Paolo Ferraro

Hemodynamic effects of magnesium sulfate on the normal human heart

Abstract Because of its antiarrhythmic properties,1 parenteral magnesium sulfate has been widely used in the last decades in treating several supraventricular or ventricular arrhythmias2,3 even in patients with cardiovascular diseases. Recently, intravenous magnesium sulfate has proved effective in treating arrhythmias associated with acute myocardial infarction4 and long QT syndrome.5 However, a systematic evaluation of its effects on cardiovascular hemodynamics has not been reported. Recent experimental6 and clinical7 observations have suggested that magnesium sulfate may exert a vasodilator effect on human coronary arteries. The present study investigates the effects of magnesium sulfate infusion on coronary and systemic hemodynamics in humans.

FK506 can activate transforming growth factor-β signalling in vascular smooth muscle cells and promote proliferation

AIMS FK506-binding protein (FKBP) 12 is an inhibitor of transforming growth factor (TGF)-beta type I receptors. Several lines of evidence support the view that TGF-beta stimulates vascular smooth muscle cell (VSMC) proliferation and matrix accumulation. We investigated the effect of FK506, also known as tacrolimus, on cellular proliferation and on matrix protein production in human VSMCs. METHODS AND RESULTS We measured cell proliferation with flow cytometry using BrdU incorporation and fluorimetrically by measuring DNA concentration with Hoechst 33258. Western blot assay of whole-cell lysates was used to measure the levels of signalling proteins involved in proliferative pathways, in particular beta-catenin, pErk, pAkt, pmTOR, and cyclin D1. Collagen synthesis was also investigated by Western blotting. The TGF-beta signal was studied by both Western blotting and confocal microscopy. We used the SiRNA technique for FKBP12 gene silencing. Our results show that FK506 stimulates VSMC proliferation and collagen type I production. FK506 enhanced beta-catenin levels and activated the extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin kinase, which are important effectors of proliferation. Accordingly, cyclin D1 expression was increased. We also demonstrate that FK506 activates the TGF-beta signal in VSMCs and that, through this mechanism, it stimulates cell proliferation. CONCLUSION FK506 can act as a growth factor for VSMCs.

Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells.

Tirofiban is a fibrinogen receptor antagonist, generated using the tripeptide Arg-Gly-Asp (RGD) as a template. RGD activates integrin receptors and integrin-mediated signals are necessary for normal cells to promote survival and stimulate cell cycle progression. We investigated whether tirofiban activated growth-stimulatory signals in endothelium. For this study human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) were used. Analysis of cell proliferation, by cell counts, showed that the number of endothelial cells doubled after 72 h of culture in the absence of tirofiban, while they were tripled and even quadrupled, in the presence of increasing doses of the drug. Moreover, tirofiban-stimulated cells had a greater ability to migrate through the transwell filters of Boyden chamber, compared to unstimulated cells. The scratch assay, which mimics cell migration during wound healing, showed that tirofiban stimulated HUVECs to migrate into the leading hedge of the scratch. Western blot showed that tirofiban increased the expression levels of VEGF and the downstream effectors Erk and cyclin D. An inhibitor of VEGFR2 counteracted tirofiban-induced-proliferation, suggesting a role for VEGF in such effect. Our study shows that tirofiban stimulates the migration and proliferation of endothelial cells suggesting that it can promote endothelial repair. Ex vivo cultures of arterial rings confirmed the growth stimulatory effect of tirofiban on endothelium. Thus, the benefits of tirofiban in those with acute coronary syndromes undergoing PTCA may be due to rapid endothelization of damaged vessel, besides antiplatelet effects.

No surprising forward jump when deploying a self-expandable stent: Two cases exploiting the combination of Emboshield Nav6 BareWire and Stentys devices

model of diabetic cardiomyopathy. Cardiovasc Pathol 2012;21(5):414–20. [5] Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003;284:14–30. [6] Hedhli N, Huang Q, Kalinowski A, et al. Endothelium derived neuregulin protects the heart against ischemic injury. Circulation 2011;123:2254–62. [7] Geisberg CA, Wang G, Safa RN, et al. Circulating neuregulin-1β Levels vary according to the angiographic severity of coronary artery disease and ischemia. Coron Artery Dis 2011;22(8):577–82. [8] Russell KS, SternDF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol 1999;277(6 Pt 2): H2205–11. [9] Panutsopulos D, Arvanitis DL, Tsatsanis C, Papalambros E, Sigala F, Spandidos DA. Expression of heregulin in human coronary atherosclerotic lesions. J Vasc Res 2005;42(6):463–74. [10] Nakaoka Y, Nishida K, Narimatsu M, et al. Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. J Clin Invest 2007;117(7):1771–81.

Regional coronary hemodynamic effects of diltiazem in man

We evaluated the changes in regional coronary hemodynamics induced by diltiazem, 0.25 mg/kg intravenously, in nine patients with 75% to 90% diameter stenosis of the left anterior descending coronary artery (LAD) (group 1) and in 10 patients with 100% occlusion of the LAD and collaterals to the distal LAD (group 2). Although diltiazem induced similar changes in systemic hemodynamics in the two groups, a decrease in anterior coronary vascular resistance (ACVR) and an increase in great cardiac vein flow (GCVF) were observed after administration of diltiazem in all patients in group 1 but in only 6 of 10 patients in group 2 (subgroup 2B). ACVR increased and GCVF decreased after administration of diltiazem in 4 of 10 patients in group 2 (subgroup 2A). Clinico-angiographic characteristics, origin of collaterals, and diltiazem-induced changes in systemic hemodynamics were similar in subgroups 2A and 2B. Thus diltiazem increases coronary flow distal to a stenotic coronary artery but can decrease regional coronary flow and increase regional coronary resistance in a minority of patients with an occluded coronary artery supplied by collaterals, probably through a steal mechanism.

Reduction of pacing-induced myocardial ischemia by intravenous magnesium sulfate

M agneslum sulfate (MgSO4) has been widely used in the last decades as treatment for supraventrlcular or ventricular arrhythmias, l,2 particularly in patients with coronary artery disease 3-6 Because a sustmned increase In heart rate during tachyarrhythmlas may provoke symptomatic or asymptomatic myocardial ~schemla in these patients, we thought it would be of interest to investigate whether this drug could also prevent myocardml ischemm associated with increased myocardial oxygen requirements. This is also in light of previous observations showing that MgSO 4 may beneficially affect myocardial oxygen supply/demand ratio by coronary vasodilatatlon, 7-1° probably due to its calcium antagonist effects. H Thus, we investigated whether MgSO 4 can reduce myocardial ischemia in response to atrial pacing m patients with fixed coronary artery disease and stable angma

Endovascular Therapy for Infrainguinal Artery Disease With Coronary Devices A Retrospective Observational Study Comparing Drug-Eluting Stents Versus Bioresorbable Vascular Scaffolds

Several devices are available for infrainguinal endovascular therapy, with drug-eluting stents (DES) among the most promising. Bioresorbable vascular scaffolds (BVS) may further improve outcomes. We have liberally used in our practice coronary DES and BVS for infrainguinal endovascular therapy and hereby report our preliminary results. We conducted an observational study by retrospectively identifying characteristics of patients undergoing infrainguinal implantation of coronary DES or BVS. We compared the risk of major adverse events (MAE: death, amputation, or target vessel revascularization [TVR]) and components of MAE in the overall sample and after propensity matching. We included a total of 204 patients (207 limbs), 148 (72.5%) treated with DES and 56 (27.5%) with BVS. Bivariate analysis showed that TVR was less common in the DES group (41.9% vs 18.4%, P = .014). However, propensity-matched analysis showed nearly identical risks of MAE, amputation, TVR, or symptom burden with DES and BVS (all P > .05). In conclusion, the present pilot experience with coronary BVS suggests that they could provide acceptable results for infrainguinal endovascular procedures, comparable to those obtained by their metallic counterpart.

Successful treatment of recurrent carotid in-stent restenosis and drug-eluting balloon failure with a coronary bioresorbable vascular scaffold: A case report

Highlights • The management of carotid in-stent restenosis remains challenging, with several potential management strategies available, but none clearly best.• Bioresorbable vascular scaffolds have proved safe and effective in patients with coronary artery disease, but their use for carotid in-stent restenosis is unprecedented, yet promising.• Bioresorbable vascular scaffolds could become a useful adjunct to the armamentarium of endovascular specialists, including those managing patients with carotid in-stent restenosis, especially if further refinements in sizes and designs are achieved.

Effects of intracoronary gallopamil on coronary hemodynamics and myocardial oxygen consumption in humans

Summary: The response of coronary hemodynamics to the intracoronary (i.c.) bolus administration of gallopamil, 1.5 and 3.0 μg/kg, was evaluated in 14 patients with normal coronary arteries. Gallopamil, 3.0 μg/kg, induced a small and transient decrease in systolic and mean arterial pressure and a small increase in the preejection period. Coronary sinus blood flow increased significantly at 30 s (p < 0.01) and returned to baseline 10 min after gallopamil administration. Coronary vascular resistance was still reduced at 10 min and returned to baseline at 15 min. Myocardial O2 consumption and extraction decreased significantly (p < 0.01) at 30 s. While myocardial O2 consumption returned to baseline 15 min after gallopamil administration, myocardial O2 extraction was still significantly reduced at this time. Milder and more transient changes were observed after i.c. administration of the lower dose (1.5 μg/kg), and no significant changes were found after i.c. administration of saline. These data show that i.e. gallopamil, in patients with normal coronary arteries, induces direct, transient, and dose-related peripheral coronary vasodilation. The reduction of myocardial O2 consumption and extraction suggests a direct negative inotropic and metabolic effect of gallopamil.

Tirofiban counteracts endothelial cell apoptosis through the VEGF/VEGFR2/pAkt axis.

Tirofiban is used in the treatment of patients with acute coronary syndrome submitted to percutaneous coronary intervention (PCI). We have, previously, shown that tirofiban stimulates VEGF expression and promotes proliferation of endothelial cells. VEGF is a well known inhibitor of endothelial cell apoptosis. TNF-α is a pro-apoptotic cytokine released in the site of a vascular injury, including balloon angioplasty. We thought to investigate whether tirofiban was able to protect endothelial cells from cell death induced by TNF-α. For this study, we used human umbilical vein endothelial cells (HUVEC). Analysis of apoptosis was performed by propidium iodide incorporation, annexin V staining and measure of active caspase 3 levels. Western blot served for a semiquantitative measure of Akt activation, VEGF, and the pro-apoptotic Bim and Bak. Our results show that TNF-α was unable to activate caspase 3 and produce cell death in the presence of tirofiban. Activation of apoptosis was preceded by upregulation of Bim and Bak that resulted decreased after addition of tirofiban. The anti-apoptosis effect of tirofiban was reproduced by VEGF and counteracted by VEGFR2 blockade and the cation chelating agent ethylene glycol tetraacetic acid (EGTA). The use of p-Akt inhibitor, BEZ235,and Akt knockdown, suggested that pAkt mediated the prosurvival effect of tirofiban. In conclusion, tirofiban protects endothelial cells from apoptosis stimulated by TNF-α, due to its ability to stimulate VEGF production.