Iris Löw-Friedrich

Therapy with Recombinant Human Erythropoietin Reduces Cardiac Size and Improves Heart Function in Chronic Hemodialysis Patients

The substitution of recombinant human erythropoietin (rhEPO) in chronic hemodialysis patients is often associated with the development of severe hypertension. In the present study, a systematical echocardiographic analysis was performed in 25 patients on maintenance hemodialysis during rhEPO therapy for at least 4 months. Referred to the total group, indices of left ventricular size decreased significantly. Left ventricular total volume and left ventricular mass were reduced considerably. Fractional fiber shortening and ejection fraction showed an impressing improvement. At a constant heart rate, stroke volume and cardiac output were reduced. Myocardial thickness did not alter under chronic rhEPO therapy. When subgroups were formed with respect to changes in blood pressure, all parameters investigated behaved very similar to the total group, irrespective of changes in blood pressure. Five patients with coronary heart disease and clinical signs of myocardial insufficiency were evaluated separately. These patients showed a decrease in left ventricular size and no evidence of a deterioration of myocardial function. We conclude from our results that rhEPO therapy in patients on maintenance renal replacement therapy has beneficial effects on left ventricular size and function; these effects are not significantly counteracted by the development of hypertension.

Cytokines induce stress protein formation in cultured cardiac myocytes

SummaryDiseases accompanied by severe cardiac impairment like sepsis and chronic uremia are frequently linked to an increase in cytokine release. In order to investigate possible toxic effects of the immune mediators on myocardial cells, we studied the contractility of cardiac myocytes and the de novo formation of stress proteins in cultured heart cells under cytokine exposition. All cytokines investigated induce, concentration-dependently, arrhythmias and cessation of spontaneous contractions. Interleukin(IL)-2, IL-3, IL-6, and tumor necrosis factor (TNF) stimulate the synthesis of a 30 kD stress protein in heart cells, whereas IL-1 additionally evokes two proteins of the 70 kD family. These findings confirm a direct interference of the interleukins and TNF with myocytes and, especially, myocardial protein formation. As the induction of stress proteins makes cells more resistant towards a subsequent challenge, the cytokines are possibly involved in the activation of cell protecting mechanisms in cardiac myocytes.

Effects of calcium channel blockers on stress protein synthesis in cardiac myocytes

Summary: The detection of “stress proteins,” certain protein groups of 70 or 30 kDa molecular weight synthesized de novo under stress conditions, serves as an assay for monitoring cellular toxicity. Typical toxins inducing stress protein formation in cardiac myocytes are CdCl2 and H2O2. The synthesis of 68, 71, and 30 kDa stress proteins is evoked by CdCl2, and H2O2 stimulates the formation of a 30 kDa protein. When fetal mouse myocardial cells are incubated first with CdCl2 and then with H2O2 or vice versa, an additive effect on stress protein synthesis can be documented. The calcium antagonists diltiazem, verapamil, and nifedipine, at concentrations above 0.05 mg/ml, stimulate the de novo synthesis of a 30 kDa stress protein. After preincubation of the cardiac myocytes with slow calcium channel blockers, the synthesis of the 70 kDa stress protein family evoked by CdCl2 is reduced. In contrast to the increased stress protein synthesis after heart cells are exposed to toxins, preincubation with calcium antagonists reduces the formation of certain stress proteins. These results indicate an interference of calcium channel blocking drugs with stress protein formation in cultured mouse myocardial cells.

Cocultures of fetal and adult cardiomyocytes yield rhythmically beating rod shaped heart cells from adult rats

SummaryDifferent models of isolated cardiomyocytes are generally used for biochemical, biophysical, and pharmacological studies. Fetal cardiomyocytes can be easily cultured for several weeks regaining their ability for rhythmical and synchronous contractions. For investigations, differentiated myocytes derived from adult hearts are closer to the in situ situation. Unfortunately, these cells at best exhibit irregular and asynchronous contractions at very low frequencies. Already 1 d after seeding calcium-tolerant rod-shaped adult cardiomyocytes on a suitable substrate, the differentiated cells begin to dedifferentiate forming a confluent monolayer. After 7–10 d their beating activities are like those of fetal cells. Therefore, we tried to combine the advantages of both cell types to achieve fully differentiated cardiomyocytes, rod-shaped and rhythmically beating, isolated from adult hearts. Using contractile fetal cells as a substrate for the adult cardiomyocytes, freshly seeded differentiated adult myocytes are paced by the contraction frequency of the fetal monolayer. As a consequence, the rod-shaped adult cardiomyocytes reach frequencies of more than 140 cycles/min without external electrical stimulation. This model enables us to study cardiomyocytes in a state very similar to the in situ situation with respect to morphology, integrity, and contractile behavior.

Long-Term Echocardiographic Examinations in Chronic Hemodialysis Patients Substituted with Recombinant Human Erythropoietin

Cardiomegaly and impaired cardiac function induced by renal anemia are frequent findings in patients with chronic renal failure. The present investigation was performed to study the cardiac effects of a therapy with recombinant human erythropoietin in patients on maintenance hemodialysis. Echocardiographic examinations showed a decrease in cardiac size and left-ventricular mass continuously over 12 months of effective erythropoietin substitution. Cardiac output was reduced, and ejection fraction and myocardial contractility increased. The development of aggravation of arterial hypertension did not counteract the beneficial effects of erythropoietin on cardiac performance.

The Synthesis of Stress Proteins in Cultured Cardiac Myocytes Is Induced by the Interleukins and Tumor Necrosis Factor

Mortality is very high in septic shock patients mainly due to cardiovascular failure. Clinical trials describe an acute septic cardiomyopathy with the typical features of severe cardiac insufficiency [1]. Several findings reported in the literature suggest a direct influence of immune mediators on the heart. The therapeutic use of interleukin (IL) 2 in oncology is frequently accompanied by severe cardiac complications resembling those observed in septic shock [2]. Patients on maintenance hemodialysis suffer from cardiac impairment; recently, increased IL-1 and tumor necrosis factor (TNF) serum levels have been documented in these patients [3]. In vitro studies indicate a direct effect of the cytokines on heart cell metabolism [4]. Our study was performed to investigate specific cardiotoxic effects of immune mediators on cultured cardiac myocytes. The detection of stress protein formation was employed as a test system to monitor cardiotoxicity [5].