Cardiotoxicity of 5-fluorouracil.

Cardiac side effects of the cytostatic agent 5-fluorouracil (5-FU) have an incidence of 1.2-7.6%. Potentially, arrhythmias, myocardial infarction and sudden cardiac death could occur. Life-threatening cardiotoxicity is rarely observed with a frequency <1%. Cardiotoxicity of 5-FU seems to differ from well known effects of other cytostatics, e.g., anthracyclines. Myocardial ischemia was suggested as potential mechanism due to occasionally observed ECG alterations during 5-FU administration. Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C. In addition, rheological side effects have to be considered. Coronary artery disease is judged to increase the risk of cardiac side effects. Despite lack of prospective trials, verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasms. In addition, modification of the cytostatic regimen has to be considered in patients who had been symptomatic. It could be assumed that 5-FU toxicity is reversible in the majority of cases when acute complications, e.g., arrhythmias, are resolved.

Caffeine inhibits cytokine expression in lymphocytes.

Caffeine alters intracellular calcium signalling patterns in lymphocytes which are important for the specific regulation of activation and effector function in lymphocytes. The effect of caffeine on calcium signalling is probably mediated via a ryanodine receptor type 3 dependent intracellular calcium store which releases calcium after exposure to caffeine. Also, caffeine decreases lymphocyte cytotoxicity against allogenic myocyte. Which cytotoxic mechanisms are actually altered by caffeine is unknown. In mouse splenocyte cultures containing about 87% lymphocytes we show that concanavalin A (ConA, 5 microg/ml) stimulated cells increase the expression of TNF-alpha, IL-2 and IFN-gamma (ELISA) significantly. Caffeine (3.75 mM) inhibits cytokine expression of ConA stimulated cells almost completely. Ryanodine (1 microM) specifically blocks ryanodine receptors and thereby prevents caffeine induced calcium release. In our experiments, however, ryanodine has no effect on ConA stimulated IL-2 and IFN-gamma expression and only suppresses TNF-alpha expression by 20%. Furthermore, ryanodine does not prevent the inhibitory effect of caffeine on TNF-alpha, IL-2 and IFN-gamma expression in stimulated effector cells. We postulate that caffeine suppresses cytokine expression and thereby contributes to decreased cytotoxicity of lymphocytes against allogenic myocytes. The ryanodine receptor dependent intracellular calcium store does not seem to play a significant role in this process. Possibly, the blockade of IP3 receptors by caffeine is more important for cytokine suppression.

Managing a complication after direct stenting: removal of a maldeployed stent with rotational atherectomy.

A 40 year old patient presented with acute anterior wall infarction. A non-calcified lesion was stented directly without significant expansion of the stent. Rotational atherectomy successfully removed parts of the maldeployed stent and resistant arterial wall substance allowing full dilatation of the lesion.

Coronary artery spasm induced by 5-fluorouracil.

The frequently used chemotherapeutic drug 5-fluorouracil (5-FU) is known to cause angina pectoris and arrhythmias; myocardial infarction and sudden cardiac death could occur. Potential reasons for these phenomena range from toxic/metabolic disturbances to coronary artery spasms. This report shows angiographically proven spasmophilia of the coronary arteries and contributes to the understanding of angina pectoris occurring during treatment with 5-FU. Thus, verapamil type calcium antagonists as well as nitrates should be administered primarily in patients with coronary artery disease and in all patients who had been symptomatic during 5-FU administration in order to prevent further episodes.

Hyperinsulinemia, lipoprotein (a), and Chlamydia pneumoniae antibodies--are they risk factors or serologic predictors for progression of coronary artery disease?

The authors studied 134 patients with unstable angina pectoris symptoms and 32 subjects without coronary artery disease (CAD) for the presence of classical risk factors such as hypercholesterolemia, smoking, and family history of CAD. In addition they analyzed plasma insulin levels, lipoprotein (a) (Lp [a]) levels, and antibody titers against Chlamydia pneumoniae. All patients had a heart catheterization. Patients with diabetes mellitus were excluded from the study. Fasting insulin, low-density lipoprotein (LDL) cholesterol and Chlamydia pneumoniae immunoglobulin G (IgG) and IgA antibody titers did not show any difference in CAD from healthy control subjects, whereas Lp(a) was increased and high-density lipoprotein (HDL) decreased in CAD patients. These data indicate that lipoprotein (a), low HDL cholesterol, and smoking, but neither hyperinsulinemia nor elevated Chlamydia pneumoniae titers, are risk factors or predictors for CAD.

Restenosis after percutaneous coronary interventions and infection.

Infectious agents may directly or indirectly (through the response of the host's immune system) modulate the growth of vascular cells. Local and/or systemic increase of cytokines could influence the extent of (re-)stenosis in the vascular tree. Further studies in this field may identify patients at a high risk for atherogenesis and restenosis. Their results should be helpful in treating restenosis after percutaneous coronary interventions.

Strategies to optimize CAD prevention in modern cardiology. The "Marburg CAD Prevention Project".

In recent years we identified numerous cardiovascular risk factors and had been able to reduce cardiovascular events by a variety of different interventions. There is no question that we can improve the course of coronary artery disease (CAD) in patients with a high-risk profile by modifying these factors. Despite this knowledge, many patients with known CAD or myocardial infarction are not treated for secondary prevention as recommended by well established guidelines (http:¿www.chd-taskforce.com). In order to improve secondary prevention in our patients we started a project, the so called "Marburg CAD Prevention Project". By this we combine our computer data base of the CAD preventional routine laboratory with the computer program CARDDAS. Individual risk factors and the angiographic findings were analyzed. Patients as well as local physicians were informed on the need to treat the important risk factors. This approach ensures that at least all of our patients with documented CAD receive the appropriate preventional recommendations and treatment.

[Prevention of coronary heart disease--"evidence-based medicine" of antilipemic therapy]. / Prävention der koronaren Herzerkrankung--"evidence-based medicine" in der Lipidsenkertherapie.

A considerable number of large scale clinical trials provide clear evidence that cholesterol lowering is one of the most important risk-reduction strategies for secondary and primary prevention of coronary artery disease. Unlike the older studies with fibrates, the most recent trials of cholesterol-lowering therapies with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have clearly shown that their use can reduce coronary artery disease and total mortality as well as the need for expensive hospitalization and revascularization procedures. Studies such as the Scandinavian Simvastatin Survival Study (4S), the West of Scotland Coronary Prevention Study (WOS), the Cholesterol and Recurrent Events (CARE) trial and most recently the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) as well as numerous other investigations, have established that decreasing elevated levels of low-density lipoprotein (LDL) cholesterol will result in a reduction in risk of coronary artery disease. In addition, HMG-CoA reductase inhibition reduces the risk for cerebral ischemia. Recent data indicate that less than half of patients with coronary artery disease receive cholesterol-lowering therapy, and few meet the LDL-cholesterol goal. Therefore clinicians treating coronary artery disease need to emphasize secondary prevention and recognize the key role of cholesterol-lowering therapy. The challenge for clinicians is to apply the important lessons learned from these clinical trials to an "evidence-based" patient care.

[Laboratory diagnosis in preventive cardiology]. / Labordiagnostik in der präventiven Kardiologie.

In recent years a large number of coronary artery disease risk factors were discovered. The knowledge of these factors improves the estimate of the coronary artery disease (CAD) risk--however it still remains to be only an "estimate". A perfect prediction of an upcoming CAD event is not possible, despite all high score laboratory technology. Therefore the use of specialized laboratory procedures should be applied carefully. Knowing the blood levels of cholesterol, triglycerides, HDL- and LDL-cholesterol and Lp(a) can be sufficient for many therapeutical decisions. Severe dyslipidemia, familial CAD and CAD without any obvious reasons demand a more specialized work-up, however, risk stratification factors such as family history, clinical history (CAD, hypertension, diabetes mellitus, smoker) and genetics are crucial, apart from the above mentioned laboratory values. Purely on the basis of the lipidologic baseline concentrations we can't give well based recommendations for the treatment of individual patients. Currently there are expert systems available which allow a risk estimate once important laboratory values (LDL cholesterol, HDL cholesterol, Triglycerides) as well as clinical data (blood pressure, family history, clinical history) are available. This system can be accessed by internet under "http:/(/)www.chd-taskforce.com".

Intrapericardial treatment of inflammatory and neoplastic pericarditis guided by pericardioscopy and epicardial biopsy--results from a pilot study.

From a registry of 136 patients undergoing pericardiocentesis, 14 patients with autoimmune and 15 patients with neoplastic effusions were selected. All underwent pericardioscopy, epicardial and pericardial biopsy with histologic, immunohistologic, and polymerase chain reaction/or in situ hybridization analysis for microbial DNAs and RNA. Pericardioscopy identified neoplastic effusions by the high occurrence of protrusions. Fibrin threads and layers and neovascularization were found in both groups. For identification of the inflammatory and neoplastic process, the combined analysis of the cytology of the effusion and epicardial biopsy evaluation proved to be most important. Epicardial biopsy demonstrated a slightly higher sensitivity for identifying neoplastic disorders in the pericardium than cytology alone. Pericardial biopsy was inconclusive. Intrapericardial administration of 1 g of crystalloid triamcinolone in autoreactive pericarditis prevented recurrence in 13 of the 14 cases after 3 months and in 12 of the 14 cases after 1 year. In neoplastic effusion, intrapericardial administration of 50 mg cis-platin for 24 h prevented recurrence of a hemodynamically relevant effusion after 3 months in all, and after 6-12 months in 14 of 15 patients. Mortality in neoplastic effusion due to noncardiac tumor progression was 47 and 80%, respectively, after 3 and 6 months, as can be expected in endstage neoplastic disease. This pilot study demonstrates that local drug application is feasible, life-saving, and well tolerated by the patients. It opens perspectives for local drug application in other cardiac disorders as well.

[Arteriosclerosis and coronary heart disease--strengths and weaknesses in the classical risk factor concept]. / Arteriosklerose und koronare Herzerkrankung--Stärken und Lücken im klassischen Risikofaktorenkonzept.

Several cardiovascular risk factors were identified (high LDL-cholesterol, low HDL-cholesterol, homocystein, Lp(a), and many others). Hypercholesterolemia has been shown to be one of the most important cardiovascular risk factors in man. Interventional studies for primary and secondary prevention demonstrate a beneficial effect of cholesterol lowering therapy. However, numerous CAD-patients suffer a second coronary event despite the appropriate lipid-lowering treatment. Furthermore moderate hypercholesterolemia has only poor predictive power indicating an upcoming myocardial infarction. Therefore we need additional research in CAD prevention and in identifying so far unknown or unconsidered CAD risk factors.

[Cytomegalovirus and herpes simplex virus in pathogenesis and progression of native arteriosclerosis and recurrent stenosis after intervention]. / Zytomegalie- und Herpes-simplex-Viren in Pathogenese und Progression der nativen Arteriosklerose und der Rezidivstenose nach Intervention.

An increasing number of clinical and experimental studies point to a contribution of various infectious organisms like chlamydia pneumoniae or herpesviruses to atherosclerosis in man. Cytomegalovirus induces atherosclerotic lesions in animals. In vitro studies reveal functional changes of endothelial cells after infection with cytomegalovirus. Infection with this virus renders endothelial cells immunogenic for cellular and humoral immune reactions. In man a significant association of infections with herpesviruses and atherosclerosis could be established in several studies. Cytomegalovirus infection has been incriminated as an independent risk factor in restenosis after coronary angioplasty.

Immunosuppressive and immunomodulatory treatment for myocarditis.

This review examines the immunologic rationale for immunosuppressive and immunomodulating therapy. The controversy as to whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trial, which demonstrated that in active myocarditis identified by the Dallas criteria but without taking into account presence or persistence of viral RNA or DNA or signs of autoreactivity, immunosuppression did not influence either central or hemodynamics or prognosis significantly. These findings concur in part with data from experimental mice and also with sporadic human data. In the acute stage of inflammatory viral heart disease, immunosuppressive drugs should be avoided. This recommendation can be upheld even in the light of the Myocarditis Treatment Trial. It is still unresolved, however, whether this also applies in chronic myocarditis with (enteroviral) persistence, in which the residual viral genome may have been rendered noninfective, making it the equivalent of a "scar" or "tombstone" of former infection. Here, demonstration of the viral genome in does not necessarily imply actively replicating virus. Furthermore, evidence is accumulating that the formerly reported incidence of enteroviral persistence in endomyocardial biopsies may have been overestimated. In autoreactive forms of myocarditis with documented humoral and cellular effector mechanisms, studies indicate that immunosuppressive treatment may be useful. However, data from the double-blind, randomized European Study of the Epidemiology and Treatment of Cardiac Inflammatory Disease must be awaited before conclusions can be made. We therefore recommend enrolling virus-negative patients in randomized, controlled treatment trials to validate the benefit of these treatment regimens. In addition, hyperimmunoglobulin therapy appears to be of particular interest because it has shown few side effects but has positive results in cytomegalovirus-associated myopericarditis in humans.

Immunosuppressive treatment for myocarditis and dilated cardiomyopathy.

This overview examines the immunological rationale for immunosuppressive and immunomodulating therapy in man and experimental animals. The controversy of whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trials has been published. It is known that in viral heart disease immunosuppressive drugs should be avoided, but in autoreactive forms of myocarditis with proven humoral and cellular effector mechanisms they may be used in controlled randomized trials to validate or refute their benefit. Immunomodulating factors, e.g. immunostimulatory or antiviral substances such as ribaverin, the interleukins and interferons have demonstrated some effect in experimental animal myocarditis but proof of their benefit in man is still lacking. Hyperimmunoglobulin therapy appears to be of particular interest because it incurs few side effects and has positive results in cytomegalovirus-associated myopericarditis in man and suspected myocarditis in children.

Left ventricular haemodynamics in murine viral myocarditis.

In susceptible DBA/2 mice infection with coxsackievirus B3 leads to severe inflammatory and necrotic lesions in the heart. There is a temporal discrepancy of peak concentrations of replicative virus in the heart and maximal cardiac inflammation. Aims of this study were, first, to determine whether haemodynamic changes occur in coxsackievirus B3-induced murine myocarditis and, second, the time frame in which those alterations may be apparent. By puncture of the left ventricle, pressures and the first derivative dp/dt as parameters of left ventricular function could be obtained on several days of the infection. Haematoxylin-eosin stains of cross-sections of the heart showed the course of inflammatory lesions in the heart; a plaque forming assay assessed virus titres in the heart. Cardiac concentrations of replicative virus peaked on day 3, inflammatory lesions in the heart were maximal on day 7. Left ventricular function was almost preserved until day 5 of the infection, then dropped significantly until day 10. The study suggests that either a cumulative virus-mediated destruction of the myofibres or virally triggered immune reactions to heart cells lead to impairment of left ventricular function.

Left ventricular hemodynamic parameters in the course of acute experimental coxsackievirus B 3 myocarditis.

In susceptible DBA/2 mice coxsackievirus B 3-induced myocarditis leads to inflammatory and necrotic lesions in the myocardium 7-10 days after virus inoculation. The purpose of this study was to determine whether hemodynamic changes occur in murine coxsackievirus B 3 myocarditis and whether they are correlated to histological cardiac lesions throughout the infection. Left ventricular function was determined by open chest puncture of the left ventricle in the course of acute coxsackievirus B 3 infection. Histological cross sections of the heart were stained with hematoxylin/eosin and scored blindly for myocarditic lesions. Left ventricular function was preserved until day 7 post-virus inoculation Left ventricular systolic pressure, +dP/dtmax and -dP/dtmax and heart rate declined significantly from day 7 to day 10. The decrease in these parameters did not correlate with viral concentrations in the heart on the day of hemodynamic measurements. The decrease was related to histological changes on day 10, but not on day 7 of the infection. The data suggest (a) that a cumulative loss of cardiac myofibers, induced either by the virus and/or by immune reactions to the heart, is likely to lead to a late depression of cardiac function, and (b) that there is a weak and only temporary structure-function relationship in the heart in coxsackievirus B 3 myocarditis. Therefore, in addition to an analysis of histological changes, the measurement of cardiac function appears to be very important in order to completely evaluate the severity of myocarditis and the usefulness of any therapy.