Bradycardiomyopathy: the case for a causative relationship between severe sinus bradycardia and heart failure.

A 28-year-old man presented with progressive fatigue. Physical examination and ECG revealed severe sinus bradycardia. Echocardiography showed features of noncompaction cardiomyopathy and moderate aortic valve regurgitation. We hypothesized that the chronic volume overload exaggerated by prolonged diastole due to the bradycardia resulted in heart failure and noncompaction cardiomyopathy look-alike features. After implantation of an AAI pacemaker, his symptoms and signs of cardiomyopathy were fully recovered.

Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin.

BACKGROUND: Mesenchymal stem cells (MSC) have multilineage differentiation and immunomodulatory capacities and are potentially useful for therapeutic applications, such as tissue regeneration and control of alloreactivity. MSC are present in most tissues including the transplantable organs. It is therefore unavoidable that MSC will be exposed to immunosuppressive drugs in a clinical transplantation setting. The molecular targets of these drugs are expressed in MSC, but the effect of their inhibition on MSC functioning is unknown. METHODS: MSC were isolated and expanded from heart tissue and the effects of the calcineurin inhibitor tacrolimus, the cell cycle inhibitor mycophenolic acid (MPA), and the mammalian target of rapamycin inhibitor on MSC survival, proliferation, differentiation, and immunosuppressive capacity were examined. RESULTS: Short-term exposure to the immunosuppressants did not induce toxicity or apoptosis in MSC, but high-dose tacrolimus induced toxicity after 7 days. MPA and rapamycin inhibited MSC proliferation at therapeutic doses. The immunosuppressants had differential effects on the differentiation capacity of MSC. Tacrolimus reduced the expression of troponin T type 2 and desmin during cardiomyogenic differentiation of MSC, whereas MPA decreased the deposition of calcified minerals during osteogenic differentiation. Rapamycin stimulated lipid production during adipogenic differentiation. Unexpectedly, MSC had adverse effects on the immunosuppressive efficacy of tacrolimus and rapamycin. There was no such effect of MSC on the function of MPA. Preincubation of MSC with tacrolimus increased the immunosuppressive capacity of MSC. DISCUSSION: This study demonstrates that therapeutic concentrations of immunosuppressive drugs affect MSC function. MSC affect the efficacy of immunosuppressive medication. These findings are important for potential clinical use of MSC in combination with immunosuppressants.