Remodeling of ventricular repolarization in a chronic doxorubicin cardiotoxicity rat model

Doxorubicin, one of the most effective anticancer drugs, is characterized by severe cardiotoxic effects, which induce cardiac remodeling and congestive heart failure. The aim of the study was to evaluate remodeling of ventricular repolarization heterogeneity in chronic doxorubicin cardiotoxicity in rats. Doxorubicin cardiotoxicity was produced by six equal intraperitoneal injections of the drug in a cumulative dose of 15 mg/kg in a 2‐week period. Electrophysiological mapping of the ventricular epicardium in situ was performed 6 weeks after the last injection of doxorubicin. Activation–recovery intervals (ARIs) were used for the evaluation of the heterogeneity in repolarization durations. The major findings were as follows: (1) ARIs on the ventricular epicardium of both ventricles were significantly prolonged in the doxorubicin group and (2) this inhomogeneous prolongation of ARIs on the ventricular epicardium resulted in (i) the increase in the dispersion of repolarization across the ventricular epicardium and (ii) the inhomogeneous alterations of the regional ARI gradients on the ventricular epicardium. These changes in repolarization could explain the electrocardiographic alterations, that is, the prolongation of the QT interval and flattening of the T wave.     

Radionuclide evaluation of renal function.

Radionuclide renal scintigraphy offers a rapid, noninvasive method of determining individual kidney function and evaluating suspected urinary tract disorders. The initial portion of this review describes the advantages and limitations of the currently available renal radiopharmaceuticals and discusses techniques for quantitating renal functions. The latter part of the review addresses the role of radionuclide scintigraphy in the evaluation of the renal transplant, possible obstruction, reflux, renovascular hypertension, trauma, and infection.     

Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity.

Metallothionein (MT) may provide protection against doxorubicin-induced heart damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of human MT-IIa gene in transgenic mice. Four healthy transgenic mouse lines were produced. Cardiac MT was constitutively overexpressed from 10- to 130-fold higher than normal. The MT concentration was not altered in liver, kidneys, lungs, or skeletal muscles. Other antioxidant components including glutathione, glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were not altered in the MT-overexpressing heart. Mice (7-wk-old) from transgenic lines expressing MT activity 10- or 130-fold higher than normal and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg, and were killed on the 4th day after treatment. As compared to normal controls, transgenic mice exhibited a significant resistance to in vivo doxorubicin-induced cardiac morphological changes, and the increase in serum creatine phosphokinase activity. Atria isolated from transgenic mice and treated with doxorubicin in tissue bath was also more resistant to functional damage induced by this drug. The results provide direct evidence for the role of MT in cardioprotection against doxorubicin toxicity.     

Synergistic effects of polydatin and vitamin C in inhibiting cardiotoxicity induced by doxorubicin in rats

The purpose of this study was to assess the synergistic effect of polydatin and vitamin C on attenuating cardiotoxicity induced by doxorubicin (DOX) in rats. Polydatin could significantly increase the activity of superoxide dismutase (SOD) and the heart rate, attenuate myocardial pathological damage, decrease malondialdehyde (MDA) content, slightly increase arterial pressure and glutathione peroxidase (GSH‐Px) activity, reduce intervals of QRS, QT, and ST, and lower free fatty acid (FFA) content. The combination of polydatin and vitamin C could significantly increase arterial pressure and heart rate, decrease QRS interval and slightly reduce ST and QT intervals, significantly attenuate myocardial pathological damage, increase the activities of GSH‐Px,T‐SOD, Na⁺K⁺‐ATPase, and Ca²⁺Mg²⁺‐ATPase, elevate phosphocreatine (PCr) and adenosine triphosphate (ATP) contents, slightly increase adenosine diphosphate (ADP) and total adenine nucleotide (TAN) contents and PCr/ATP, and significantly decrease the contents of MDA and FFA, when compared with those in the DOX group. Meanwhile, the improvement effects on FFA content, the activities of ATPase and SOD, and contents of ATP and TAN in combination group were more obvious than those in polydatin group, and the improvement effects on arterial pressure, heart rate, interval of QRS, GSH‐Px activity, and MDA, ADP, and PCr contents in combination group were slightly obvious when compared with those in polydatin group. In addition, the mRNA expression levels of AMPK‐α2 and PPAR‐α were slightly improved in combination group. The results illustrate that the combination of polydatin and vitamin C has the ability to enhance the myocardial protective effects by its antioxidative effect and improve energy metabolism.     

Diltiazem in the prevention and treatment of cocaine-induced cardiotoxicity in dogs

Cocaine can induce serious cardiovascular sequelae, including myocardial depression and coronary artery constriction. The objective of this study was to determine, in the experimental canine model, whether the calcium channel blocker diltiazem, administered intravenously, can ameliorate cocaine-induced cardiotoxicity. The study was conducted in two parts. In the first part of the study, the protective effect of diltiazem against cocaine-induced cardiotoxicity was evaluated. Dogs given pentobarbital were pretreated with either diltiazem 0.25 mg/kg or saline, and then given a 10-mg/kg intravenous bolus of cocaine. In the second part of the study, the role of diltiazem in the treatment of cocaine-induced left ventricular myocardial dysfunction was evaluated. All dogs received a 10-mg/kg intravenous bolus of cocaine. The dogs then received either diltiazem 0.25 mg/kg intravenously or saline. Administration or diltiazem before cocaine reduced the cardiotoxic effects of cocaine. Compared with the control group, there was less depression of the first derivative of left ventricular pressure (LV dP/dt), cardiac output, and left ventricular end diastolic pressure. ST segment elevation occurred in the majority of the control animals after cocaine injection but in none of the animals pretreated with diltiazem. In the second part of the study, cocaine produced left ventricular dysfunction in all animals and ST segment elevation on the electrocardiogram in a majority of the animals. Treatment with diltiazem after the onset of cocaine-induced myocardial dysfunction did reverse the ST segment elevation. It did not, however, improve the hemodynamics significantly compared with the control group. Partial recovery of left ventricular function occurred at 15 minutes in both groups. It was concluded that, in the canine model, administration of diltiazem before injection of cocaine prevents myocardial depression and ST segment elevation. Diltiazem is also effective as treatment to reverse cocaine-induced ST segment elevation but not cocaine-induced myocardial depression.     

Modulation of cytochrome C oxidase-va is possibly involved in metallothionein protection from doxorubicin cardiotoxicity

Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic (MT-TG) mouse model have demonstrated that MT protects from doxorubicin (DOX)-induced oxidative heart injury. The molecular mechanisms that underlie this cardioprotection, however, have yet to be defined. In the present study, we tested the hypothesis that MT overexpression activates cytoprotective mechanisms, leading to cardiac protection from DOX toxicity. MT-TG mice and nontransgenic wild-type (WT) controls were treated i.p. with DOX at a single dose of 20 mg/kg and sacrificed on the third day after the treatment. An expression proteomic analysis involving two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to identify MT-induced changes in cytoprotection-related proteins. We identified 18 proteins that were modified by DOX treatment in the heart. These proteins included those involved in cellular antioxidant defense, enzymes of the mitochondrial electron transport chain, enzymes involved in beta-oxidation of fatty acids and glycolysis, and proteins involved in regulation of cardiac muscle contraction. However, the most dominant modification by MT is the cytochrome c oxidase subunit Va (CCO-Va). In response to DOX treatment, a specific isoform of CCO-Va was enhanced in the MT-TG but not in the WT mouse hearts. Because CCO-Va is a critical component in the mitochondrial electron transport chain, the results suggest that the cardioprotective effect of MT may be related to an increased expression or a differential modification of CCO-Va.     

Radionuclide imaging in the evaluation of osteomyelitis and septic arthritis

Despite controversy over its exact role, radionuclide imaging plays an important role in the evaluation of patients suspected of having osteomyelitis. The differentiation between osteomyelitis and cellulitis is best accomplished by using a three-phase technique using Tc-99m methylene diphosphonate (MDP). Frequently, it is necessary to obtain multiple projections and magnification views to adequately assess suspected areas. It is recommended that a Ga-67 or In-111 leukocyte scan be performed in those cases where osteomyelitis is strongly suspected clinically and the routine bone scan is equivocal or normal. Repeated bone scan after 48 to 72 h may demonstrate increased radioactivity in the case of early osteomyelitis with the initial photon-deficient lesion. In-111 leukocyte imaging is useful for the evaluation of suspected osteomyelitis complicating recent fracture or operation, but must be used in conjunction with clinical and radiographic correlation. The recognition of certain imaging patterns appears helpful to separate osteomyelitis from septic arthritis or cellulitis.     

Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes

The relative cardiotoxicity of pegylated (STEALTH) liposomal doxorubicin (PL-DOX; Doxil) was compared to nonliposomal doxorubicin (Adriamycin) in rabbits and dogs treated i.v. for up to 22 weeks. No histological evidence of cardiotoxicity was seen in dogs treated with placebo liposomes or PL-DOX every 3 weeks for a total of 10 doses (cumulative doxorubicin dose = 10 mg/kg) either 1 or 5 weeks post-treatment. All dogs treated with the same cumulative dose of free doxorubicin showed marked cardiotoxicity (vacuolization and myofibrillar loss in the myocardium) at both time points. In rabbits, progressive cardiomyopathy was seen in both treatment groups, but was more frequent and severe with free doxorubicin (67% of doxorubicin-treated rabbits, cumulative dose = 12 to 14 mg/kg versus 16% of PL-DOX-treated animals, cumulative dose = 14 to 21 mg/kg). Five doxorubicin-treated rabbits died of congestive heart failure or with histologic evidence of cardiotoxicity (median severity score = 6). No PL-DOX-treated rabbits died of congestive heart failure, although two animals that died early showed microscopic evidence of mild cardiotoxicity (median severity score = 2.5). Cardiotoxicity increased during the post-treatment period in both treatment groups. Rabbits received up to 50% more PL-DOX with no increase in cardiotoxicity. Thus, results in two species demonstrate that the cardiotoxicity of doxorubicin is significantly decreased when administered as PL-DOX. Significantly more PL-DOX can be given without incurring an increased risk of cardiomyopathy. Recent clinical studies have confirmed that PL-DOX is also less cardiotoxic than the same dose of unencapsulated doxorubicin in humans.     

超声心动图评估化疗相关心脏毒性的研究进展

辅助化疗已被广泛用于治疗恶性肿瘤,但化疗相关心脏毒性却成为影响患者生存质量和生存率的重要因素。早期、准确预测心脏毒性十分重要。超声心动图因操作简便、经济及无创等优点已广泛应用于评估心功能,其相关新技术可弥补常规超声心动图的不足、提高评估心功能的敏感度和准确率,使早期、准确评估心脏毒性成为可能。本文就超声心动图及其新技术评估化疗相关心脏毒性的研究进展进行综述。     

阿霉素致兔早期心脏毒性模型的建立及超声评价

目的探讨建立阿霉素致兔早期心脏毒性模型的可行性并利用背向散射积分参数联合经胸超声心动图进行评估。方法10只兔每周静脉注射阿霉素2mg/kg,共为4周,同时选10只兔注射同等剂量生理盐水作为对照组。每周对二组兔心脏进行常规超声测量及进行背向散射积分参数测定。结果①常规超声参数阿霉素组与正常对照组无明显差别。②阿霉素组与正常对照组心肌IBS%呈周期性变化,第4周后心肌IBS%较正常对照组明显增高(P<0.05),第3周后CVIB明显减低(P<0.05)。③病理结果显示与人类阿霉素早期心脏毒性相似的改变。结论经静脉注射阿霉素可以形成早期心脏毒性模型,心肌背向散射积分技术联合经胸超声心动图可有效监测评估模型的建立和效果。     

One-dimensional scanning multiphoton imaging reveals prolonged calcium transient and sarcomere contraction in a zebrafish model of doxorubicin cardiotoxicity

Doxorubicin (DOX) is a potent chemotherapeutic agent known to induce cardiotoxicity. Here we applied one-dimensional scanning multiphoton imaging to investigate the derangement of cardiac dynamics induced by DOX on a zebrafish model. DOX changed the cell morphology and significantly prolonged calcium transient and sarcomere contraction, leading to an arrhythmia-like contractile disorder. The restoration phase of calcium transient dominated the overall prolongation, indicating that DOX perturbed primarily the protein functions responsible for recycling cytosolic calcium ions. This novel finding supplements the existing mechanism of DOX cardiotoxicity. We anticipate that this approach should help mechanistic studies of drug-induced cardiotoxicity or heart diseases.     

Radionuclide esophageal transit: an evaluation of therapy in achalasia

We measured quantitative esophageal transit, expressed as percentage of esophageal retention, before and after pneumatic dilatation in two patients with achalasia. In the sitting position they ingested a 500 ml liquid meal containing 500 muCi technetium Tc 99m sulfur colloid. Radioactivity counts of the entire esophagus were plotted at five-minute intervals for 30 minutes. In five normal control subjects the esophagus essentially cleared in less than one minute. Both patients with achalasia had definite retention 30 minutes before dilatation and had quantitative improvement after dilatation. Radionuclide scintigraphic esophageal transit probably correlates better than other parameters with the physiologic degree of obstruction in achalasia.     

前脑利钠肽评价柔红霉素致急性白血病患儿心脏不良反应研究

目的 通过监测急性白血病患儿柔红霉素化疗前后血浆前脑利钠肽(NT-pro-BNP)及心肌酶谱(CK、CKMB)水平变化并进行对照研究,以探讨NT-pro-BNP对柔红霉素引起患儿心肌损伤的敏感程度的评价作用.方法 选取62例确诊急性白血病并接受正规化疗的患儿,根据柔红霉素的累积剂量将其分为三组:A组累积剂量≤60 mg/m2;B组累积剂量60～120 mg/m2;C组累积剂量＞120mg/m2.15例患儿应用去甲柔红霉素或米托蒽醌作为替代柔红霉素治疗分为D组.用电化学发光免疫法测定患儿血浆NT-pro-BNP,用速率法检测心肌酶谱(CK、CKMB).结果 所有人选患儿在应用柔红霉素治疗后NT-pro-BNP水平与未接受柔红霉素化疗时相比明显升高(P=0.000),而应用柔红霉素前后心肌酶谱比较无显著差异(CK,P=0.085;CKMB,P=0.076).柔红霉素累积剂量＞60 mg/m2时NT-pro-BNP水平明显升高(P＜0.01),当累积剂量＞120 mg/m2时CKMB水平开始升高(P＜0.05).15例患儿应用去甲氧柔红霉素或米托蒽醌代替柔红霉素治疗后,NT-pro-BNP水平从(239.9±230.0)ng/L降为(137.0±131.9)ng/L(P＜0.05).结论 ①NT-pro-BNP能比心肌酶谱早期预测柔红霉素引起心脏不良反应.②选用二至三代蒽环类药物可明显减轻患儿心肌不良反应,改善心肌功能.     

Radionuclide studies in chronically hemodialyzed patients. Bone scintigraphy for the evaluation and control of renal osteopathy

The clinical applicability of bone scintigraphy (Tc99m MDP) was evaluated in 42 patients on maintenance hemodialysis. Typical scintigraphic findings are shown which were related to hormonal and biochemical parameters of calcium and phosphate metabolism. Visual grading of representative regions for metabolic bone disease in bone scans was compared to scintimetry which applies a bone to soft tissue ratio to grade osseous abnormalities. It could be shown that visual interpretation and grading of the findings according to a score is sufficient to assess the degree and extent of renal bone disease. Semiquantitative analysis of bone scintigrams by scintimetry did not improve the diagnostic information.     

Paradoxical inhibition of cardiac lipid peroxidation in cancer patients treated with doxorubicin. Pharmacologic and molecular reappraisal of anthracycline cardiotoxicity.

Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342 +/- 131 vs 112 +/- 44 nmol/ml, mean +/- SD; P < 0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m(2) rapidly ( approximately 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134 +/- 95 vs 112 +/- 37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by approximately 80% in response to the infusion of as little as 13 mg DOX/m(2). Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX.