sirolimus and Arrhythmias--Cardiac

We assessed the relation between female sex and sirolimus-eluting stent (SES) use on long-term outcomes in acute myocardial infarction.. There are no data on sex-specific differences in long-term benefit of SES use compared with bare-metal stent (BMS) use among patients undergoing primary percutaneous coronary interventions.. We performed a post hoc analysis of the MULTISTRATEGY trial. Hazard ratios (HRs) of events with 95% CI for sex and stent type were computed using Cox proportional regression with adjustment for confounders.. A total of 744 patients, 64 years old (55-73 years old), 179 (24.1%) women, were enrolled. After a follow-up of 1,080 days, SES use was associated with a significant reduction of major adverse cardiovascular events, that is, the composite of all-cause death, reinfarction, or clinically driven target vessel revascularization (TVR) (13.9% vs 23.6%, adjusted HR 0.62, 95% CI 0.41-0.94, P = .026) and of TVR (6.1% vs 15.1%, adjusted HR 0.35, 95% CI 0.19-0.63, P < .001) in men. Conversely, SES use was not associated to a better outcome among women (major adverse cardiovascular events 21.9% in SES vs 18.2% in the BMS group, adjusted HR 1.27, 95% CI 0.53-3.02, P = .59; TVR 6.6% vs 9.1%, adjusted HR 0.62, 95% CI 0.17-2.21, P = .46).. In this analysis, the clinical benefit of SES use, over BMS, at 3-year follow-up was restricted to men and was not observed among women.

Topics: Abciximab; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Arrhythmias, Cardiac; Drug-Eluting Stents; Female; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Italy; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Sex Factors; Sirolimus; Tirofiban; Tyrosine

Sirolimus constitutes a safe and effective treatment for cardiac manifestations of tuberous sclerosis complex (TSC) in children but only four cases describing prenatal treatment of rhabdomyomas with mTOR inhibitors have been published.. In this case, sirolimus was initiated at 26 weeks´ gestation in a pregnant woman with TSC with a fetus with a large rabdomyoma conditioning severe arrythmia. There was a significant reduction in the tumor size with ongoing treatment and a partial reversion of the arrythmia.. m-TOR inhibitors can be considered for severe cases of fetal rhabdomyomas with poor prognosis given its potencial benefits.

Topics: Arrhythmias, Cardiac; Child; Female; Fetus; Heart Neoplasms; Humans; Pregnancy; Rhabdomyoma; Sirolimus; Tuberous Sclerosis

The heart contraction is controlled by the Ca2+-induced Ca2+ release (CICR) between L-type Ca2+ channels and ryanodine receptors (RyRs). The FK506-binding protein FKBP12.6 binds to RyR subunits, but its role in stabilizing RyR function has been debated for long. Recent reports of high-resolution RyR structure show that the HD2 domain that binds to the SPRY2 domain of neighbouring subunit in FKBP-bound RyR1 is detached and invisible in FKBP-null RyR2. The present study was to test the consequence of FKBP12.6 absence on the in situ activation of RyR2.. Using whole-cell patch-clamp combined with confocal imaging, we applied a near threshold depolarization to activate a very small fraction of LCCs, which in turn activated RyR Ca2+ sparks stochastically. FKBP12.6-knockout and FK506/rapamycin treatments increased spark frequency and LCC-RyR coupling fidelity without altering LCC open probability. Neither FK506 nor rapamycin further altered LCC-RyR coupling fidelity in FKBP12.6-knockout cells. In loose-seal patch-clamp experiments, the LCC-RyR signalling kinetics, indexed by the delay for a LCC sparklet to trigger a RyR spark, was accelerated after FKBP12.6 knockout and FK506/rapamycin treatments. These results demonstrated that RyRs became more sensitive to Ca2+ triggers without FKBP12.6. Isoproterenol (1 μM) further accelerated the LCC-RyR signalling in FKBP12.6-knockout cells. The synergistic sensitization of RyRs by catecholaminergic signalling and FKBP12.6 dysfunction destabilized the CICR system, leading to chaotic Ca2+ waves and ventricular arrhythmias.. FKBP12.6 keeps the RyRs from over-sensitization, stabilizes the potentially regenerative CICR system, and thus may suppress the life-threatening arrhythmogenesis.

Topics: Animals; Arrhythmias, Cardiac; Calcium Channels, L-Type; Calcium Signaling; Genotype; Isoproterenol; Kinetics; Male; Membrane Potentials; Mice, Knockout; Microscopy, Confocal; Models, Molecular; Myocytes, Cardiac; Patch-Clamp Techniques; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Receptor Cross-Talk; Ryanodine Receptor Calcium Release Channel; Sirolimus; Stochastic Processes; Tacrolimus; Tacrolimus Binding Proteins

MEK, PI3, p38, tyrosine, and mTOR kinases are not involved in the regulation of heart resistance to the arrhythmogenic action of short-term ischemia/reperfusion in non-adapted rats.

Topics: Animals; Arrhythmias, Cardiac; Flavonoids; Imidazoles; MAP Kinase Kinase Kinases; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyridines; Rats; Rats, Wistar; Sirolimus; TOR Serine-Threonine Kinases

We investigated the inward rectifier potassium current (I(K1)), which can be blocked by intracellular Ca(2+), in heart failure (HF).. We used the whole-cell patch-clamp technique to record I(K1) from single rat ventricular myocytes in voltage-clamp conditions. Fluorescence measurements of diastolic Ca(2+) were performed with Indo-1 AM. HF was examined 8 weeks after myocardial infarction (coronary artery ligation).. I(K1) was reduced and diastolic Ca(2+) was increased in HF cells. The reduction of I(K1) was attenuated when EGTA was elevated from 0.5 to 10 mM in the patch pipette and prevented with high BAPTA (20 mM). Ryanodine (100 nM) and FK506 (10 microM), both of which promote spontaneous SR Ca(2+) release from ryanodine receptor (RyR2) during diastole, reproduced the effect of HF on I(K1) in normal cells but had no effect in HF cells. The effects of ryanodine and FK506 were not additive and were prevented by BAPTA. Rapamycin (10 microM), which removes FKBP binding proteins from RyR2 with no effect on calcineurin, mimicked the effect of FK506 on I(K1). Cyclosporine A (10 microM), which inhibits calcineurin via cyclophilins, had no effect. In both HF cells and normal cells treated by FK506, the protein kinase C (PKC) inhibitor staurosporine totally restored the inward component of I(K1), but only partially restored its outward component at potentials corresponding to the late repolarizing phase of the action potential (-80 to -40 mV).. I(K1) is reduced by elevated diastolic Ca(2+)in HF, which involves in parallel PKC-dependent and PKC-independent mechanisms. This regulation provides a novel paradigm for Ca(2+)-dependent modulation of membrane potential in HF. Since enhanced RyR2-mediated Ca(2+)release also reduces I(K1), this paradigm might be relevant for arrhythmias related to acquired or inherited RyR2 dysfunction.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Depression, Chemical; Egtazic Acid; Heart Failure; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardium; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying; Protein Kinase C; Rats; Rats, Wistar; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sirolimus; Staurosporine; Tacrolimus