Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992-2001.

OBJECTIVE: To evaluate the longitudinal development of the tricuspid gradient (TG) for screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc). METHODS: Doppler echocardiography was performed 506 times in order to estimate TG in 227 consecutive patients with SSc. The value of biochemical markers for predicting TG levels and development was assessed through analyses of pro-brain natriuretic peptide (proBNP), calcitonin-gene related peptide, thrombomodulin and von Willebrand factor in 76 patients with a borderline increase in TG, defined as TG 24-38 mmHg, and for the purpose of comparison also in 10 patients with a normal TG (< 23 mmHg) and in 10 patients with increased TG (TG > 38 mmHg). RESULTS: TG > 23 mmHg was found in 102 patients (44.9%) at the first assessment point and in 139 patients (61.2%) respectively, cumulatively at follow-up. TG values > 33 mmHg were measured in 24 patients (10.6%) initially and in 38 patients (16.7%) cumulatively in a subsequent assessment. Age and the presence of interstitial lung disease (ILD) were associated with more frequent occurrence of TG > 23 and > 33 mmHg initially and at follow-up, but were not associated with progression rate. The change in TG (mean +/- S.D.) was 1.34 +/- 4.55 mmHg/yr. ProBNP correlated to TG. CONCLUSION: An increased TG, indicating possible PAH, is common and progressive in SSc. Age and ILD increase the risk of increased TG. Patients with or without ILD have similar progression of TG. ProBNP has potential as an adjunct to TG in selecting patients eligible for invasive treatment.

Correlation between plasma concentrations of calcitonin gene related peptide and pulmonary pressure in patients with systemic sclerosis.

OBJECTIVE: To examine plasma levels of calcitonin gene related peptide (p-CGRP) in patients with systemic sclerosis (SSc) and pulmonary hypertension (PH). MATERIAL AND METHODS: Twenty nine patients with SSc, 10 with diffuse form, 18 with limited form and one with overlapping systemic lupus erythematosus were examined. Twelve patients displayed normal systolic pulmonary artery pressure (PAPsyst) < or =30 mm Hg and 17 increased PAPsyst >30 mm Hg. Eight patients had isolated PH without interstitial lung disease (ILD) and nine had PH and ILD (secondary PH). PAPsyst was measured non-invasively by Doppler cardiography. CGRP was determined by radioimmunoassay. RESULTS: Patients with PH had higher p-CGRP than patients with normal pressure. A positive relation was found between p-CGRP and PAPsyst and between p-CGRP and erythrocyte sedimentation rate (ESR), particularly in patients with isolated PH. CONCLUSION: In patients with SSc p-CGRP correlates with pulmonary pressure and with ESR. Whether CGRP reflects disease activity or is released secondary to pulmonary vasoconstriction needs to be investigated further.

Left atrial appendage outflow velocity index is superior to conventional criteria for prediction of maintenance of sinus rhythm after cardioversion. An echocardiographic study in patients with atrial fibrillation of a few months' duration.

OBJECTIVE: To investigate whether left atrial appendage outflow velocity alone or in relation to left atrial diameter is a superior predictor of sinus rhythm maintenance after cardioversion compared with traditional clinical or echocardiography parameters. DESIGN: Sixty-two patients with their first episode of atrial fibrillation were examined using echocardiography before DC-cardioversion. At one month's follow-up, 42 patients had maintained sinus rhythm (group A), and 20 had relapsed into atrial fibrillation (group B). There were no differences in arrhythmia duration or antiarrhythmic therapy between the groups. RESULTS: Left atrial diameter measured by echocardiography was smaller in group A (42 mm, 95% CI 40.9-44.1 mm) compared with group B (46 mm, 95% CI 43.4-48.2, p < 0.05). Patients in group A had a higher left atrial appendage outflow velocity at 0.44 m/s (95% CI 0.39-0.49) compared with 0.34 m/s (95% CI 0.30-0.37) in group B (p < 0.01). The ratio of left atrial appendage flow to left atrial diameter was 0.011 (95% CI 0.009-0.012) in group A compared with 0.008 (95% CI 0.007-0.009) in group B, and 63% (95% CI 33-78) of the patients in group A had velocity ratio >0.009 compared with 20% (95% CI 2-38) in group B, (p < 0.01). Stepwise multiple logistic regression analysis showed that a velocity ratio >0.009 was the only predictor for maintenance of sinus rhythm one month after cardioversion with an odds ratio of 6.4 (95% CI 1.9-23.8), (p = 0.004). CONCLUSION: The ratio of left atrial appendage outflow velocity to left atrial diameter is superior to the traditionally used criteria for prediction of maintenance of sinus rhythm following DC-conversion of first-episode atrial fibrillation.

Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation.

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

Low individualized growth hormone (GH) dose increased renal and cardiac growth in young adults with childhood onset GH deficiency.

OBJECTIVE: In childhood onset GH deficiency (GHD) a reduction in left ventricular mass (LV-mass) and impairment of systolic function as well an impairment in glomerular filtration rate (GFR) has been shown. The aim of the present study was to assess if a low GH dose resulted in an improvement in morphological and functional parameters of these organs. DESIGN AND PATIENTS: Eleven patients with childhood onset GHD were investigated before and after 10 months of GH treatment at a dose of 1.5 IU/day (range 1-2), corresponding to 0.02 IU/kg/day or 7 microg/ kg/day. The GH dose resulted in a serum IGF-I level in the normal range in all but one patient. MEASUREMENTS: Doppler echocardiography of the heart and ultrasound examination of the kidneys was performed. Glomerular filtration rate (GFR) was estimated with iohexol clearance and urinary proteinuria was measured with 24-h urinary samples collected for analyses of albumin, alpha-1-microglobulin, IgG and albumin/creatinine clearance ratio. Body composition was measured by bioelectric impedance analysis. RESULTS: L V-mass index increased significantly after GH treatment (P = 0.04), and there was a clear trend for a positive correlation between the increase in serum IGF-I and the increase in LV-mass index, although it did not reach significance (r= 0.57, P = 0.07). GH treatment did not increase cardiac fractional shortening. Kidney length increased significantly (P = 0.02) with an average increase of 1 cm (range - 0.5-1.5 cm). No significant changes in median GFR or serum creatinine were recorded. Three patients with subnormal GFR before GH treatment normalized after 10 months of treatment. Urine analysis showed no abnormalities before or after GH treatment. A significant decrease in percentage fat mass was recorded (P = 0.03). CONCLUSION: A low individualized GH dose to adults with childhood onset GHD resulted in an increase in LV-mass index and kidney length. Re-establishing GH treatment with a low dose in this patient group can lead to a further somatic maturation of these organs, probably not accomplished previously.

Organ damage in treated middle-aged hypertensives compared to normotensives: results from a cross-sectional study in general practice.

BACKGROUND: High blood pressure contributes to organ damage. However, during the past two decades there have been great advances in the medical treatment of hypertension. Technical progress has also made it easier to visualize organ damage. Hence we found it of interest to examine heart, brain and retina in a group of middle-aged treated hypertensives, comparing the results with those from a group of middle-aged normotensives. METHODS: The subjects were 40 (20 men) treated hypertensives and 40 (20 men) normotensives, who had previously taken part in a study in which ambulatory blood pressure monitoring had been performed. The heart was examined by echocardiography, the retina by photography and the brain by magnetic resonance imaging. RESULTS: Office blood pressure and 24-h systolic/diastolic blood pressure (S/D) were 141/86 (13/7) mmHg and 128/81 (11/6) mmHg in the hypertensives and 125/78 (10/8) mmHg and 118/74 (8/5) mmHg in the normotensives, respectively. Left ventricular mass was 101 (27) g/m2 in the hypertensives and 85 (18) g/m2 in the normotensives (p = 0.0025). The corresponding figures for the left atrium were 21.1 (3.1) mm/m2 in the hypertensives and 19.5 (2.2) mm/m2 in the normotensives (p < 0.001). E/A wave quotient was 1.09 (0.26) in the hypertensives and 1.26 (0.26) in the normotensives (p = 0.0045), while left ventricular systolic function did not differ between the groups. Ten hypertensives and one normotensive subject had left ventricular mass above normal range. Narrow retinal arteries were found in 22 hypertensives and 8 normotensives (p < 0.001). Brain magnetic resonance changes (deep white matter and/or periventricular) were found in 19 hypertensives and 9 normotensives (p = 0.0431). CONCLUSIONS: The hypertensives differed significantly from the normotensives concerning left ventricular mass, left atrium, left ventricular diastolic function and retinal vessel changes. Deep white matter and periventricular changes in the brain were also significantly different in the two groups. We can only speculate as to whether earlier antihypertensive treatment or further blood pressure reduction could have affected these differences.

Transoesophageal echocardiography-guided cardioversion of atrial fibrillation or flutter. Selection of a low-risk group for immediate cardioversion.

AIMS: Despite exclusion of left atrial thrombi by transoesophageal echocardiography, cardioversion-related thromboembolism has been reported in atrial fibrillation or flutter. To define a low-risk group for cardioversion without previous anticoagulation, patients were selected for immediate cardioversion if there were no thrombi, no echo spontaneous contrast and the outflow velocity of the left atrial appendage was greater than 0.25 m. s(-1)on transoesophageal echocardiography. METHODS AND RESULTS: Two hundred and forty-two consecutive patients referred for cardioversion of atrial fibrillation or flutter with a duration of more than 2 days and no anticoagulation therapy were examined with transoesophageal echocardiography. After the transoesophageal echocardiography examination, patients who were eligible for immediate cardioversion were anticoagulated with low molecular weight heparin (dalteparin) subcutaneously, together with warfarin prior to cardioversion. Dalteparin treatment was continued until the patient had reached therapeutic prothrombin values. Based on the transoesophageal echocardiographic findings the patients were divided into two groups: immediate cardioversion, group A, with a mean age of 62+/-13 years (n=162); or conventional warfarin treatment before cardioversion, group B, with a mean age of 67+/-10 years (P<0.05) (n=80). In group A, lone atrial fibrillation or flutter was more common (53%; 95% CI: 45-61) compared to group B (34%; 95% CI: 23-44, P<0.05), while heart disease was more common in group B (45%; 95% CI: 34-56) compared to group A (31%; 95% CI: 24-39, P<0.05). Echocardiography revealed thrombi in 5% (95% CI: 2.6-8) of the patients, left atrial size was larger, fractional shortening lower, and a higher proportion had impaired left ventricular function in group B. No thromboembolic event occurred at or after cardioversion in any of the patients; however, before planned cardioversion one transitory ischaemic attack, one lethal stroke and one cardiac death occurred in three of the patients with thrombi despite warfarin therapy. One-month follow-up maintenance of sinus rhythm was 75% in group A compared to 45% in group B (P<0.01). CONCLUSION: After using our transoesophageal echocardiographic exclusion criteria (no thrombi, no spontaneous echo contrast and left atrial appendage outflow velocity > or = 25 m. s(-1)) cardioversion can safely be performed in 2/3 of patients with atrial fibrillation or flutter without previous anticoagulation therapy. These patients maintained sinus rhythm significantly better after 1 month compared to patients with prolonged warfarin therapy before cardioversion.

Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors.

We recently reported that female patients with hypopituitarism receiving controlled thyroid and steroid hormone substitution, but without GH replacement, had a more than 2-fold increase in cardiovascular mortality compared to the general population. In the present study we investigated the incidence of cardiovascular disease as well as the prevalence of cardiovascular risk factors in 33 females with hypopituitarism for 6-46 yr (median, 18) compared to those in 33 control subjects recruited from the general population in the same geographical area and matched for sex, age, smoking habits, educational level, and residence location. The patients were with a very high probability GH deficient, as 29 had subnormal serum insulin-like growth factor I levels, and the other 4 were GH deficient, as assessed by an insulin tolerance test. The incidence of cardiovascular disease was significantly higher among the hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2-11.3), and the consumption of cardioactive drugs was also significantly higher (P = 0.002). Hypopituitary patients had a lower degree of physical exercise during their spare time (P = 0.02), a higher waist/hip ratio (P = 0.01), lower high density lipoprotein cholesterol (P = 0.002), and higher low density/high density lipoprotein ratio (P = 0.009). Furthermore, the patients had a significantly increased left atrium size (P = 0.05), but no difference was observed for other cardiac measures. In the patients, serum insulin-like growth factor I levels significantly correlated with left ventricular mass index (r = 0.48; P = 0.006), suggesting that GH has a strong impact on cardiac size. More episodes of bradycardia (P = 0.05), but no increased occurrence of extrasystolies, were encountered in the patients during 24-h continuous electrocardiogram monitoring. Carotid artery intima-media thickness and plaque numbers did not differ between patients and controls. In conclusion, hypopituitary females exhibit an increased incidence of cardiovascular disease, higher cardioactive drug consumption, and an increased prevalence of cardiovascular risk factors. The increased cardiovascular morbidity could not be ascribed to inadequate estrogen or thyroid hormone treatment, and unsubstituted GH deficiency is probably an important contributing factor.

High incidence of cardiovascular disease and increased prevalence of cardiovascular risk factors in women with hypopituitarism not receiving growth hormone treatment: preliminary results.

Recently, epidemiological evidence has suggested that hypopituitarism with untreated growth hormone deficiency (GHD) is associated with a high incidence of cardiovascular mortality and that women are particularly at risk. In the present study, the incidence of cardiovascular disease and prevalence of cardiovascular risk factors in 33 such women was assessed and compared with matched controls. A significantly higher number of diagnosed circulatory disorders occurred in the women with hypopituitarism compared with controls, and drug consumption for cardiovascular disorders was also significantly higher in this group. Furthermore, patients with hypopituitarism had a significantly higher waist:hip ratio and a higher ratio of low-density lipoprotein to high-density lipoprotein than controls. Electrocardiogram data showed that hypopituitarism was associated with more episodes of bradycardia. In summary, women with hypopituitarism had an increased incidence of cardiovascular disease and a less favourable risk factor profile compared with matched controls. The data add support to previous studies that have shown increased risks of cardiovascular mortality associated with hypopituitarism with untreated GHD. We conclude that adequate cardiovascular surveillance programmes are required for patients with pituitary insufficiency.

No serious late cardiac effects after adjuvant radiotherapy following mastectomy in premenopausal women with early breast cancer.

PURPOSE: To assess cardiac mortality, coronary artery disease, myocardial dysfunction, and valvular heart disease in women younger than 65 years of age, at least 10 years after adjuvant radiotherapy following mastectomy in early breast cancer. METHODS AND MATERIALS: Ninety women (45-64 years old) with Stage II breast cancer without relapse, included in the South Sweden Breast Cancer Trial (premenopausal arm), with or without adjuvant postoperative radiotherapy +/- cyclophosphamide were examined with myocardial scintigraphy and echocardiography/Doppler, 10-17 years after radiotherapy. Thirty-four patients had been irradiated for left-sided tumors, 33 for right-sided tumors, and 23 patients had not been treated with radiotherapy. The radiotherapy (conventional roentgen, electron beams, and high-energy photon beams combined, in each patient) included the chest wall and the regional lymph nodes, with a specified target dose of 38-48 Gy, administered in daily fractions of 1.9-2.4 Gy, 5 days/week. RESULTS: No cardiac deaths were found among the original 275 patients randomized to adjuvant therapy. In the 90 patients examined, abnormal findings were recorded for ECG (14 patients), exercise test (5 patients), myocardial scintigraphy (6 patients), thickening of valve cusps (14 patients), and mild valvular regurgitation (20 patients). All patients had normal systolic function. Diastolic dysfunction was observed in 6 patients (abnormal relaxation in 4 patients and restrictive filling abnormality in 2 patients). Although no significant differences were found between the 3 study groups, there was a tendency to more abnormal findings after radiotherapy. CONCLUSION: Women younger than 50 years of age at the time of adjuvant radiotherapy following mastectomy in early breast cancer, had no serious cardiac sequelae 13 years (median) later, despite partly old-fashioned radiation techniques.

[Heart failure after myocardial infarction: diagnosis, treatment, prevention. Echocardiography should be a routine procedure in myocardial infarction]. / Hjartsvikt efter infarkt: diagnostik, behandling, förebyggande. Ekokardiografi bör bli rutin vid hjrtinfarkt.

Post-infarction prognosis is considerably impaired if left ventricular systolic dysfunction and/or symptomatic heart failure develops. As the symptoms of left ventricular dysfunction are often subtle or completely lacking, such patients can be identified only by objective evaluation of left ventricular function. However, as symptoms of heart failure may develop despite normal left ventricular function, objective evaluation of left ventricular function is also important in symptomatic patients, since prognosis is especially poor in the presence of systolic dysfunction. As echocardiography is the most suitable and accessible method in the context, also allowing assessment of cardiac dimensions and valvular function, its extended use in post-infarction patients is imperative. Left ventricular dysfunction should be prevented by adequate measures to limit the extent of infarction and prevent its recurrence. To improve prognosis, the use of ACE (angiotensin converting enzyme) inhibitors should be considered whenever left ventricular dysfunction is present, irrespective of symptomatology. Treatment with amiodarone has recently been shown to reduce mortality among patients with post-infarction heart failure, and should also be considered in such cases, especially if there is a need of antiarrhythmic therapy. Although beta-receptor blockers have well-documented beneficial effects in myocardial infarction, their effect on patients with latent or overt heart failure has not been specifically studied. The use of angiotensin II antagonists in patients with post-infarction heart failure or left ventricular dysfunction is currently under investigation.

Cardiac changes in stroke patients and controls evaluated with transoesophageal echocardiography.

In stroke patients several cardiac changes associated with embolism can be detected with transoesophageal echocardiography. Potential major cardiac embolic sources (e.g. atrial fibrillation, thrombi of left ventricle/atrium, vegetation, myxoma, dilated cardiomyopathy) have a causal relationship to embolism. Other changes with no certain causal relationship are regarded as potential minor cardiac embolic sources (e.g. atrial septal aneurysm, patent foramen ovale, mitral annular calcification, mitral valve prolapse, protruding atheroma of the aorta). We compared the prevalences of major and minor potential cardiac embolic sources in a stroke population with that in controls. One hundred and twenty-one patients with first-ever stroke were compared with 68 randomly selected controls. All subjects underwent magnetic resonance imaging of the brain, carotid ultrasound and transthoracic/transoesophageal echocardiography. The patients were slightly older (mean age 70.7 +/- 10.3 years) than the controls (65.5 +/- 15.5 years) (p < 0.05). Potential major cardiac embolic sources were found in 27% of the patients and in 4% of the controls (p < 0.001). The most common major potential embolic source was atrial fibrillation, detected in 22/121 patients. Fifteen of these also had spontaneous echocontrast in the left atrium. Eleven left atrial thrombi were found (four of these patients had atrial fibrillation and seven had sinus rhythm). A history of heart disease was more common in patients with a potential major cardiac embolic source or a carotid artery stenosis (77%) than in those patients without (44%) (p < 0.01). After excluding subjects with a major potential cardiac embolic source and/or carotid artery stenosis, no differences in the prevalence of minor potential cardiac embolic sources were found between patients (55%) and control subjects (47%) (p = NS). Even when subjects without a major potential cardiac embolic source or a carotid artery stenosis were categorized into three age groups (35-54, 55-74 and > 74 years) the prevalence of potential minor cardiac embolic sources did not differ between patients and controls. To conclude, major potential cardiac embolic sources are more common in an older population with first-ever stroke than in a comparable control group. However, potential minor cardiac embolic sources did not differ in prevalence in the patients compared with controls. Certain changes (e.g. atrial septal aneurysm) might have a potential embolic role in younger stroke patients but in our study no difference was found between older stroke patients and controls.

The influence of 5-fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture.

BACKGROUND: Cardiotoxicity still remains an unexplained toxic manifestation of 5-fluorouracil (5-FU). Clinical and experimental data suggest that endothelium of coronary arteries could be involved in the pathophysiological mechanisms of the syndrome. In order to further explain 5-FU induced cardiotoxicity, we investigated the influence of this drug on endothelial cells (EC) in a cell culture model. MATERIALS AND METHODS: The influence of 5-FU on EC, with respect to DNA synthesis, cell death and release of prostacyclin by endothelial cells (EC) was studied. For comparison, we tested methotrexate (MTX), an antimetabolite without cardiotoxic properties, in the same way. Human endothelial cell lines (HEC) and bovine endothelial cells (BEC) were incubated with increasing concentrations of 5-FU and MTX for 48 hours. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells and 6-keto-prostaglandin F1 were measured. RESULTS: DNA synthesis decreased significantly in both HEC and BEC, and the release of prostacyclin by BEC increased significantly when incubated with 5-FU. This effect was not seen with MTX. CONCLUSION: The results indicate specific susceptibility of benign EC to 5-FU. Such susceptibility was confirmed by the release of prostacyclin by the BEC, indicating leakage secondary to EC injury.

Potential cardioembolic sources in an elderly population without stroke. A transthoracic and transoesophageal echocardiographic study in randomly selected volunteers.

Transoesophageal echocardiography renders a better image than transthoracic echocardiography of cardiac changes especially at the atrial level, and of atherosclerotic changes in the aorta. Although several studies on stroke patients have included transthoracic and transoesophageal echocardiography, the relevance of the reported findings remains unclear because of limited information on the prevalence of cardiac changes related to cardioembolism in a control population without stroke. In order to define a non-hospitalized group of volunteers without previous stroke or transient ischaemic attack, we randomly selected a group of 68 volunteers (mean age 65.4 years). These volunteers were divided into two groups: the elderly group, 65 years or older (n = 38) and the younger group, younger than 65 years (n = 30). The subjects underwent transthoracic and transoesophageal echocardiography, sonography of the carotid arteries, and magnetic resonance imaging of the brain. The prevalences of atrial septal aneurysm, patent foramen ovale, mitral annulus calcification, and protruding plaque in the aorta were investigated. We found atrial septal aneurysm in 13%, patent foramen ovale in 22%, protruding plaque in the aorta in 7%, and mitral annular calcification in 22% of the 68 subjects. No significant differences were found between the two age groups with the exception of mitral annular calcification, which was seen more often in the older group (P < 0.001). Total cardiac changes related to thromboembolism (including three cases with atrial fibrillation in the older group and other less common cardiac embolic sources) were more common in the older than in the younger group (23/38 vs 9/30; P < 0.05). If mitral annular calcification was excluded, no difference was found between the elderly and the younger group, 14/38 vs 8/30; ns. Even when subjects with a history of heart disease or a pathological ECG were omitted, no differences between the two age groups were found. The causal relationship between a possible embolic source and a clinical embolic event remains unsettled. The high prevalence of cardiac changes in a control population has to be considered when evaluating the significance of similar findings in patients with stroke.

The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits.

Cardiotoxicity is an unexplained toxic manifestation of 5-fluorouracil (5-FU). Its possible mechanism could be a direct cytotoxic effect on the vascular endothelium. We have tested this hypothesis in an experimental study in rabbits, using scanning and transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear). The perfusion fixation method at physiological pressure and temperature was used. Both local and systemic effects of 5-FU on endothelium were studied 1, 3, 7, 14 and 30 days after in vivo treatment with 5-FU. Fifteen rabbits were used and five additional animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell oedema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter, a scale of negative points (0.0-3.0) was used. We found severe cell damage with accompanying thrombus formation. The findings support the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on endothelium, is the pathophysiological mechanism behind 5-FU cardiotoxicity.

The influence of 5-fluorouracil on the endothelium in small arteries. An electron microscopic study in rabbits.

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU induced cardiotoxicity is a still relatively unknown side-effect of this drug. This phenomenon could be due to a direct cytotoxic effect on the endothelial cells. We tested this hypothesis in an experimental study in rabbits, by scanning or transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear) after in vivo treatment with 5-FU. Both local and systemic effects of 5-FU on endothelium were studied 15, 30, 60 and 120 minutes after intra-arterial or intraperitoneal treatment. Perfusion fixation at physiological pressure and temperature was used in order to minimize damage to the endothelium during the preparation procedure. Eighteen rabbits weighing 2.5-3.0 kg were used, and 6 animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell edema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter a scale of negative points was used. Irreversible cell damage was observed in 5-FU treated animals: disruption of the endothelial sheet and patchy exposure of the subendothelium, sometimes as a focus for thrombus formation. Our findings support the hypothesis that the thrombogenic effect of 5-FU secondary to its direct cytotoxic effect on endothelium might be one of the pathophysiological mechanisms behind 5-FU induced cardiotoxicity.