Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

New Targeted Drugs for Acute Myeloid Leukemia and Antifungals: Pharmacokinetic Challenges and Opportunities.

BACKGROUND: Acute myeloid leukemia (AML) is a life-threatening disease whose treatment is made difficult by a number of mutations or receptor overexpression in the proliferating cellular clones. Life expectancy of patients diagnosed with new, relapsed-refractory, or secondary AML has been improved by drugs targeted at such moieties. Regrettably, however, clinical use of new AML drugs is complicated by pharmacokinetic interactions with other drugs the patient is exposed to. SUMMARY: The most relevant drug-drug interactions (DDI) with clinical implications build on competition for or induction/inhibition of CYP3A4, which is a versatile metabolizer of a plethora of pharmacological agents. Here, we review DDI between AML drugs and the agents used to prevent or treat invasive fungal infections (IFI). The pathophysiology of AML, characterized by functionally defective white blood cells and neutropenic/immunosuppressive effects of concomitant induction chemotherapy, can in fact increase the risk of infectious complications, with IFI causing high rates of morbidity and mortality. Triazole antifungals, such as posaconazole, are strong inhibitors of CYP3A4 and may thus cause patient's overexposure to AML drugs that are metabolized by CYP3A4. We describe potential strategies to minimize the consequences of DDI between triazole antifungals and targeted therapies for AML and the role that collaboration between clinical pharmacologists, hematologists, and clinical or laboratory microbiologists may have in these settings. KEY MESSAGES: Therapeutic drug monitoring and clinical pharmacology stewardship could represent two strategies that best express multidisciplinary collaboration for improving patient management.

Ibrutinib and Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Focus on Atrial Fibrillation and Ventricular Tachyarrhythmias/Sudden Cardiac Death.

BACKGROUND: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. In this review, we aimed to summarize and critically evaluate the association between first- and second-generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA). SUMMARY: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient's predisposing risk factors and concomitant cardiac morbidities. More recently, both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib, and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents. KEY MESSAGES: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK inhibitors.

Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Cardiac Anthracycline Accumulation and B-Type Natriuretic Peptide to Define Risk and Predictors of Cancer Treatment-Related Early Diastolic Dysfunction.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT: DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.

Predictors of Early or Delayed Diastolic Dysfunction After Anthracycline-Based or Nonanthracycline Chemotherapy: A Pharmacological Appraisal.

Diastolic dysfunction (DD) is an early manifestation of cancer drug cardiotoxicity. Anthracyclines are considered as more cardiotoxic than other chemotherapeutics, but previous studies have shown that both anthracycline-based and nonanthracycline chemotherapy can cause an early DD, detected 1 week after the end of chemotherapy. Here we characterized if DD also occurred in a delayed form, detected 6 months after chemotherapy. Sixty-seven comorbidity-free patients were examined. DD was diagnosed by echocardiography and cardiac biomarkers. Early or delayed DD occurred in 26 or 13 patients, respectively, sharing a pattern of grade I DD (impaired relaxation at echocardiography) or elevated B-type natriuretic peptide. Binary logistic analysis showed that age, gender, and type of chemotherapy (anthracycline-based vs. nonanthracycline) did not independently increase the probability of early or delayed DD. Early DD was predicted by the patient's cardiovascular profile and in particular by diastolic indices that were in ranges of normality but showed measurable discrepancies from mean control values. Delayed DD was not predicted by the patient's cardiovascular profile but was predicted by postchemotherapy adjuvant treatments (e.g., chest radiation or hormone therapy). Early and delayed DD were accompanied by moderate left ventricular ejection fraction decrements. These findings show that anthracycline-based and nonanthracycline chemotherapy can induce early or delayed DD, which are governed by different patient- or treatment- related factors. Pharmacologic interventions that prevent DD or mitigate its progression toward a more serious cardiac dysfunction should be considered. SIGNIFICANCE STATEMENT: Predictors of early or delayed diastolic dysfunction (DD) were investigated in patients with cancer treated with anthracycline-based or nonanthracycline chemotherapy. The type of chemotherapy did not predict the risk of DD. Early DD was predicted by the patient's cardiovascular profile. Delayed DD was predicted by the adjuvant treatments the patient received after chemotherapy. These findings show that any chemotherapeutic can cause DD; however, the trajectories of DD are differently influenced by patients' characteristics or postchemotherapy exposure to additional cardiotoxic hits.

Sodium-Glucose Cotransporter Inhibitors Reduce Mortality and Morbidity in Patients With Heart Failure: Evidence From a Meta-Analysis of Randomized Trials.

BACKGROUND: Recent trials demonstrated the clinical efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients. STUDY QUESTION: We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes. DATA SOURCES: We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021. STUDY DESIGN: This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death. RESULTS: Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67-0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization. CONCLUSIONS: Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs.

Choosing Antifungals for the Midostaurin-Treated Patient: Does CYP3A4 Outweigh Recommendations? A Brief Insight from Real Life.

INTRODUCTION: Patients treated with midostaurin and chemotherapy are at risk of invasive fungal disease. Prophylactic posaconazole is recommended for these patients, but posaconazole strongly inhibits the CYP3A4 isozyme that metabolizes midostaurin. Posaconazole therefore introduces a risk of patient's overexposure to midostaurin. METHODS: Blood samples were obtained from 4 patients treated with midostaurin for newly diagnosed FLT3-mutAML. Patients had received a concomitant treatment with posaconazole, isavuconazole, or micafungin, respectively. All blood samples were drawn before daily dose administration of midostaurin. RESULTS: Posaconazole caused a ≥8-fold increase of midostaurin plasma levels at through, which was accompanied by a decreased plasma exposure to O-demethylated or hydroxylated midostaurin metabolites. We also show that hematologists react to risk perception by replacing posaco-nazole with antifungals like micafungin or isavuconazole, which lack a strong inhibition of CYP3A4 and fail to modify midostaurin pharmacokinetics but are not formally recommended in these settings. DISCUSSION: In real-life scenarios, concerns about CYP3A4 inhibition may outweigh compliance with recommendations. Large studies are needed to survey the risk:benefit of hematologist's decision to replace posaconazole with other antifungals.

Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

INTRODUCTION: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure. Dose reductions from 45 mg to 30 or 15 mg/day are increasingly considered to improve PNT safety but a plasma threshold of ∼40 nM must be achieved to ensure that antileukemic activity is preserved. Therapeutic drug monitoring (TDM) would be appropriate for patients treated by PNT. We, therefore, developed and validated a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) assay to measure PNT plasma levels. METHODS: PNT and its deuterated internal standard were extracted from human plasma by one-step protein precipitation. PNT was separated and quantified by HPLC-MS/MS operating in the multiple reaction monitoring acquisition mode. RESULTS: The method was linear from 9.4 to 940 nM PNT. Limits of detection and lower limits of quantification (LLOQ) were, respectively, 1 and 9.4 nM. Selectivity, sensitivity, matrix effect, short-, and long-term stability met criteria of international guidelines for bioanalytical method validation. Intra- and inter-day accuracy and precision were calculated on 4 different concentrations (QCLow, QCMedium, QCHigh, and LLOQ), with all values being <15%. The method was successfully probed in leukemia Ph + ALL patients to show that PNT doses <45 mg/day caused lower plasma exposure but still achieved PNT levels at or above the 40 nM threshold. CONCLUSIONS: We developed a highly sensitive and selective HPLC-MS/MS method to quantify PNT in human plasma. This method might be used for TDM and to guide dose reductions if unnecessary high PNT levels are detected in a patient.

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial.

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as ß-blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5 weeks, 12 of 12 patients on ranolazine recovered from diastolic dysfunction, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes the potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT: The antianginal drug ranolazine causes cardiac relaxant effects that might relieve diastolic dysfunction. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.

Cardiotoxicity of Targeted Cancer Drugs: Concerns, "The Cart Before the Horse," and Lessons from Trastuzumab.

PURPOSE OF REVIEW: Modern oncology is witnessing a renaissance of its pharmacologic armamentarium. Old generation drugs, such as anthracyclines and other cytotoxic or cytostatic drugs, were plagued with a lack of specificity and with the possible occurrence of untoward effects in the cardiovascular system and other healthy tissues. The old drugs are now combined with, or replaced by, new agents that are more specific in attacking some unique moieties and vital functions of cancer cells, causing less noxious effects in healthy tissues. Regrettably, however, the new "targeted" drugs still cause varying levels of cardiac or vascular toxicity. Here, we describe the case of trastuzumab, a monoclonal antibody that dramatically improved the life expectancy of women with Erbb2-overexpressing breast tumor, while also raising concerns about a possible incidence of cardiac dysfunction. RECENT FINDINGS: The scientific community counts experts that label trastuzumab as a "cardiotoxic agent" and other experts that maintain a more benign assessment. We describe the biologic foundations and clinical evidence for such controversy. We show that trastuzumab cardiotoxicity is probably overrated, leading some experts to raise unjustified overconcerns about the cardiotoxicity of trastuzumab as a single agent or in combination with anthracyclines or other old and new drugs. We analyze the biases that caused trastuzumab cardiotoxicity to be overrated. Trastuzumab is a life-saving agent showing a moderate and clinically manageable cardiac dysfunction, and yet, it is portrayed as cardiotoxic. We take the trastuzumab lesson to reaffirm that cardio-oncologists should provide cancer patients with the best therapeutic opportunity, as is the case for trastuzumab, while also devising the necessary strategies of risk assessment and mitigation.

Correction to: Cardiotoxicity of Targeted Cancer Drugs: Concerns, "The Cart Before the Horse," and Lessons from Trastuzumab.

In the original publication, there were two errors in Fig. 2. "Anhracyline" should be "Anthracycline" and "targetd" should be "targeted." The original article has been corrected.

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.

The Endogenous Lusitropic and Chronotropic Agent, B-Type Natriuretic Peptide, Limits Cardiac Troponin Release in Cancer Patients with an Early Impairment of Myocardial Relaxation Induced by Anthracyclines.

We have reported that cancer patients treated with anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone B-type natriuretic peptide (BNP). Post-hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained normal relaxation. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction, but high BNP levels resulted in positive chronotropism and inappropriate tachycardia. Some patients developed increased circulating levels of cardiac troponin I isoform (cTnI), a marker of cardiomyocyte necrosis. Here we have characterized whether cTnI elevations correlated with diastolic dysfunction that manifested as impaired relaxation or a high level of BNP. The effects of high BNP levels on cTnI elevations were also characterized. We show that impaired relaxation or high BNP levels were significantly more frequent in patients with cTnI elevations. High BNP levels diminished the plasma peak and area under the curve of cTnI, but this result was accompanied by inappropriate tachycardia. cTnI elevations occurred only in patients treated with anthracyclines; moreover, the association of impaired relaxation or high BNP levels with cTnI elevations was significantly more frequent in doxorubicin-treated patients compared with patients treated with its analog, epirubicin. These findings describe cause-and-effect relations between impaired relaxation and cardiomyocyte necrosis, illuminate the role of anthracycline analogs, denote that the beneficial effects of BNP in relieving impaired relaxation and cardiomyocyte necrosis are counterbalanced by inappropriate tachycardia. Patients showing troponin elevations and impaired relaxation or high BNP levels should be treated with lusitropic drugs that lack a positive chronotropism.