Cardiotoxicity of 5-fluorouracil and capecitabine in a pancreatic cancer patient with a novel mutation in the dihydropyrimidine dehydrogenase gene.

CONTEXT: 5-fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the pathway that catabolises the pyrimidines. 5-fluorouracil and its oral prodrug capecitabine are used in the treatment of a number of solid tumors, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and alopecia. Cardiotoxicity is a relatively uncommon side effect of 5-fluorouracil and capecitabine. CASE REPORT: This article reports the case of a 63-year-old male with locally invasive pancreatic cancer who developed recurrent chest pain and ischemic electrocardiogram changes after treatment with 5-fluorouracil and capecitabine. Full sequencing of the dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the thymidylate synthetase (TYMS) gene promoter region was performed. Pharmacogenetic testing revealed p453L (1358C>T) type DPYD germ line mutation. This mutation has not been reported previously in association with 5-fluorouracil induced cardiotoxicity. CONCLUSION: Cardiotoxicity associated with 5-fluorouracil and capecitabine administration is infrequently reported in the literature and appears to be dose and schedule dependent. Genetic variations such as polymorphic abnormality of DPYD are potential causative factors for a significant portion of serious adverse reactions to 5-fluorouracil-based therapy.

Impact of anesthesia on valvular function in normal rats during echocardiography.

Anesthetic agents have different effects on hemodynamic and cardiac functional parameters. The influence of these changes on valvular function has not been studied in small animals. For this purpose, 48 male Wistar rats were divided into three equal groups. An echocardiogram was performed under inhaled isoflurane 2% gas (group I) or under intraperitoneal pentobarbital 50 mg/kg (group II) or ketamine/xylazine (group III) 40/8 mg/kg. Aortic regurgitation was only found in group III (80%, p < 0.0001 vs. groups I and II). Pulmonary and mitral regurgitation (PR, MR) were observed in all groups but were more frequent in group III (PR 67%, MR 100%) compared with group I (PR 13%, p = 0.003; MR 44%, p = 0.001 vs. group III) and group II (PR 19%, p = 0.011; MR 25%, p < 0.0001 vs. group III). Moreover, valvular regurgitations in group III (except tricuspid regurgitation) were more severe compared with groups I and II. The findings in group III were the result of increased blood pressure and afterload, left ventricular (LV) dilation and decreased function. Also in group III, the regurgitations diminished over time as the blood pressure decreased and LV function recovered. Isoflurane and pentobarbital had less pronounced effects on valvular function (5 and 10 min after induction, respectively) compared with ketamine/xylazine and, therefore, might be the anesthetics of choice for valvular evaluation in male Wistar rats. In conclusion, anesthesia causes hemodynamic changes that may result in functional valvular regurgitations in normal rats.

Pergolide use in Parkinson disease is associated with cardiac valve regurgitation.

OBJECTIVE: To determine if pergolide injures heart valves, by comparing echocardiographic findings in pergolide-treated patients with those of a historical control group. METHODS: Letters were sent to all patients in the authors' practice believed to be taking pergolide, and those responders who wished to continue it were urged to undergo echocardiography. Echocardiograms were obtained on 46 patients, and scores for valvular regurgitation were compared with those from an age-matched control group derived from the Framingham Study. The composite valve regurgitation score was modeled as a linear function of total milligrams lifetime use of pergolide, controlling for age. RESULTS: Eighty-nine percent of pergolide-treated patients had some degree of valvular insufficiency. For each of the three valves for which there are control data, we found an approximately 2- to 3-fold increased risk of abnormal valves in the pergolide patients (odds ratio [OR] approximately 3) and an estimated 14-fold increased risk of concerning tricuspid regurgitation (OR = 18.4). The composite valve score (the sum of valve scores for each of the four valves) was a function of lifetime pergolide use. CONCLUSION: Pergolide may injure cardiac valves, resulting most commonly in tricuspid regurgitation.

Static and dynamic pressure-volume curves reflect different aspects of respiratory system mechanics in experimental acute respiratory distress syndrome.

INTRODUCTION: A lower inflection point, an upper inflection (or deflection) point, and respiratory system compliance can be estimated from an inspiratory static pressure-volume (SPV) curve of the respiratory system. Such data are often used to guide selection of positive end-expiratory pressure (PEEP)/tidal volume combinations. Dynamic pressure-volume (DPV) curves obtained during tidal ventilation are effortlessly displayed on modern mechanical ventilator monitors and bear a theoretical but unproven relationship to the more labor-intensive SPV curves. OBJECTIVE: Attempting to relate the SPV and DPV curves, we assessed both curves under a range of conditions in a canine oleic acid lung injury model. METHODS: Five mongrel dogs were anesthetized, paralyzed, and monitored to assure a stable preparation. Acute lung injury was induced by infusing oleic acid. SPV curves were constructed by the super-syringe method. DPV curves were constructed for a range of PEEP and inspiratory constant flow settings while ventilating at a frequency of 15 breaths/min and tidal volume of 350 mL. Functional residual capacity at PEEP = 0 cm H2O was measured by helium dilution. The change in lung volume by PEEP at 8, 16, and 24 cm H2O was measured by respiratory inductance plethysmography. RESULTS: The slope of the second portion of the DPV curve did not parallel the corresponding slope of the SPV curve. The mean lower inflection point of the SPV curve was 13.2 cm H2O, whereas the lower inflection point of the DPV curve was related to the prevailing flow and PEEP settings. The absolute lung volume during the DPV recordings exceeded (p < 0.05) that anticipated from the SPV curves by (values are mean +/- SEM) 267 +/- 86 mL, 425 +/- 129 mL, and 494 +/- 129 mL at end expiration for PEEP = 8, 16, and 24 cm H2O, respectively. CONCLUSIONS: The contours of the SPV curve are not reflected by those of the DPV curve in this model of acute lung injury. Therefore, this study indicates that DPV curve should not be used to guide the selection of PEEP/tidal volume combinations. Furthermore, an increase in end-expiratory lung volume occurs during tidal ventilation that is not reflected by the classical SPV curve, suggesting a stable component of lung volume recruitment attributable to tidal ventilation, independent of PEEP.

[Appetite suppressants and heart valve disorders]. / Atteintes valvulaires des anorexigènes.

Serotoninergic appetite-suppressant drugs, fenfluramine and dexfenfluramine, were withdrawn from the market in September 1997 on account of two major cardiopulmonary complications: primary pulmonary hypertension and valvular regurgitation. The valvular heart diseases involve mainly left-sided valves, and contrary to physiological valvular regurgitations, they appear mostly on the aortic valve. Prolonged exposure (> 3 months) appears to confer a higher risk of cardiac valve involvement. Pathological features are similar to carcinoid or ergot alkaloid-induced valve diseases, and suggest a common pathophysiological mechanism which would also explain pulmonary hypertension by the toxic effect of high levels of circulating serotonin. After the first reports documenting a dramatically high prevalence of valvular side effects (up to 33% according to the Food and Drug Administration), recent studies reported a lower prevalence and severity. The long-term outcome and the real incidence are unknown and require further research and epidemiological data. A clinical survey of the patients exposed to serotoninergic appetite-suppressants is necessary, to be repeated 6 to 8 months later in the absence of an initial cardiac murmur. Doppler echocardiographic examination should be performed after prolonged exposure (> 3 months) or a high dosage of these drugs, in circumstances such as the presence of cardiovascular symptoms, a cardiac murmur, or an uncertain cardiac examination because of weight of patients.

Methysergide-induced heart disease: a case of multivalvular and myocardial fibrosis.

Methysergide (Sansert) is known to cause mitral and aortic valvular fibrosis and dysfunction, but has generally not been known to damage right heart valves or the myocardium, and cardiac fibrosis has not been considered to be a risk if therapy is intermittently interrupted. The woman who is the subject of this case report developed catheterization-proven severe tricuspid and moderate aortic and mitral regurgitation during noncontinuous therapy with methysergide. In addition, right ventricular endomyocardial biopsy revealed extensive endocardial and intramyocardial fibrosis.