Fundación Hospital Cardiológico Infantil Latinoamericano Dr. Gilberto Rodríguez Ochoa

Ente Adscrito al Ministerio del Poder Popular para la Salud. El Servicio Aurónomo Hospital Cardiológico Infantil Latinoamericano Dr. Gilberto Rodríguez Ochoa, creado el 20 de agosto de 2006, con el objetivo de cubrir la gran demanda de pacientes entre 0 y 18 años de edad con malformaciones cardíacas de Venezuela y Latinoamérica.

Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.

BACKGROUND: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team. METHODS: All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion. RESULTS: Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT. CONCLUSIONS: The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.

A review regarding the article 'The cardioprotective potential of sodium-glucose cotransporter 2-inhibitors in breast cancer therapy-related cardiac dysfunction-A systematic review'.

Breast cancer is one of the most common types of cancer, representing 15 % of all new cancer cases in the United States. Approximately 12.4 % of all women will be diagnosed with breast cancer during their lifetime. In the past decades, a decrease in cancer-related mortality is evident as a result of early screening and improved therapeutic options. Nonetheless, breast cancer survivors face long-term treatment side effects, with cardiotoxicity being the most significant one, which lead to increased morbidity and mortality. Breast cancer patients are particularly susceptible to cancer therapeutics-related cardiac dysfunction (CTRCD) as treatment regimens include cardiotoxic drugs, primarily anthracyclines and anti-human epidermal growth factor receptor 2 (anti-HER2) agents (recombinant humanized monoclonal antibodies directed against HER2 such as trastuzumab and pertuzumab). Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Discontinuation of trastuzumab however, can lead to worse cancer outcomes. There have been case reports, registry-based, retrospective cohort-based and mechanistic studies suggesting the cardioprotective potential of SGLT2i in CTRCD. It is not known whether SGLT2i can prevent the development of incident HF or reduce the risk of HF in patients receiving trastuzumab with or without other concurrent anti-HER2 agent or sequential anthracycline for treatment of HER2 positive breast cancer. Based on these, there is now a call for randomized controlled trials to be performed in this patient cohort to advise guideline-directed therapy for CTRCD, which will in turn also provide detailed safety information and improve cancer and cardiovascular outcomes.

Role of Statin Therapy in Prevention of Anthracycline-Induced Cardiotoxicity: A Three Dimentional Echocardiography Study.

BACKGROUND: Recent advances in the treatment of breast cancer have resulted in improved overall cancer survival; however, cancer therapy related cardiac dysfunction is considered a major adverse effect of several chemotherapeutic agents, particularly anthracyclines. Hence, there is a need to develop proper cardioprotective strategies to limit myocardial injury following chemotherapy. OBJECTIVE: To evaluate the effect of statin therapy on prevention of anthracycline- induced cardiotoxicity in female patients with breast cancer. PATIENTS AND METHODS: The current study is a prospective, randomized, single-blind, placebo-controlled trial in which we enrolled a total of 110 female patients with newly diagnosed breast cancer who received anthracycline based chemotherapy. Patients were randomly assigned in 1:1 ratio into two groups, study group in which patients received 40 mg of oral atorvastatin and control group in which patients received placebo. A comprehensive echocardiographic examination was performed to all patients prior to receiving the chemotherapy and after 6 months, assessment of LV ejection fraction was done by 3D-echocardiography. All echocardiographers were blinded to all the patients' characteristics and assignment to either group. RESULTS: The mean age of patients assigned to the control group was 49.8±10.51 years old, while patients assigned to the intervention group had mean age of 47.84± 9.16 years old, both the control group and the intervention group were similar in demographic data and baseline clinical characteristics. There was a highly significant difference between the two groups regarding both the absolute LVEF assessed by 3D- echocardiography at 6 months and the percentage of change compared to baseline values, patients assigned to the control group had mean LVEF of 52.92% at 6 months with percentage of change reaching -7.06%, while those assigned to the intervention group had mean LVEF reaching 56.22% at 6 months with a percentage of change reaching -3.64% (P-value: 0.008 and 0.004 for the absolute value and percentage of change respectively). There was a significant difference between the two groups regarding incidence of development of cancer therapy related cardiac dysfunction (CTRCD); defined as drop in LVEF more than 10% and to a value below 53% assessed by 3D echocardiography, among the control group 15 patients (30%) developed CTRCD after 6 months from starting Anthracyclines based chemotherapy, while, among the intervention group only 6 patients (12%) developed CTRCD. (P-value= 0.027) CONCLUSION: Prophylactic use of atorvastatin may prevent the development of cancer therapy related cardiac dysfunction in breast cancer patients receiving anthracycline based chemotherapy.

RISK SCORE MODEL FOR PREDICTING CARDIOTOXICITY IN BREAST CANCER: DIAGNOSTIC VALUE OF HIGH-SENSITIVITY CARDIAC TROPONIN T. / ШКАЛА РИЗИКУ КАРДІОТОКСИЧНОСТІ У ХВОРИХ НА РАК ГРУДНОЇ ЗАЛОЗИ: ДІАГНОСТИЧНЕ ЗНАЧЕННЯ ВИСОКОЧУТЛИВОГО СЕРЦЕВОГО ТРОПОНІНУ Т.

Cardiovascular diseases are the second leading cause of death among breast cancer (BC) patients. Prediction of cardiovascular toxicity (CT) is an important part of the successful treatment and survival of patients. OBJECTIVE: to develop a risk score model for cardiovascular toxicity (CT) predicting, based on cardiovascular risk factors (RFs), RFs associated with cancer therapy, and troponin levels. MATERIAL AND METHODS: The study included 76 BC patients with a prospective analysis of their clinical and treatment data, RFs, echocardiographic indicators before the start of treatment and after 6 months, and an increase in troponin level. Among all RFs, the most significant RFs of CT were: radiation therapy, treatment with anthracyclines, and cardiovascular diseases. Based on the obtained results, a combined CT risk score was developed and proposed.According to the sum of points, patients were divided into groups: group 1 - with a low risk of CT development, the sum of points < 5; group 2 - moderate risk, 6-7 points; group 3 - high risk, > 8 points. RESULTS: In a pilot prospective study, an analysis of the RFs of CT was provided, compared to echocardiography data and the degree of troponin increase in dynamic observation; the risk score model for the CT prediction was developed for BC patients stratification. According to the developed score, BC patients with a total of > 8 points are considered to have a high risk of CT complications. CONCLUSIONS: The use of the proposed risk model score with calculation of the RFs of CT along with high-sensitivity troponin increase during cancer treatment allows predicting the risk of CT developing at the early stages - before the onset of clinical manifestations. Accordingly, these BC patients have a high risk of CT, and the use of personalized cardiac monitoring together with cardioprotective therapy can prevent cardiovascular complications.

Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.

Damage to the mitochondria may lead to serious conditions that are difficult to treat. Doxorubicin is one of the most widely used chemotherapeutic drugs for the treatment of malignancies in children and adults, and reportedly causes damage to the mitochondria. Unfortunately, the dangerous cardiac side effects of doxorubicin appear when the patient is in the midst of a vigorous fight against the disease, either by taking doxorubicin alone or in combination with other drugs. This study aimed to determine whether exogenous healthy and functional mitochondria are internalized by cells, can it help the survival of these cells, and can reduce cardiotoxicity. For this purpose, isolated, pure, and functional exogenous mitochondria were injected into the tail vein of a rat model of doxorubicin-induced cardiotoxicity. After that, the heart function of the rats and their antioxidant status, inflammatory markers, and histopathological examination were investigated. Our findings show that intravenous mitochondrial transplantation provided efficient mitochondrial uptake and reduced cardiotoxicity by reducing ROS production, lipid peroxidation, and inflammation. In addition, the levels of ATP and antioxidant enzymes increased after mitochondrial transplantation; therefore all of these complex processes resulted in the reduction of apoptosis and necrosis in rat heart tissue. These promising results open the way to more effective cancer treatment without the side effects of related drugs. Transplanting exogenous mitochondria probably enhances the cell's mitochondrial network, potentially treating mitochondria-related disorders such as cardiovascular and neurodegenerative diseases, although the exact relationship between mitochondrial damage and these conditions remains unclear.

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats.

Exercise training is an encouraging approach to treat cardiac dysfunction in type 2 diabetes (T2DM), but the impact of its intensity is not understood. We aim to investigate whether and, if so, how moderate-intensity training (MIT) and high-intensity interval training (HIIT) alleviate adverse cardiac remodeling and dysfunction in rats with T2DM. Male rats received standard chow (n = 10) or Western diet (WD) to induce T2DM. Hereafter, WD rats were subjected to a 12-week sedentary lifestyle (n = 8), running MIT (n = 7) or HIIT (n = 7). Insulin resistance and glucose tolerance were assessed during the oral glucose tolerance test. Plasma advanced glycation end-products (AGEs) were evaluated. Echocardiography and hemodynamic measurements evaluated cardiac function. Underlying cardiac mechanisms were investigated by histology, western blot and colorimetry. We found that MIT and HIIT lowered insulin resistance and blood glucose levels compared to sedentary WD rats. MIT decreased harmful plasma AGE levels. In the heart, MIT and HIIT lowered end-diastolic pressure, left ventricular wall thickness and interstitial collagen deposition. Cardiac citrate synthase activity, mitochondrial oxidative capacity marker, raised after both exercise training modalities. We conclude that MIT and HIIT are effective in alleviating diastolic dysfunction and pathological cardiac remodeling in T2DM, by lowering fibrosis and optimizing mitochondrial capacity.

Método MasQsano. Detección de enfermedades cardiacas no conocidas en reconocimientos médicos deportivos / MasQsano method. Detection of unknown cardiac diseases in sports medical examinations

El reconocimiento médico deportivo es considerado como un punto de partida para cualquier deportista antes de incorporarse a la actividad física o deportiva. Su objetivo principal es la detección de patologías que pudieran poner en riesgo su vida y aquellas que una vez corregidas pueden potenciar el rendimiento físico. Es por ello por lo que debe realizarse por un equipo de salud multidisciplinario experto en el área. De esta manera, resulta importante revisar la evidencia científica y conocer directamente el estado de salud de un grupo de adultos y niños deportistas, su incidencia de enfermedades cardiovasculares y el rol de la enfermería en su aplicación. Este estudio, evaluó una muestra de 7.340 deportistas con edades comprendidas entre los 3 y 17 años, compuesta de 1.693 femeninos y 5.647 masculinos, a los cuales se les realizó el reconocimiento médico deportivo, de acuerdo con un protocolo registrado y establecido previamente en los clubes deportivos de 2 provincias españolas con el apoyo del personal de enfermería durante el año 2021. De estos, se obtuvo un total de 112 casos de patologías cardiacas, de los cuales el 54% tenía conocimiento de patología cardiaca y el 64% no era conocido. De este grupo de patologías cardíacas no conocidas, el 5,9% de los casos requirió intervención quirúrgica, el 21,1% se encuentra en revisión y el 73% fue dado de alta. El total de casos con patologías cardíacas no conocida representa un 0,70% de la muestra. Así mismo, se determinó el rol fundamental de enfermería en la aplicación de este protocolo.(AU)

The sports medical examination is considered a starting point for any athlete before taking up physical or sporting activity. Its main objective is to detect pathologies that could put your life at risk and those that, once corrected, can enhance physical performance. This is why it must be carried out by a multidisciplinary health team with expertise in the area. In this way, it is important to review the scientific evidence and learn directly about the health status of a group of adult and child athletes, their incidence of cardiovascular diseases and the role of nursing in their application. This study evaluated a sample of 7340 athletes aged between 3 and 17 years, composed of 1693 females and 5647 males, who underwent a sports medical examination, according to a registered and previously established protocol in sports clubs in 2 Spanish provinces with the support of nursing staff during the year 2021. Of these, a total of 112 cases of cardiac pathologies were obtained, of which 54% were known to have a cardiac pathology and 64% were unknown. Of this group of unknown cardiac pathologies, 5.9% of the cases required surgical intervention, 21.1% are under review and 73% were discharged. The total number of cases with unknown cardiac pathologies represents 0.70% of the sample. The fundamental role of nursing in the application of this protocol was also determined.(AU)

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

A planning strategy may reduce the risk of heart diseases and radiation pneumonia: Avoiding the specific heart substructures.

BACKGROUND: Dose to heart substructures is a better predictor for major adverse cardiac events (MACE) than mean heart dose (MHD). We propose an avoidance planning strategy for important cardiac substructures. MATERIAL AND METHODS: Two plans, clinical and cardiac substructure-avoidance plan, were generated for twenty patients. Five dose-sensitive substructures, including left ventricle, pulmonary artery, left anterior descending branch, left circumflex branch and the coronary artery were chosen. The avoidance plan aims to meet the target criteria and organ-at-risk (OARs) constraints while minimizing the dose parameters of the above five substructures. The dosimetric assessments included the mean dose and the maximum dose of cardiac substructures and several volume parameters. In addition, we also evaluated the relative risk of coronary artery disease (CAD), chronic heart failure (CHF), and radiation pneumonia (RP). RESULTS: Pearson correlation coefficient and R2 value of linear regression fitting demonstrated that MHD had poor prediction ability for the mean dose of the cardiac substructures. Compared to clinical plans, an avoidance plan is able to statistically significantly decrease the dose to key substructures. Meanwhile, the dose to OARs and the coverage of the target are comparable in the two plans. In addition, it can be observed that the avoidance plan statistically decreases the relative risks of CAD, CHF, and RP. CONCLUSIONS: The substructure-avoidance planning strategy that incorporates the cardiac substructures into optimization process, can protect the important heart substructures, such as left ventricle, left anterior descending branch and pulmonary artery, achieving the substantive sparing of dose-sensitive cardiac structures, and have the potential to decrease the relative risks of CAD, CHF, and RP.

Radiopaque and X-ray-Responsive Nanomedicine for Preventive Therapy of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a common radiotherapy complication. Reducing radiation exposure and post-irradiation antioxidant therapy are promising approaches. Here, a liquid metal-based core-shell nanomedicine (LMN) composed of a gallium core and a multifunctional polymeric shell with radiopaque, X-ray shielding, and X-ray-responsive antioxidation properties for preventive therapy of RIHD is developed. The liquid metal provides radiopaque properties to enhance X-ray and computed tomography imaging and attenuate radiation to prevent primary myocardial damage. Under X-ray radiation, cleavage of the diselenide bond on the polymeric shell results in the release of LMN and controlled antioxidation. In vitro and in vivo experiments have demonstrated that LMN significantly reduces myocardial injury and impaired cardiac function, stabilizes mitochondrial function, and inhibits myocardial fibrosis. This nanomedicine with radiographic contrast, radiation shielding, and responsive features provides a new strategy for the prevention of radiation-related diseases.

Sugar Substitutes Don't Help Weight Control and May Increase Risk of Heart Disease and Diabetes, WHO Warns.

This Medical News article discusses a recent WHO guideline that advises against using nonsugar sweeteners to lose weight or reduce the risk of noncommunicable diseases.

Berberine attenuates sunitinib-induced cardiac dysfunction by normalizing calcium regulation disorder via SGK1 activation.

Sunitinib (SNT)-induced cardiotoxicity is associated with abnormal calcium regulation caused by phosphoinositide 3 kinase inhibition in the heart. Berberine (BBR) is a natural compound that exhibits cardioprotective effects and regulates calcium homeostasis. We hypothesized that BBR ameliorates SNT-induced cardiotoxicity by normalizing the calcium regulation disorder via serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Mice, neonatal rat cardiomyocytes (NRVMs), and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study the effects of BBR-mediated SGK1 activity on the calcium regulation disorder caused by SNT as well as the underlying mechanism. BBR offered prevention against SNT-induced cardiac systolic dysfunction, QT interval prolongation, and histopathological changes in mice. After the oral administration of SNT, the Ca2+ transient and contraction of cardiomyocytes was significantly inhibited, whereas BBR exhibited an antagonistic effect. In NRVMs, BBR was significantly preventive against the SNT-induced reduction of calcium transient amplitude, prolongation of calcium transient recovery, and decrease in SERCA2a protein expression; however, SGK1 inhibitors resisted the preventive effects of BBR. In hiPSC-CMs, BBR pretreatment significantly prevented SNT from inhibiting the contraction, whereas coincubation with SGK1 inhibitors antagonized the effects of BBR. These findings indicate that BBR attenuates SNT-induced cardiac dysfunction by normalizing the calcium regulation disorder via SGK1 activation.

Dairy Food Consumption Is Associated with Reduced Risk of Heart Disease Mortality, but Not All-Cause and Cancer Mortality in US Adults.

Previous evidence has linked animal protein intake, including dairy foods, with an increased risk in mortality from all-causes and certain chronic diseases, including cancer and heart disease. The objective of the current analysis was to examine associations between total dairy consumption with mortality from all-causes, cancer, and heart disease. Data for adults (≥19 y; n = 54,830) from the Third National Health and Nutrition Examination Survey (NHANES) and NHANES 1999-2014 were linked with mortality data through 2015. Individual usual intake for dairy foods were estimated using the National Cancer Institute method. Hazard ratio (HR) models were fit for mortality types (all cause, cancer, heart disease) and measures of usual intakes of dairy. Multivariable analysis further adjusted for age, gender, ethnicity, waist circumference, smoking status, education level, chronic condition status (i.e., based on cancer, myocardial infarct, and diabetes/diabetes medication reported), weight loss attempts, and % kcal from animal protein. No associations were seen between dairy food intake and mortality risk from all-causes [HR = 0.97; confidence intervals (CI): 0.85-1.11; p = 0.67], and cancer [HR = 0.95; CI: 0.75-1.20; p = 0.65] when comparing the lowest quartile to the highest quartile of consumption. Dairy food consumption was associated with a 26% reduced risk for heart disease mortality when comparing the lowest quartile to the highest quartile [HR = 0.74; CI: 0.54-1.01; p = 0.05]. Further analyses in different age groups showed that dairy food consumption was associated with 39% and 31% reduced risk for heart disease mortality in older adults 51-70 and ≥51 y, respectively [adults 51-70 y: HR = 0.61; CI: 0.41-0.91; p = 0.01; adults ≥51 y: HR = 0.69; CI: 0.54-0.89; p = 0.004]. These results contradict previous findings that have linked dairy foods to increased mortality risk. Further, dairy foods as part of a healthy dietary pattern, may help lower heart disease mortality risk.

PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.

AIMS: Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity. METHODS AND RESULTS: We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homoeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3. CONCLUSION: We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer therapy.