronary sinus (CS) to delineate the LAA function during catheter ablation for atrial fibrillation. Methods We included 21 consecutive patients (age 62±9 years, 5 women, 6 paroxysmal AF) who underwent catheter ablation for AF. An 8-Fr phased-array ICE catheter was used to obtain images of the LAA, while in sinus rhythm. The LAA was visualized with the ICE probe placed sequentially in the left atrium (LA, Figure A), with the ultrasound section plane parallel to the long axis of the left ventricle (LV), and in the CS, with the ultrasound section plane perpendicular to the LV long axis (Figure B). LAA emptying flow velocity, and LAA fractional area change (FAC) were used to evaluate LAA function. There were no procedural complications. Results ICE imaging was possible in all cases. The LAA peak flow velocity was similar when the ICE catheter was placed in the LA and in the CS (64±7 cm/s and 62±5cm/s respectively, P=NS). The LAA FAC was significantly lower when the ICE catheter was placed in the CS when compared to an LA location (14±6% vs 36±14%; P<0.001). The LAA FAC measured from the LA correlated with the mitral annular plane systolic excursion while the LAA FAC measured from the CS did not. Thus, LAA contraction in a plane perpendicular to the LV long axis is independent of the LV longitudinal contraction. These results suggest that in our patient group most of the LAA contraction was due to the longitudinal movement of the LV base during systole and diastole. Conclusions Imaging of LAA using an ICE probe positioned in the LA and CS was feasible in all cases. The LV longitudinal contraction appears to impact the LAA function.

Doxorubicin (DOX) is an effective anticancer drug, but its use is limited by dose-dependent heart toxicity. Quercetin is a natural antioxidant frequently studied for its beneficial properties. Moreover, a wide range of dietary supplements are available for human use. This in vivo study aimed to explore the potential cardioprotective effects of quercetin in chronic DOX treatment. A total of 32 Wistar rats were randomly divided into four groups: control, DOX, DOX/Q-50, and DOX/Q-100, treated with saline, 2.5 mg/kg body-weight DOX, 2.5 mg/kg body-weight DOX + 50 mg quercetin, and 2.5 mg/kg body-weight DOX + 100 mg quercetin, respectively, for two weeks. Rats were monitored using cardiac ultrasound (US) and markers for cardiac injury. Oxidative damage and ultrastructural changes in the heart were investigated. Chronic DOX treatment led to a decline in cardiac function and elevated values of NT pro-BNP, troponin I, and CK-MB. Quercetin treatment slightly improved certain US parameters, and normalized serum NT pro-BNP levels. Furthermore, DOX-induced SOD1 depletion with consequent Nrf2 activation and DNA damage as shown by an increase in γH2AX and 8HOdG. Quercetin treatment alleviated these alterations. Oral administration of quercetin alleviated serum markers associated with DOX-induced cardiotoxicity. Furthermore, it exhibited a favorable impact on the cardiac US parameters. This suggests that quercetin may have potential cardioprotective properties.

Background: Achieving bidirectional mitral isthmus block is still challenging. Conventional ablation methods involve radiofrequency applications on the endocardial aspect of the lateral mitral isthmus, and often epicardial applications inside the coronary sinus. Aim: To evaluate the impact of the systematic use of ethanol infusion in the vein of Marshall on the achievement of acute mitral isthmus block of additional epicardial component lesion. Methods: We evaluated patients referred to two centres for long-standing persistent atrial fibrillation ablation or recurrent peri-mitral flutter. All patients had pulmonary vein isolation and mitral isthmus line using ethanol infusion in the vein of Marshall for the first procedure and additional radiofrequency ablation lesion if necessary. For redo procedures, additional ablations (atrial lines and complex fractionated atrial electrogram ablations, if needed) were also performed. Results: We included 149 patients, and ethanol infusion in the vein of Marshall was not performed in 27 patients (18%). Among 122 patients, 115 had long-standing persistent atrial fibrillation (94.2%) and seven had peri-mitral flutter (5.8%). The mean duration of continuous atrial fibrillation was 53 months before ablation. Acute bidirectional mitral isthmus block was obtained in 115 (94.2%) of the 122 patients who received ethanol infusion in the vein of Marshall (77% when considering the total population). The mean radiofrequency delivery time to obtain mitral isthmus block was 2.6 minutes for the endocardial mitral isthmus radiofrequency ablation and 2.6 minutes for the epicardial mitral isthmus radiofrequency ablation. Failure to obtain mitral isthmus block was associated with increased mitral isthmus length and left atrial dilation. No major complications related to ethanol infusion in the vein of Marshall were observed. Conclusion: Ethanol infusion in the vein of Marshall, when feasible (82%), was a safe approach to obtaining a high success rate (94%) of acute bidirectional endocardial and epicardial mitral isthmus block. (c) 2023 Elsevier Masson SAS. All rights reserved.

Background: Papillary muscles are structures integrated into the mitral valve apparatus, having both electrical and mechanical roles. The importance of the papillary muscles (PM) is mainly related to cardiac arrhythmias and mitral regurgitation. The aim of this review is to offer an overview of the anatomy and physiology of the papillary muscles, along with their involvement in cardiovascular pathologies, including arrhythmia development in various conditions and their contribution to secondary mitral regurgitation. Methods: A literature search was performed on PubMed using the following relevant keywords: papillary muscles, mitral valve, arrhythmia, anatomy, and physiology. Results: During the cardiac cycle, papillary muscles have continuous dimensional and pressure changes. On one hand, their synchrony or dyssynchrony impacts the process of mitral valve opening and closure, and on the other hand, the pressure changes can trigger electrical instability. There is increased awareness of papillary muscles as an arrhythmic source. Arrhythmias arising from PM were found in patients with or without structural heart disease, via Purkinje fibres, due to increased automaticity or triggered activity. Conclusions: Despite the interest in mitral valve physiology, there are still many unknowns in relation to the papillary muscles, especially with regard to their role in arrhythmogenesis and the pathogenesis of mitral regurgitation.

Gold nanoparticles (Au-NPs) have been explored as potential vectors for enhancing the antitumor efficacy of doxorubicin (DOX) while minimizing its cardiotoxic effects. However, the impacts of DOX Au-NPs on cardiac function and oxidative stress remain inadequately understood. This study aimed to explore the effects of DOX Au-NPs in comparison to free DOX, focusing on oxidative stress markers, inflammation, ultrastructural changes, and cardiac function. Male rats were divided into the following four groups: control, citrate Au-NPs, DOX, and DOX Au-NPs. Cardiac function was assessed using echocardiography, and oxidative stress was evaluated through Nrf2, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, and the GSH/GSSG ratio. The ultrastructure of cardiac tissue was assessed by transmission electron microscopy (TEM). Rats treated with DOX Au-NPs exhibited significant cardiac dysfunction, as indicated by a reduction in fractional shortening and ejection fraction. Oxidative stress markers, including elevated MDA levels and a reduced GSH/GSSG ratio, were significantly worse in the DOX Au-NP group. SOD levels decreased, indicating compromised antioxidant defenses. Citrate Au-NPs also caused some alterations in cardiac function and ultrastructure but without other molecular alterations. DOX Au-NPs failed to mitigate cardiotoxicity, instead exacerbating oxidative stress and cardiac dysfunction. DOX Au-NPs possess cardiotoxic effects, necessitating further investigation into alternative nanoparticle formulations or therapeutic combinations to ensure both efficacy and safety in cancer treatment.

Reflex syncope (RS) is the most prevalent form of syncope, yet its pathophysiology and clinical presentation are not well understood. Despite controversy, the ‘ventricular theory’ remains the most plausible hypothesis to explain RS in susceptible patients. Certain assumptions regarding the geometry and function of the heart are essential in supporting this theory. Given these considerations, the goal of this review was to try to integrate data on heart morphology and function in a phenotype of a patient susceptible to RS. Previous research suggests that a small left ventricle and atria, in addition to a normo- or hypercontractile myocardium, predispose to more syncopal events. These findings have been confirmed in different subsets of patients, including those with small heart and chronic fatigue syndrome, highlighting common pathophysiologic pathways in these subgroups of population. Heart geometry and function seem to play a role in different treatment strategies for RS patients, including the administration of medications, pacing, and possibly cardioneural ablation. In addition, parameters related to the geometry of the heart chambers and of the electrical activation of the heart seem to have predictive value for syncope recurrence. These parameters could be included in the future and improve the accuracy of predictive models for RS.

Abstract Background Right ventricular (RV) dysfunction is an important predictor of survival in patients with heart failure (HF) with both preserved (HFpEF) and reduced ejection fraction (HFrEF). To date there is limited data on the value of the electrocardiogram in predicting RV function. Purpose Given these considerations the aim of our study was to assess the possible relationship between several electrocardiographic (ECG) parameters and right ventricular function evaluated by echocardiography. Methods We included 109 patients (age 61±14 years, 68men) of whom 89 had HF (HFpEF N=62 and HFrEF N=27) and 20 patients without HF. Twelve-lead ECG and echocardiograms were performed in all patients. We assessed echocardiographic parameters of global and regional RV function. Results Time to Intrinsicoid deflection in lead V1 (TID-V1) and the QTc interval measured in lead V1 (QTc-V1) were significantly more prolonged in patients with HF vs. patients with no HF (36±24ms vs. 23±15ms; p=0.03, and 450±40ms vs. 427±20ms; p=0.047 respectively). TID-V1 correlated significantly with the tricuspid annulus systolic excursion (TAPSE) and RV fractional area change (FAC; r=-0.31; p=0.02, and r=-0.35; p=0.029 respectively). QTc-V1 correlated with parameters of global and regional RV function including FAC, RV apex longitudinal strain, RV free wall strain, and global RV strain (r=-0.42; p=0.0004, r=0.35; p=0.0032, r=0.21; p=0.045, and r=0.41; p=0.0005). RV dysfunction as defined by RV-FAC<35% was predicted by TID-V1 > 30ms with a sensitivity of 61% and specificity of 75%; AUC=0.752 and by QTc-V1>440ms with a sensitivity of 80% and specificity of 57%; AUC=0.888, and by a multivariate logistic regression model that also included TID-V1 and QTcV1, age, TAPSE, and LV ejection fraction with an AUC=0.967 (Figure). Conclusions Lead V1 time to intrinsic deflection and QTc-V1 predict RV dysfunction independent of echocardiographic parameters of ventricular function in patients with HF.

Abstract Background The size and distribution of the coronary veins (CV) reflect both intracavitary pressure and myocardial blood flow, and therefore, in patients with cardiomyopathy, CV anatomy could potentially become a biomarker of disease severity. While the left coronary veins have been well described, there are few descriptions of the right CV system. Purpose Given these considerations, the aim of the study was to evaluate the anatomy of the right CV system and its potential prognostic significance in patients with advanced cardiomyopathy. Methods We analyzed CV angiograms from 121 patients (age 67±14 years) undergoing cardiac resynchronization therapy (CRT). The right ventricular (RV) veins were seen to fill during the injection of contrast through multiple connections with the left sided venous system. Patients were followed for a median of 43 [IQR 3-73] months, during which 12 patients expired. Results Anterior cardiac veins (ACV), which overlay the RV wall were observed in 85 (70%) patients and had a maximum ostial diameter of 2.04±0.8 mm. Multiple ACVs were seen in 62 patients. These veins were observed to empty directly into the venous sinus of right atrium (VSRA), into the RV, the right atrium (RA), or into the small cardiac vein (SCV) in 68, 9, 5, and 3 patients respectively. The right marginal vein (RMV) was visualized in 21 (17%) patients, had a diameter of 2.3±1.2 mm, and ran a course along the right border of the RV, emptying directly into RV, RA or into VSRA in 9, 4 and 8 patients respectively. The VSRA present in 91 (75%) patients, coursed parallel to the right coronary sulcus, collecting blood from the ACV’s and RMV’s and drained into the RA (Figure A); in 7 patients, 2 VSRA ostia were noted. VSRA lengths and diameters varied (11-119 mm, mean 41±25 mm) and (1.2-6.9mm, mean 2.7±1.2mm) respectively. The VSRA lengths correlated significantly with RV fractional area change, RV systolic pressure, tricuspid regurgitation severity evaluated by echocardiography, and P wave amplitude in ECG lead II (r=-0.65; p=0.041, r=0.88; p=0.019, r=0.52; p=0.030, and r=0.79; p=0.031 respectively). The VSRA diameters, which were significantly larger in patients with obstructive sleep apnea (3.6±1.5 vs. 2.3±1.2mm; p=0.021) correlated significantly with RV systolic pressure, and tricuspid regurgitation severity by echocardiography (r=0.77; p=0.009, and r=0.63; p=0.006 respectively). Patients who expired during follow-up had a significantly longer VSRA than patients who remained alive (Figure B). The VSRA length, RV fractional area change, and baseline QRS duration independently predicted survival in a Cox multivariate model that also included age and left ventricular ejection fraction. Conclusions RV venous system demonstrates a highly variable anatomy that has not been previously well described. The size of the VSRA correlated with parameters of RV function and predicted survival in patients undergoing CRT.Figure

Heart failure is a clinical syndrome associated with poor quality of life, substantial healthcare resource utilization, and premature mortality, in large part related to high rates of hospitalizations. The clinical manifestations of heart failure are similar regardless of the ejection fraction. Unlike heart failure with reduced ejection fraction, there are few therapeutic options for treating heart failure with preserved ejection fraction. Molecular therapies that have shown reduced mortality and morbidity in heart failure with reduced ejection have not been proven to be effective for patients with heart failure and preserved ejection fraction. The study of pathophysiological processes involved in the production of heart failure with preserved ejection fraction is the basis for identifying new therapeutic means. In this narrative review, we intend to synthesize the existing therapeutic means, but also those under research (metabolic and microRNA therapy) for the treatment of heart failure with preserved ejection fraction.

Background and Objectives: Dual antiplatelet therapy (DAPT) is essential in the treatment of patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the effectiveness of antiplatelet medication in our practice and to investigate the factors that influence it. Materials and Methods: A prospective cohort observational study was conducted, in which 193 patients with ACS were enrolled. The patients were stented in the catheterization laboratory between May 2019 and October 2020, before and during the COVID-19 pandemic, and were receiving DAPT. Their platelet functions were tested using a Multiplate Analyzer. In addition to this, clinical data, demographics, laboratory tests, and cardiovascular risk factors were also analyzed. Results: 43.46% of the patients treated with aspirin were found to be resistant to it. This phenomenon was more common in men (48.17% vs. 31.48%, p = 0.036), and it was associated with being under the age of 50 (OR: 2.08; 95% CI: 1.11–3.90) and weighing over 70 kg (OR: 3.00; 95% CI: 1.21–7.40). Most of the patients treated with clopidogrel were in the optimal treatment window, while about half of the patients treated with ticagrelor had an exaggerated pharmacological response. Among the laboratory parameters, leukocytosis and platelet count were found to be determinants of platelet reactivity for both the aspirin and ticagrelor treatments. Conclusions: Many patients treated with antiplatelet agents are outside of the treatment window. The results obtained showed that low doses of gastro-resistant aspirin tablets are ineffective, and their efficacy can be influenced by various clinical and laboratory factors. Patients receiving ticagrelor have significantly reduced platelet reactivity, influenced only by certain laboratory indicators. The pandemic significantly influenced the results of the platelet aggregation tests only in patients treated with clopidogrel.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.