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)

Imatinib specifically inhibits receptor tyrosine kinase signaling and is clinically used to treat leukemia. Receptor tyrosine kinases not only mediate tumor growth but also initiate adverse signaling in heart failure. We investigated whether imatinib, by inhibiting the platelet-derived growth factor receptor-beta (PDGFRbeta), prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats. Eight-week-old male homozygous Ren2 and Sprague Dawley rats were treated either with imatinib (30 mg/kg; STI-571) or placebo for 8 weeks (Ren2 n=12 for each group; Sprague Dawley n=6 for each group). Imatinib did not affect blood pressure or left ventricular (LV) hypertrophy in both groups. Imatinib attenuated the decline in fractional shortening (imatinib versus Ren2 placebo 45+/-4.5% versus 32+/-3%; n=7-11; P<0.05) and in diastolic function in Ren2 rats (baseline diastolic dP/dt corrected for systolic blood pressure Ren2 imatinib versus Ren2 placebo 38.6+/-0.67 versus 35.3+/-0.41 [1 . s(-1)]; n=7-11; P<0.05). This was associated with decreased cardiac fibrosis and decreased activation of PDGFRbeta and extracellular signal-regulated kinase 1/2. Renal microvascular hypertrophy and perivascular fibrosis in Ren2 rats were significantly decreased by imatinib. In vitro, imatinib blocked angiotensin II-induced activation of the PDGFRbeta and significantly decreased fibroblast proliferation and collagen production. In conclusion, imatinib did not affect LV hypertrophy but attenuated the decline in cardiac function and reduced renal microvascular damage associated with reduced activation of the PDGFRbeta. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRbeta has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.
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PMID:Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats. 1643 51

A recent preclinical study suggested that imatinib may be cardiotoxic in some patients. We reviewed all reported serious adverse events of cardiac adverse events occurring in patients on clinical trials involving imatinib. Among 1276 patients enrolled, 22 (1.7%) were identified as having symptoms that could be attributed to systolic heart failure. The median age was 70 years (range, 49 to 83 years). The median time from start of imatinib therapy was 162 days (range, 2-2045 days). At the time these events were reported, 8 (0.6%) were considered possibly or probably related to imatinib. A total of 18 patients had previous medical conditions predisposing to cardiac failure: congestive heart failure (CHF; 6 [27%] patients), diabetes mellitus (6 [27%] patients), hypertension (10 [45%] patients), coronary artery disease (CAD; 8 [36%] patients), arrhythmia (3 [14%] patients), and cardiomyopathy (1 [5%] patient). Of the 22 patients, 11 continued imatinib therapy with dose adjustments and management for the CHF symptoms without further complications. Imatinib therapy as a causal factor of CHF is uncommon, mainly seen in elderly patients with preexisting cardiac conditions. Patients with previous cardiac history should be monitored closely and treated aggressively with standard medical therapy, including diuretics, if they develop symptoms suggestive of heart failure.
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PMID:Congestive heart failure is a rare event in patients receiving imatinib therapy. 1744 98

(1) Imatinib, a tyrosine kinase inhibitor, was first marketed for the treatment of chronic myeloid leukaemia and some gastrointestinal stromal tumours. Its indications have gradually expanded over the years. (2) There is no consensus treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia. In a trial comparing imatinib versus chemotherapy as initial treatment for 55 patients, the haematological response rate was higher with imatinib. Non-comparative trials provided haematological response rates of about 90%, but it is not known whether or not this translates into a survival advantage. In three non-comparative trials including patients with relapsed or refractory disease after chemotherapy, 50% of patients showed a survival time of at least 7 months. In the absence of any direct comparisons, we do not know if this represents an improvement over the results obtained with the best palliative care. (3) The only potential cure for myelodysplastic syndromes is allogeneic haematopoietic stem cell transplantation but this is not always feasible. Some myelodysplastic syndromes are associated with myeloproliferation and PDGFR gene rearrangements; imatinib is the first drug available for these patients. The manufacturer has compiled data on 55 patients treated with imatinib. Most patients had a favourable haematological response, but no survival data were published. (4) The severity of the hypereosinophilic syndrome is highly variable. Forms associated with FIP1L1-PDGFRalpha gene rearrangements have a poor prognosis. Clinical evaluation of imatinib in this setting is based on a compilation of data concerning 176 treated patients. The haematological response rate was high in patients with the mutant gene, but it is not known whether this translated into increased survival. (5) Dermatofibrosarcoma protuberans is a rare form of mainly localised skin cancer. Treatment is based on surgical excision but relapses are frequent. In one series, 9 out of 12 patients treated with imatinib had at least a partial tumour response, making surgical excision possible in 3 cases. (6) Imatinib has diverse and frequent adverse effects; nausea and vomiting, oedema, fluid retention, cutaneous disorders and heart failure. There is some evidence pointing to a risk of urologic cancers and altered bone metabolism.
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PMID:Imatinib: new indication. New indications, but not robust evidence. 1862 99

Hypereosinophilic syndrome (HES) is a rare disorder characterized by persistent marked eosinophilia combined with eosinophil-mediated organ damage. Myeloproliferative variants are associated with a high prevalence of cardiac involvement, which is very unusual in lymphocytic variants. Imatinib mesylate (Gleevec(R)) is a small molecule with tyrosine kinase activity that has shown marked effects in some individuals with HES. In this case report, we present a patient with a hypereosinophilic syndrome (lymphocytic variant) that first manifested as hypereosinophilia and heart failure secondary mainly to right ventricle systolic dysfunction. A week after imatinib therapy instauration the eosinophil count was within normal range but the patient suffered a severely left ventricular dysfunction that was restablished after early drug withdrawal. Surgical removal of a new onset mass in right atrium was required because of progressively growth despite anticoagulant therapy. Clinicians should be aware of the variable heart manifestations in patients with HES and the potential cardiotoxicity of imatinib.
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PMID:Atypical cardiac manifestation of hypereosinophilic syndrome and reversible cardiotoxicity to imatinib. 1905 37

Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy-specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem.
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PMID:Why do kinase inhibitors cause cardiotoxicity and what can be done about it? 2072 98

In vitro studies have suggested that imatinib may be toxic to cardiac myocytes. Though retrospective studies have not shown clinical heart failure, these did not look for subtle cardiac damage. We have carried out a prospective cardiac assessment in 59 chronic myeloid leukaemia (CML) patients treated with imatinib for a median of 3.4 years, using echocardiography and MUGA scanning, with the latter repeated after a further year. We report no evidence of myocardial deterioration, either at baseline or over 12 months of imatinib treatment. Imatinib cardiotoxicity is not an important clinical consideration for CML patients or their advisors.
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PMID:A prospective evaluation of cardiac function in patients with chronic myeloid leukaemia treated with imatinib. 2097 Jan 88

In 2002, patients with inoperable or metastatic gastrointestinal stromal tumours had a median overall survival time of about 19 months with available treatment options. When it was first marketed in this setting in 2002, the efficacy of imatinib, a tyrosine kinase inhibitor, was mainly based on one trial evaluating a surrogate endpoint. This review examines new data, focusing on overall survival. Longer-term data have been published for 56 patients enrolled in a trial comparing imatinib doses of 400 mg and 600 mg per day. The median overall survival time was 57 months and the median progression-free survival time was about 24 months, with no statistically significant difference between the two doses. Two randomised unblinded trials with similar designs compared imatinib doses of 400 mg and 800 mg/day in a total of more than 1600 patients. Combined analysis of the two trials showed no statistically significant difference in median overall survival between the two doses (48.8 months). In contrast, median progression-free survival was significantly longer with the higher dose, by about 4 months. Another trial compared continued treatment versus imatinib withdrawal after a year of treatment in patients whose tumour had stabilised on imatinib 400 mg/day. Imatinib withdrawal was associated with a higher risk of progression. However, when treatment was resumed at a dose of 400 mg/day after disease progression in 26 patients, the median overall survival time was similar to that in patients receiving continuous treatment. Initially, clinical evaluation showed that imatinib provoked many adverse effects, some of which were potentially severe. Cases of heart failure, secondary malignancies, bone remodelling and hepatic and ovarian disorders have since been reported. In the two trials comparing daily imatinib doses of 400 mg and 800 mg, about half of the patients experienced a serious adverse effect. The frequency of serious adverse effects was significantly higher with a daily dose of 800 mg than with 400 mg. The mortality rate was higher with imatinib 800 mg/day. In practice, compared with cytotoxic chemotherapy, imatinib provides a tangible overall survival benefit in patients with inoperable or metastatic gastrointestinal stromal tumours, at a cost of varied, frequent and potentially life-threatening adverse effects.
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PMID:Imatinib and inoperable or metastatic gastrointestinal stromal tumours. Longer follow-up confirms the overall survival benefit. 2164 23

Because it is safe and well tolerated, imatinib is a standard first-line therapy for chronic myeloid leukemia (CML). Although there have been sporadic reports of imatinib-induced cardiotoxicity, including left ventricle (LV) dysfunction and heart failure, the evidence for it is contradictory. Here, we reported a case of an 88-year-old male patient with CML developed decompensated heart failure following imatinib therapy. Four days after the initiation of imatinib, the patient developed orthopnea, edema and a pleural effusion accompanied by abdominal distension, nausea and vomiting. The chest X-ray film showed an enlarged cardiac profile. The echocardiogram demonstrated a decreased LV ejection fraction and enlarged left-side cardiac chambers. B-type natriuretic peptide concentrations were markedly increased. The patient recovered soon after the withdrawal of imatinib and introduction of comprehensive therapy for heart failure. Imatinib-induced cardiotoxicity in elderly patients is a potentially serious complication that merits further evaluation.
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PMID:Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review. 2334 47

A 78-year-old male, who had CKD and chronic heart failure, was referred to our hospital for evaluation of leukocytosis. His bone marrow contained 12% blast cells and chromosome analysis showed the Ph chromosome as well as other changes. The patient was diagnosed with the accelerated-phase CML because FISH and RT-PCR disclosed BCR/ABL fusion signals and minor BCR/ABL, respectively. Imatinib was administered, but the CML was resistant to this treatment. We gave him nilotinib employing a reduced and intermittent administration protocol because of the progression of anemia and heart failure. The patient achieved PCyR in 8 months, but, 12 months later, his WBC count increased and 83% of the cells were blasts. Because the probable diagnosis was the blast crisis of CML, we switched from nilotinib to dasatinib. However, leukocytosis worsened and he died of pneumonia. It was later revealed that he had a normal karyotype and both FISH and RT-PCR analysis of BCR/ABL were negative. His final diagnosis was Ph negative AML developing from Ph positive CML in PCyR. Since there were no dysplastic changes indicative of MDS, it was assumed that the AML was not secondary leukemia caused by the tyrosine kinase inhibitor but, rather, de novo AML.
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PMID:[Development of Ph negative acute myeloid leukemia in a patient with minor-BCR/ABL positive chronic myeloid leukemia achieving a partial cytogenetic response during tyrosine kinase inhibitor treatment]. 2625 79

We are pleased to announce that the following 4 articles have been selected for the the UEDA Heart Awards for the Year 2016.First PlaceDelivery of Imatinib-Incorporated Nanoparticles into Lungs Suppresses the Development of Monocrotaline-Induced Pulmonary Arterial HypertensionSatoshi Akagi, Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Hiromi Matsubara, Aiko Ogawa, Tetsuya Matoba, Kensuke Egashira, Hiroshi ItoInt Heart J 2015 ; 56(3) : 354-359Second PlaceVasopressin V2 Receptor Antagonist Tolvaptan Is Effective in Heart Failure Patients With Reduced Left Ventricular Systolic Function and Low Blood PressureSatoshi Suzuki, Akiomi Yoshihisa, Takayoshi Yamaki, Koichi Sugimoto, Hiroyuki Kunii, Kazuhiko Nakazato, Yukihiko Abe, Tomiyoshi Saito, Takayuki Ohwada, Hitoshi Suzuki, Shu-ichi Saitoh, Isao Kubota, Yasuchika Takeishi, on behalf of the AVCMA investigatorsInt Heart J 2015 ; 56(2) : 213-218Third PlaceWaon Therapy Improves Quality of Life as Well as Cardiac Function and Exercise Capacity in Patients With Chronic Heart FailureMitsuo Sobajima, Takashi Nozawa, Yasutaka Fukui, Hiroyuki Ihori, Takashi Ohori, Nozomu Fujii, Hiroshi InoueInt Heart J 2015 ; 56(2) : 203-208Association of Fish Consumption-Derived Ratio of Serum n-3 to n-6 Polyunsaturated Fatty Acids and Cardiovascular Risk With the Prevalence of Coronary Artery Disease : A Cross-Sectional Pilot StudyShigemasa Tani, Atsuhiko Takahashi, Ken Nagao, Atsushi HirayamaInt Heart J 2015 ; 56(3) : 260-268November 2016International Heart Journal Association.
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PMID:Announcement: UEDA Heart Award for 2016. 2791 90


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