Main Risk Factor in Long-Term Postoperative Aortic Root Enlargement After Aortic Valve Surgery Associated with Ascending Aorta Replacement.

AIM: Dilatation of the aortic root (AR) after aortic valve surgery associated with ascending aorta replacement (AVS+AAR) is an important concern in long-term follow-up (FU). This study aimed to identify factors that may be associated with this late complication. MATERIAL AND METHODS: Two-hundred-sixteen consecutive patients (150 males and 66 females) who underwent AVS+AAR from June 2009 to April 2018 at a single center were retrospectively analyzed. The mean trans-thoracic echocardiographic (TTE) FU was 44.9 ± 22.2 months. An increase of 10% in AR size compared to the pre-operative baseline was the outcome variable. The Student t-test or chi-square test was used as appropriate. For a survival analysis, a Kaplan-Meier curve was computed and a log-rank p-value was calculated. Cox's regression model was used to assess the predictive value of variables over time. A p-value < 0.05 was significant. RESULTS: No significant differences were observed among patients who underwent aortic valve repair and those who underwent aortic valve replacement (log-rank = 0.917). In patients who underwent valve replacement, AR enlargement was associated with the difference between the diameter of the prosthetic valve and the diameter of the straight vascular prosthesis (OR 0.87, P = 0.024). Based on the difference in diameter between vascular and valve prosthesis, we arbitrarily classified the patients into two groups: a small group (S) (n = 52), in which the difference was ≤ 5 mm, and a large group (L) (n = 34), in which the difference was > 5 mm. Significant AR enlargement was observed in 30.8 % of the S group and 14.7 % of the L group (log-rank = 0.026). A difference of more than 5 mm between the aortic valve prosthesis and the vascular prosthesis protected against AR enlargement in the long-term FU (OR 12.31, P = 0.033), even after adjusting for age and sex (OR 00.32, P = 0.043). CONCLUSION: According to our findings, a difference between the size of the aortic valve prosthesis and the vascular prosthesis of less than or equal to 5 mm was the only factor that increased the risk of AR enlargement after AVS+AAR in long-term FU.

Low-Dose Anthracycline and Risk of Heart Failure in a Pharmacokinetic Model of Human Myocardium Exposure: Analog Specificity and Role of Secondary Alcohol Metabolites.

Cumulative doses of doxorubicin and other antitumor anthracyclines may cause heart failure (HF). Cardiotoxicity is determined by cardiac exposure to anthracyclines and to more toxic secondary alcohol metabolites that are formed inside cardiomyocytes or diffuse from the bloodstream. Concerns exist that HF might be caused by cumulative anthracycline doses that were thought to be safe. Patients with gain-of-function polymorphism of carbonyl reductase 3 (CBR3), which converts anthracyclines to secondary alcohol metabolites, would be at a higher risk of HF. Recently, a pharmacokinetic model was developed that simulated clinical exposure of human myocardium to anthracyclines and incorporated simulations of CBR3 polymorphism. It was shown that HF risk could occur after lower doxorubicin doses than previously reported, particularly for patients with CBR3 polymorphism. In this study, we show that also daunorubicin and idarubicin, but not epirubicin, might cause HF after reportedly safe cumulative doses. CBR3 polymorphism increased HF risk from daunorubicin and idarubicin to a greater extent as compared with doxorubicin. This was caused by daunorubicin and idarubicin forming higher levels of toxic metabolites in human myocardium; moreover, daunorubicin and idarubicin metabolites diffused from plasma and accumulated in cardiac tissue, whereas doxorubicin metabolite did not. CBR3 polymorphism did not aggravate HF risk from epirubicin, which was caused by the very low levels of formation of its toxic metabolite. These results support concerns about HF risk from low-dose anthracycline, characterize the analog specificity of HF risk, and illuminate the role of secondary alcohol metabolites.

Preoperative atorvastatin reduces bleeding and blood products use in patients undergoing on-pump coronary artery bypass grafting.

AIMS: Statins are a widely recognized weapon in the primary and secondary prevention of coronary artery disease for their pleiotropic effects. However, recent reports from the cerebrovascular and pharmacological literature are insinuating concerns about a potential increase in the haemorrhagic risk among statin users.The effect of statins in postoperative bleeding should be carefully investigated in major cardiac surgery that exposes per se to risk of bleeding. METHODS: In this retrospective cohort study, we evaluated 441 patients who received atorvastatin until surgery and 213 patients who had never been treated with statins, undergoing elective primary isolated on-pump coronary artery bypass grafting. Postoperative bleedings, blood products use and complications were monitored during hospitalization. RESULTS: Preoperative and intraoperative variables were similar between groups. Early and overall postoperative bleedings were reduced among statin users, who had lower C-reactive protein values in the first postoperative day. Atorvastatin carries a strong protective effect against major bleedings, with a propensity score-adjusted odds ratio of 0.28 (P < 0.01). Also, blood products use for statin-treated patients was lower compared with controls, with fewer transfused patients and fewer red-packed cells units per transfused patient. CONCLUSION: Preoperative atorvastatin use is associated with reduced risk of bleeding and blood products use after coronary artery bypass grafting, likely due to a reduction in the postoperative inflammatory response. Statin continuation at the highest tolerable dose should be encouraged before cardiac surgery. The preoperative use of statins in cardiac surgery as 'bleeding-preventers' might have profound clinical implications.

Modeling Human Myocardium Exposure to Doxorubicin Defines the Risk of Heart Failure from Low-Dose Doxorubicin.

The antitumor anthracycline, doxorubicin (DOX), can cause heart failure (HF) upon cumulative administration. Lowering the cumulative dose of DOX proved useful to minimize HF risk, and, yet, there is a growing concern that HF might occur after doses that were thought to be safe. Clinical trials that prospectively address such concerns are lacking. Because HF risk correlates with cardiac exposure to DOX, cumulative doses associated with HF risk were re-explored by modeling the accumulation of anthracycline pools in human myocardium. Ex vivo myocardial samples were used in vitro to simulate DOX rapid infusions. The accumulation of anthracycline pools was measured and incorporated into equations from which a risk versus dose curve was obtained. The experimental curve identified a 5% risk dose that was congruent with a previously reported clinical value (380 versus 400 mg/m2, respectively); however, 1-2% risk occurred after lower doses than reported. Simulations of gain-of-function polymorphism of carbonyl reductase 3, which converts DOX to its poorly diffusible alcohol metabolite, doxorubicinol (DOXOL), expanded anthracycline pools and caused 5% or 1-2% risk doses to decrease to 330 or 180-230 mg DOX/m2, respectively. These data show there is no safe dose of DOX. Diminishing cardiac exposure to circulating DOX may represent a cardioprotective strategy. We show that DOX slow infusions or liposomal DOX, which reduce cardiac exposure to DOX, caused formation of smaller anthracycline pools, did not generate DOXOL, increased the 5% risk dose to 750-800 mg/m2, and prevented HF risk aggravation by carbonyl reductase polymorphism.

Heart rate variability: a new tool to predict complications in adult cardiac surgery.

Heart rate variability (HRV) refers to the variations between consecutive heartbeats, which depend on the continuous modulation of the sympathetic and parasympathetic branches of the autonomic nervous system. HRV has been shown to be effective as a predictor of risk after myocardial infarction and an early warning sign of diabetic neuropathy, and in the cardiology setting is now recognized to be a useful tool for risk-stratification after hospital admission and after discharge. Recent evidences suggest that HRV analysis might predict complications even in patients undergoing cardiac surgery, and the present review summarizes the importance of HRV analysis in adult cardiac surgery and the perspectives for HRV use in current clinical practice. Although future larger studies are warranted before HRV can be included into daily clinical practice in adult cardiac surgery, HRV is a novel tool which might detect autonomic instability in the early postoperative phase and during hospital stay, thus predicting or prompt-diagnosing many of the post-operative complications.

Papillary Muscle Approximation Versus Restrictive Annuloplasty Alone for Severe Ischemic Mitral Regurgitation.

BACKGROUND: Guidelines recommend surgery for patients with severe ischemic mitral regurgitation (MR). Nonrandomized studies suggest that subvalvular repair is associated with longer survival, but randomized studies are lacking. OBJECTIVES: This study sought to investigate the benefit of papillary muscle surgery on long-term clinical outcomes of patients with ischemic MR. METHODS: Ninety-six patients with severe ischemic MR were randomized to either undersizing restrictive mitral annuloplasty (RA) or papillary muscle approximation with undersizing restrictive mitral annuloplasty (PMA) associated with complete surgical myocardial revascularization. The primary endpoint was change in left ventricular end-diastolic diameter (LVEDD) after 5 years, measured as the absolute difference from baseline, which was evaluated by paired Student t tests. Secondary endpoints included changes in echocardiographic parameters, overall mortality, the composite cardiac endpoint (major adverse cardiac and cerebrovascular events [MACCE]), and quality of life (QOL) during the 5-year follow-up. RESULTS: At 5 years, mean LVEDD was 56.5 ± 5.7 mm with PMA versus 60.6 ± 4.6 mm with RA (mean change from baseline -5.8 ± 4.1 mm and -0.2 ± 2.3 mm, respectively; p < 0.001). Ejection fraction was 44.1 ± 6% in the PMA group versus 39.9 ± 3.9% in the RA group (mean change from baseline 8.8 ± 5.9% and 2.5 ± 4.3%, respectively; p < 0.001). There was no statistically significant difference in mortality at 5 years, but freedom from MACCE favored PMA in the last year of follow-up. PMA significantly reduced tenting height, tenting area, and interpapillary distance soon after surgery and for the long-term, and significantly lowered moderate-to-severe MR recurrence. No differences were found in QOL measures. CONCLUSIONS: Compared with RA only, PMA exerted a long-term beneficial effect on left ventricular remodeling and more effectively restored the mitral valve geometric configuration in ischemic MR, which improved long-term cardiac outcomes, but did not produce differences in overall mortality and QOL.

The concomitant management of cancer therapy and cardiac therapy.

Antitumor drugs have long been known to introduce a measurable risk of cardiovascular events. Cardio-Oncology is the discipline that builds on collaboration between cardiologists and oncologists and aims at screening, preventing or minimizing such a risk. Overt concern about "possible" cardiovascular toxicity might expose cancer patients to the risk of tumor undertreatment and poor oncologic outcome. Careful analysis of risk:benefit balance is therefore central to the management of patients exposed to potentially cardiotoxic drugs. Concomitant or sequential management of cardiac and cancer therapies should also be tailored to the following strengths and weaknesses: i) molecular mechanisms and clinical correlates of cardiotoxicity have been characterized to some extent for anthracyclines but not for other chemotherapeutics or new generation "targeted" drugs, ii) anthracyclines and targeted drugs cause different mechanisms of cardiotoxicity (type I versus type II), and this classification should guide strategies of primary or secondary prevention, iii) with anthracyclines and nonanthracycline chemotherapeutics, cardiovascular events may occur on treatment as well as years or decades after completing chemotherapy, iv) some patients may be predisposed to a higher risk of cardiac events but there is a lack of prospective studies that characterized optimal genetic tests and pharmacologic measures to minimize excess risk, v) clinical toxicity may be preceded by asymptomatic systolic and/or diastolic dysfunction that necessitates innovative mechanism-based pharmacologic treatment, and vi) patient-tailored pharmacologic correction of comorbidities is important for both primary and secondary prevention. Active collaboration of physicians with laboratory scientists is much needed for improving management of cardiovascular sequelae of antitumor therapy. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Staged transthoracic approach to persistent atrial fibrillation (TOP-AF): study protocol for a randomized trial.

BACKGROUND: Persistent atrial fibrillation frequently shows multiple different electrophysiological mechanisms of induction. This heterogeneity causes a low success rate of single procedures of ablation and a high incidence of recurrence. Surgical ablation through bilateral thoracotomy demonstrates better results after a single procedure. Prospective observational studies in inhomogeneous populations without control groups report a remarkable 90% of success with hybrid or staged procedures of surgical ablation coupled with catheter ablation. In this trial, we will examine the hypothesis that a staged approach involving initial minimally invasive surgical ablation of persistent atrial fibrillation, followed by a second percutaneous procedure in case of recurrence, has a higher success rate than repeated percutaneous procedures. METHODS/DESIGN: This is a controlled (2:1) randomized trial comparing use of a percutaneous catheter with minimally invasive transthoracic surgical ablation of persistent atrial fibrillation. The inclusion and exclusion criteria, definitions, and treatment protocols are those reported by the 2012 Expert Consensus Statement on catheter and surgical ablation of atrial fibrillation. Patients will be randomized to either percutaneous catheter (n = 100) or surgical (n = 50) ablation as the first procedure. After 3 months, they are re-evaluated, according to the same guidelines, and receive a second procedure if necessary. Crossover will be allowed and data analyzed on an "intention-to-treat" basis. Primary outcomes are the incidence of sinus rhythm at 6 and 12 months and the proportions of patients requiring a second procedure. DISCUSSION: The use of a staged strategy combining surgical and percutaneous approaches might be more favorable in treatment of persistent atrial fibrillation than the controversial single percutaneous ablation. TRIAL REGISTRATION: ISRCTN08035058 Reg 06.20.2013.

Long-term results of an open flexible prosthetic band for mitral insufficiency.

BACKGROUND: use of a prosthetic ring is an integral part of any mitral valve repair and can influence the long-term stability of the results. We evaluated the long-term results of the AnnuloFlex ring implanted as an open flexible band in patients affected by degenerative mitral disease. METHODS: between 2001 and 2010, 82 patients (52 women, 30 men) with a mean age of 62 years, underwent repair of a prolapsing mitral valve with an AnnuloFlex band. One patient was reoperated on for a technical error and received a mechanical prosthesis, 3 were missing at follow-up, and the other 78 were prospectively followed up with clinical interviews and transthoracic echocardiography. RESULTS: the mean follow-up was 7.0 ± 1.8 years. Six patients died; 2 deaths were considered valve-related. The overall survival estimate at 10 years was 88.6% (95% confidence interval: 76.1%-94.8%). Freedom from endocarditis was 97.1% (95% confidence interval: 89.1%-98.5%). Freedom from thrombosis or hemorrhage was 93.7% (95% confidence interval: 81.6%-97.9%). Freedom from new or increased regurgitation was 93.1% (95% confidence interval: 87.3%-97.3%). The cumulative freedom from any valve-related event was 78.6% (95% confidence interval: 69.7%-97.1%). A single case of systolic anterior motion occurred before hospital discharge. CONCLUSION: the long-term results of the AnnuloFlex band are excellent and stable.

Atrial natriuretic peptide property on the ischemic myocardium inducing HSP72.

BACKGROUND: The purpose of this study was to investigate the effectiveness of atrial natriuretic peptide on ischemic myocardium through the induction of heat-shock protein 72. METHODS: 30 isolated rabbit hearts perfused on isolated heart apparatus were randomly assigned to receive either warm Krebs-Henseleit solution with 1 µmol L(-1) atrial natriuretic peptide (n = 15) or warm Krebs-Henseleit solution without atrial natriuretic peptide (n = 15) in preischemic, ischemic, and postischemic conditions. In all rabbit hearts, global ischemia was produced by clamping the aortic and atrial inflow lines. Concentrations of atrial natriuretic peptide were measured in hearts with left ventricular dysfunction following ischemia, and correlated with the hypertrophic growth sustained by overexpression of heat-shock protein 72 microRNA-133. RESULTS: The levels of atrial natriuretic peptide were markedly higher in the group that received atrial natriuretic peptide, and strongly correlated with both band lengths of heat-shock protein 72 and overexpression of microRNA-133 in the hypertrophic myocyte. CONCLUSIONS: Perfusion levels of atrial natriuretic peptide induce increased expression of heat-shock protein 72 microRNA-133 in dysfunctional left ventricle.

Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by Advanced glycation endproducts.

BACKGROUND: Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage. METHODS: Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 µM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed. RESULTS: Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage. CONCLUSIONS: Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes.

Usefulness of preprocedural levels of advanced glycation end products to predict restenosis in patients with controlled diabetes mellitus undergoing drug-eluting stent implantation for stable angina pectoris (from the Prospective ARMYDA-AGEs Study).

Diabetes mellitus (DM) remains the main predictor of restenosis rates and cardiovascular events following successful percutaneous coronary intervention (PCI) despite the use of drug-eluting stents (DES). HbA1c <6.0% is considered an index of optimized metabolic control in patients with DM, but several studies are downsizing its role in the clinical management of these patients. Increasing evidence points at the role of advanced glycation end products (AGEs) in restenosis pathogenesis independently on Hb1AC levels. Thus, we investigated the predictive value of preprocedural AGE levels for in-stent restenosis in a population of euglycaemic diabetic patients undergoing PCI with DES implantation. One hundred twenty-five consecutive patients with DM in optimized glycemic control admitted for stable angina pectoris and treated with elective DES implantation at a tertiary hospital were prospectively included. The primary end point of the ARMYDA-AGEs study was to compare rates of angiographic ISR at 6 months after the intervention according to pre-PCI levels of AGEs. Secondary end points were the correlations of AGE levels with occurrence of periprocedural myocardial damage, major adverse cardiac events, and in-stent late loss at 6-month control coronary angiography. AGE levels >17 µM was found to be an independent predictor of ISR at 6 months and stent lumen loss. AGEs failed to predict occurrence of secondary endpoints. In conclusion, elevated AGE levels predict occurrence of in-stent restenosis after DES implantation in patients with DM on optimized glycemic control and might represent a dosable marker of adverse outcome after PCI.

In situ electrostimulation drives a regenerative shift in the zone of infarcted myocardium.

Electrostimulation represents a well-known trophic factor for different tissues. In vitro electrostimulation of non-stem and stem cells induces myogenic predifferentiation and may be a powerful tool to generate cells with the capacity to respond to local areas of injury. We evaluated the effects of in vivo electrostimulation on infarcted myocardium using a miniaturized multiparameter implantable stimulator in rats. Parameters of electrostimulation were organized to avoid a direct driving or pacing of native heart rhythm. Electrical stimuli were delivered for 14 days across the scar site. In situ electrostimulation used as a cell-free, cytokine-free stimulation system, improved myocardial function, and increased angiogenesis through endothelial progenitor cell migration and production of vascular endothelial growth factor (VEGF). In situ electrostimulation represents a novel means to stimulate repair of the heart and other organs, as well as to precondition tissues for treatment with cell-based therapies.

The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients.

Cardiotoxicity from the antitumor anthracycline doxorubicin correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O(2)(.-)) and hydrogen peroxide (H(2)O(2)), and formation of the long-lived secondary alcohol metabolite doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non-Hodgkin lymphoma was observed with the novel anthracenedione pixantrone. We characterized whether pixantrone and mitoxantrone caused different effects on doxorubicin levels, redox activation, and doxorubicinol formation. Pixantrone and mitoxantrone were probed in a validated ex vivo human myocardial strip model that was either doxorubicin-naïve or preliminarily subjected to doxorubicin loading and washouts to mimic doxorubicin treatment and elimination in the clinical setting. In doxorubicin-naïve strips, pixantrone showed higher uptake than mitoxantrone; however, neither drug formed O(2)(.-) or H(2)O(2). In doxorubicin-pretreated strips, neither pixantrone nor mitoxantrone altered the distribution and clearance of residual doxorubicin. Mitoxantrone showed an unchanged uptake and lacked effects on doxorubicin levels, but synergized with doxorubicin to form more O(2)(.-) and H(2)O(2), as evidenced by O(2)(.-)-dependent inactivation of mitochondrial aconitase or mitoxantrone oxidation by H(2)O(2)-activated peroxidases. In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might also be safe in doxorubicin-naïve patients.

Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. I. Amrubicin accumulates to a lower level than doxorubicin or epirubicin.

Antitumor anthracyclines such as doxorubicin and epirubicin are known to cause cardiotoxicity that correlates with anthracycline accumulation in the heart. The anthracycline amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-ß-d-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] has not shown cardiotoxicity in laboratory animals or patients in approved or investigational settings; therefore, we conducted preclinical work to characterize whether amrubicin attained lower levels than doxorubicin or epirubicin in the heart. Anthracyclines were evaluated in ex vivo human myocardial strips incubated in plasma to which anthracycline concentrations of 3 or 10 µM were added. Four-hour incubations were performed to characterize myocardial anthracycline accumulation derived from anthracycline uptake in equilibrium with anthracycline clearance. Short-term incubations followed by multiple washouts were performed to obtain independent measurements of anthracycline uptake or clearance. In comparison with doxorubicin or epirubicin, amrubicin attained very low levels in the soluble and membrane fractions of human myocardial strips. This occurred at both 3 and 10 µM anthracycline concentrations and was caused primarily by a highly favorable clearance of amrubicin. Amrubicin clearance was facilitated by formation and elimination of sizeable levels of 9-deaminoamrubicin and 9-deaminoamrubicinol. Amrubicin clearance was not mediated by P glycoprotein or other drug efflux pumps, as judged from the lack of effect of verapamil on the partitioning of amrubicin and its deaminated metabolites across myocardial strips and plasma. Limited accumulation of amrubicin in an ex vivo human myocardial strip model may therefore correlate with the improved cardiac tolerability observed with the use of amrubicin in preclinical or clinical settings.

Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin.

Anthracycline-related cardiotoxicity correlates with cardiac anthracycline accumulation and bioactivation to secondary alcohol metabolites or reactive oxygen species (ROS), such as superoxide anion (O2·â») and hydrogen peroxide H2O2). We reported that in an ex vivo human myocardial strip model, 3 or 10 µM amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-ß-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] accumulated to a lower level compared with equimolar doxorubicin or epirubicin (J Pharmacol Exp Ther 341:464-473, 2012). We have characterized how amrubicin converted to ROS or secondary alcohol metabolite in comparison with doxorubicin (that formed both toxic species) or epirubicin (that lacked ROS formation and showed an impaired conversion to alcohol metabolite). Amrubicin and doxorubicin partitioned to mitochondria and caused similar elevations of H2O2, but the mechanisms of H2O2 formation were different. Amrubicin produced H2O2 by enzymatic reduction-oxidation of its quinone moiety, whereas doxorubicin acted by inducing mitochondrial uncoupling. Moreover, mitochondrial aconitase assays showed that 3 µM amrubicin caused an O2·â»-dependent reversible inactivation, whereas doxorubicin always caused an irreversible inactivation. Low concentrations of amrubicin therefore proved similar to epirubicin in sparing mitochondrial aconitase from irreversible inactivation. The soluble fraction of human myocardial strips converted doxorubicin and epirubicin to secondary alcohol metabolites that irreversibly inactivated cytoplasmic aconitase; in contrast, strips exposed to amrubicin failed to generate its secondary alcohol metabolite, amrubicinol, and only occasionally exhibited an irreversible inactivation of cytoplasmic aconitase. This was caused by competing pathways that favored formation and complete or near-to-complete elimination of 9-deaminoamrubicinol. These results characterize amrubicin metabolic advantages over doxorubicin and epirubicin, which may correlate with amrubicin cardiac safety in preclinical or clinical settings.

Anthracycline cardiotoxicity.

INTRODUCTION: Anthracyclines are widely prescribed anticancer agents that cause a dose-related cardiotoxicity, often aggravated by nonanthracycline chemotherapeutics or new generation targeted drugs. Anthracycline cardiotoxicity may occur anytime in the life of cancer survivors. Understanding the molecular mechanisms and clinical correlates of cardiotoxicity is necessary to improve the therapeutic index of anthracyclines or to identify active, but less cardiotoxic analogs. AREAS COVERED: The authors review the pharmacokinetic, pharmacodynamic and biochemical mechanisms of anthracycline cardiotoxicity and correlate them to clinical phenotypes of cardiac dysfunction. Attention is paid to bioactivation mechanisms that converted anthracyclines to reactive oxygen species (ROS) or long-lived secondary alcohol metabolites. Preclinical aspects and clinical implications of the "oxidative stress" or "secondary alcohol metabolite" hypotheses are discussed on the basis of literature that cuts across bench and evidence-based medicine. Interactions of anthracyclines with comorbidities or unfavorable lifestyle choices were identified as important cofactors of the lifetime risk of cardiotoxicity and as possible targets of preventative strategies. EXPERT OPINION: Anthracycline cardiotoxicity is a multifactorial process that needs to be incorporated in a translational framework, where individual genetic background, comorbidities, lifestyles and other drugs play an equally important role. Fears for cardiotoxicity should not discourage from using anthracyclines in many oncologic settings. Cardioprotective strategies are available and should be used more pragmatically in routine clinical practice.