Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trastuzumab (Herceptin), currently prescribed for metastatic breast cancer, has recently been shown to be effective as adjuvant therapy in early receptor 2 (HER2)-positive breast cancer. Cardiotoxicity is a serious adverse effect. A decrease in left ventricular ejection fraction (LVEF) occurs in as many as 27% of women treated with trastuzumab when combined with standard chemotherapy. The pathophysiology of this effect, which differs from the cardiotoxicity of anthracyclines, remains poorly understood. While overt heart failure is reversed with standard therapy, the longer-term consequences of asymptomatic declines in LVEF remain unknown. Monitoring 3-monthly for 5-10% changes in LVEF, the criteria for cessation of trastuzumab therapy in the clinical trials, is not possible for the population of women who might benefit from trastuzumab for early breast cancer. Extension of this therapy to an older and less fit population than those enrolled in the trials, with less rigorous cardiac screening, may result in significantly more cardiotoxicity.
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PMID:Monitoring the introduction of new drugs--Herceptin to cardiotoxicity. 1734 85

Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.
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PMID:Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. 1765 6

Trastuzumab, a drug targeting human epidermal growth factor receptor 2, improves survival rate in women with metastatic breast cancer. Symptomatic heart failure, a serious adverse effect of trastuzumab, occurs in 1% to 4% of patients treated with the antibody, whereas left ventricular ejection fraction declines substantially in 10% of patients. The prevalence of cardiotoxic effects of trastuzumab appears to increase with exposure to anthracyclines. Serial assessment of left ventricular function with 2-dimensional echocardiography or radionuclide ventriculography is the most practical means of monitoring cardiotoxicity. Patients who develop cardiotoxicity while receiving trastuzumab therapy generally improve once use of the agent is discontinued.
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PMID:Trastuzumab-induced cardiotoxicity: heart failure at the crossroads. 1824 29

Three women aged 53, 52 and 36 years, respectively, underwent surgery for breast cancer, i.e. right-sided grade II invasive ductal carcinoma, left-sided grade III invasive ductal carcinoma, and left-sided multifocal grade III invasive ductal carcinoma, respectively. All 3 received adjuvant anthracycline-containing chemotherapy followed by trastuzumab. They developed significant cardiac dysfunction, as determined by a decrease in left ventricular ejection fraction (LVEF), which necessitated trastuzumab discontinuation. Trastuzumab therapy was resumed in the third patient after LVEF recovery but was stopped definitively when the LVEF decreased again. Trastuzumab has been shown to improve both disease-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, symptomatic cardiac failure due to cardiomyopathy has been observed in 0.6-4.1% of patients treated with trastuzumab after adjuvant anthracycline-based chemotherapy, whereas in 5-19% of the patients the decline in cardiac function led to permanent discontinuation of trastuzumab therapy. Cardiac function should be monitored regularly during trastuzumab therapy. An LVEF less than 50% or an absolute reduction of more than 10% warrant treatment discontinuation and close follow-up. Cardiac dysfunction is usually reversible; however, the long-term consequences of LVEF reduction following trastuzumab therapy are still unknown and warrant close attention, given the relatively young age and long life expectancy of these patients.
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PMID:[Cardiotoxicity of trastuzumab of significance in the adjuvant treatment of breast cancer]. 1827 65

The rapidly evolving insights into the protective and modulatory function of neuregulin-1 (NRG-1) in the adult heart are discussed in this review. The actions of NRG-1 in the adult heart have begun to be elucidated following the unexpected clinical observation that trastuzumab can cause ventricular dysfunction and increases the risk of cardiomyopathy induced by anthracyclines. Trastuzumab is an inhibitory antibody against the NRG receptor erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and is used in the treatment of breast cancer. In vitro studies have demonstrated that NRG-1 promotes growth and survival of isolated cardiomyocytes. Ventricular dysfunction following anti-ErbB2 treatment was initially explained by a loss of ErbB2-dependent cell survival pathways in the heart. However, in vivo studies in genetically modified mice did not uniformly confirm this finding. More recent studies have revealed that NRG-1 counterbalances the adrenergic inotropic response of the adult myocardium through an obligatory interaction with the muscarinic cholinergic system. In addition, it was demonstrated that cardiac NRG-1 synthesis and release from the cardiac endothelium, the principal source of NRG-1 in the heart, is dynamically controlled by neurohormonal and biomechanical stimuli, allowing adaptive tuning of ErbB signaling during cardiovascular stress. Cardiac NRG-1 is beginning to emerge as a cardioprotective factor implicated in the physiological regulation of myocardial performance and sympathovagal balances. Cardiac NRG-1/ErbB signaling has implications for the treatment of both cancer and heart failure. As novel ErbB inhibitors are currently being tested in broader oncological indications, there is a need to better understand their cardiovascular side effects. It is possible that pharmacological activation of ErbB signaling is an indirect, beneficial effect of the drugs currently used in heart failure, and this could be a promising therapeutic approach for prevention or reversal of myocardial dysfunction. Heart Fail Monit 2008;5(4):119-24.
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PMID:Neuregulin-1 and its potential role in the control of cardiac function. 1827 95

Trastuzumab is a recombinant humanized monoclonal antibody used for the treatment of advanced breast cancer. It improves survival and increases response to chemotherapy. The major side effect of trastuzumab is cardiotoxicity manifesting as a reduction in left ventricular systolic function, either asymptomatic or with signs and symptoms of heart failure. Although reversible in most cases, cardiotoxicity frequently results in the discontinuation of trastuzumab. The objective of this review is to summarize facts about trastuzumab-induced cardiotoxicity and to highlight the areas of future investigations. We searched PubMed for trials involving trastuzumab used as an adjuvant therapy for breast cancer, including the metastatic breast cancer setting, and focused on cardiotoxicity.
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PMID:Trastuzumab-induced cardiomyopathy. 1851 38

Trastuzumab-related cardiac dysfunction may be manageable and completely reversible with suitable cardiac medication, allowing optimal breast cancer treatment to continue. We present the case of a 42-year-old woman who developed severe systolic left ventricular failure with impaired contractility of the right ventricle, pulmonary hypertension, and clots in the left ventricular cavity during adjuvant treatment for breast cancer. The patient was initially diagnosed with early breast cancer and underwent surgery on her left breast. She received 6 cycles of anthracycline chemotherapy followed by radiation therapy in the left breast area, then 5 cycles of trastuzumab. After the fifth cycle of trastuzumab, she experienced dyspnoea and leg edema. Fluid was detected in the pleural cavities but no lung metastases were identified. Echocardiography was performed, revealing a severely reduced left ventricular ejection fraction (10%) with impaired contractility of the right ventricle and pulmonary hypertension. Standard medication for heart failure resulted in complete recovery of normal systolic and diastolic function of the left and right ventricles. The combination of low molecular weight heparin and acetylsalicylic acid completely resolved the thrombotic complications. The patient regained her full range of social, occupational, and family activities. This case study is the first to demonstrate the manageability and reversibility of trastuzumab-related cardiac complications in a patient who had developed severe heart failure complicated with left ventricular thrombosis during sequential anthracycline and trastuzumab therapy for breast cancer. The findings contradict other opinions that trastuzumab-related acute heart failure is analogous to stunning or hibernation and recovers without specific cardiac treatment.
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PMID:Manageability of acute severe heart failure complicated with left ventricular thrombosis during therapy for breast cancer. 2037 51

We analyzed 127 consecutive patients who received trastuzumab-based chemotherapy from December, 2003 to February, 2009 in our hospital. Of 127 patients, cardiac dysfunction appeared in 6 patients(4. 7%). Cardiac dysfunction was defined as a decline in left ventricular (LV) ejection fraction (EF) < or =55% with absolute reduction of at least 10% from baseline. Among the 6 patients with cardiac dysfunction, one patient suffered symptomatic heart failure. Other patients were asymptomatic. The 4 patients of the 5 patients recovered their cardiac dysfunction after withdrawal of trastuzumab. Patients with trastuzumab-associated cardiac dysfunction had a history of administration of epirubicin or taxane, lower registration LVEF, and larger LV end-diastolic dimension (> or =49 mm). We recommend that LV function be assessed by echocardiography or multigated radionuclide angiography scans prior to instituting trastuzumab therapy and at three-month intervals during therapy. Trastuzumab should be discontinued in patients who develop a decrease in LVEF below 45% or congestive heart failure.
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PMID:[Trastuzumab-associated cardiac dysfunction]. 2041 23

Trastuzumab is the standard of care for the treatment of patients with ERB2-positive breast cancer. In a minority of patients, trastuzumab is associated with an increased incidence of cardiac dysfunction that ranges from asymptomatic decreases in left ventricular ejection fraction to symptomatic heart failure. In trials in the adjuvant setting, the difference in the incidence of cardiac events between the control and trastuzumab-containing arms was less than 4%. The baseline evaluation and oncologic setting (adjuvant versus metastatic disease) drive algorithms for the cardiac monitoring and management of these patients. When a patient develops documented left ventricular dysfunction, standard treatments for the management of heart failure should be prescribed. Trastuzumab cardiac dysfunction is an important clinical entity that can be managed effectively and individualized to maximize the cancer treatment benefit and minimize the risk and consequences of cardiac dysfunction.
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PMID:Management of trastuzumab-related cardiac dysfunction. 2072

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.
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PMID:Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues. 2114 9


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