Arturo Giordano

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.

Metabolic and hemodynamic effects of peptide leukotriene C4 and D4 in man

The time course of the effects of intravenous or intracoronary administration of peptide leukotrienes on metabolic parameters and on systemic and coronary hemodynamics was evaluated in 15 patients with normal coronary arteries. Peptide leukotriene C4 (2 nmol given as a bolus intravenous injection) induced an early fall (at 2 min) in mean arterial pressure (P<0.02) associated with a rise in heart rate (P<0.001) and in plasma levels of epinephrine (P<0.05) and norepinephrine (P<0.005), but without significant changes in coronary blood flow or coronary vascular resistance. Mean arterial pressure, heart rate, norepinephrine, and epinephrine returned to baseline values 10 min after leukotriene C4 administration. In contrast, at 10 min post leukotriene C4, with coronary blood flow and myocardial oxygen consumption unchanged, an increase in coronary vascular resistance (P<0.05) and in myocardial oxygen extraction (P<0.01) was observed, which returned to baseline values at 20 min post leukotriene C4. Peptide leukotriene D4(3 nmol, given in the left coronary artery) induced an early (20 s) and transient fall in mean arterial pressure (P<0.001 ) paralleled by a rise in heart rate and plasma levels of epinephrine and norepinephrine, all of which returned to baseline at 10 min. Coronary vascular resistance increased at 10 and 15 min (P<0.02 and P<0.05, respectively) and myocardial oxygen extraction at 15 min (P<0.02). These results suggest that small doses of peptide leukotrienes induce both an early and transient fall in mean arterial pressure associated with secondary sympathoadrenergic activation, and a late increase in small coronary arteriolar resistance.

Cardiovascular and Metabolic Effects of Peptide Leukotrienes in Mana

Leukotrienes are a group of biologically active compounds derived from certain polyunsaturated fatty acids (e.g., arachidonic acid).’ Before it is transformed to leukotrienes, the precursor acid must be hydrolytically released from phospholipids. This release is catalyzed by phospholipase A: or by the sequential action of phospholipase C and diglyceride l i p a ~ e . ~ The first step in the biosynthesis of leukotrienes is catalyzed by the enzyme, 5-lipoxygenase, which peroxidizes arachidonic acid at carbon 5 to form (SS)-hydroperoxy-6-truns11,14-cis-icosatetraenoic acid (5-HPETE). This compound then is converted to the unstable epoxide intermediate, leukotriene A,., Depending upon the enzymes available, leukotriene A, may subsequently be hydrolyzed to (5S),( 12R)-dihydroxy-6,14-cis-8,1 O-truns-icosatetraenoic acid (leukotriene B,)’ or it may be converted, by means of addition of glutathione at carbon 6 , to leukotriene C, (LTC,) by leukotriene C synthase. LTC, and its metabolites-leukotrienes D4 (LTD,) and E, (LTE,)-were described originally as “slow reacting substance of anaphylaxis” (SRS-A) and are now collectively referred to as peptide leukotrienes. These compounds are very potent proinflammatory mediators and they contract smooth muscle cells from bronchus, lung parenchyma, gastrointestinal, and urogenital which means that they are implicated in the pathophysiology of several human diseases. Peptide leukotrienes are released during immunological and nonimmunological activation of several inflammatory cells such as human basophils,” lung mast cells,I2 and e o s i n ~ p h i l s . ’ ~ ~ ’ ~ They also are released in vivo during anaphylactic reactions in humans.‘’

Effects of histamine on coronary hemodynamics in humans: Role of H1and H2receptors

To evaluate whether histamine exerts a direct effect on coronary hemodynamics in humans, and to investigate the role played by H1 and H2 receptors in this response, intracoronary saline solution or histamine (4 micrograms) was administered in 10 patients with normal coronary arteries during diagnostic cardiac catheterization. Histamine injection was repeated after intravenous cimetidine (400 mg) and diphenhydramine (10 mg). The electrocardiogram, arterial pressure and thermodilution coronary blood flow were continuously monitored during and for 40 seconds after each injection. Immediately after histamine injection there was a significant increase in coronary blood flow (65 +/- 6%) and a decrease in coronary vascular resistance (-40 +/- 3%) (both p less than 0.001), with minor changes in the RR interval and the mean arterial pressure. H2 receptor blockade with cimetidine did not affect these changes, while H1 receptor blockade with diphenhydramine significantly reduced the histamine-induced increase in coronary blood flow and the decrease in coronary vascular resistance (26 +/- 6%, p less than 0.005 and -18 +/- 5%, p less than 0.001, respectively). Twenty to 30 seconds after histamine injection, a significant decrease in mean arterial pressure (-17 +/- 2%, p less than 0.001) and in the RR interval (-4 +/- 1%, p less than 0.01) was observed. These changes persisted after H2 receptor blockade with cimetidine, but were completely abolished after H1 receptor blockade with diphenhydramine. In each case coronary and systemic hemodynamics returned to normal within 40 seconds of the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Nephropathy after administration of iso-osmolar and low-osmolar contrast media: evidence from a network meta-analysis.

BACKGROUND/OBJECTIVES Contrast-induced nephropathy (CIN) may be a severe complication to the administration of iodine-based contrast media for diagnostic or interventional procedure using radiation exposure. Whether there is a difference in nephrotoxic potential between the various agents is uncertain. We aimed to perform a systematic review and network meta-analysis of randomized trials on iodine-based contrast agents. METHODS Randomized trials of low-osmolar or iso-osmolar contrast media were searched in CENTRAL, Google Scholar, MEDLINE/PubMed, and Scopus. Risk of CIN was appraised within a hierarchical Bayesian model computing absolute rates (AR) and odds ratios (OR) with 95% credibility intervals, and probability of being best (Pbest) for each agent. RESULTS A total of 42 trials (10048 patients) were included focusing on 7 different iodine-based contrast media. Risk of CIN was similarly low with iodixanol (AR=5.7% [2.2%-13.9%], Pbest=18.8%), iomeprol (AR=6.0% [2.2%-15.4%], Pbest=24.8%), iopamidol (AR=6.1% [2.2%-15.5%], Pbest=21.5%), and ioversol (AR=6.0% [2.1%-16.4%], Pbest=31.3%). Conversely, CIN was twice as common with iohexol (AR=11.2% [4.1%-29.5%], Pbest=0.1%) and ioxaglate (AR=11.0% [4.0%-26.9%], Pbest<0.1%), with both proving less safe than iodixanol (respectively OR=2.18 [1.22-3.92] and 2.05 [1.26-3.29]), iomeprol (OR=2.08 [1.04-4.17] and 1.96 [1.06-3.48]) and iopamidol (OR=2.04 [1.15-3.85] and 1.92 [1.06-3.45]). Data on iopromide were less conclusive (AR=6.9% [2.6%-17.1%], Pbest=3.6%). CONCLUSIONS Iodixanol, iomeprol, iopamidol and ioversol are iodine-based contrast media with a similar renal safety profile. Iohexol and ioxaglate have a poorer renal safety profile, whereas further data may be required on iopromide.

Beneficial impact on cardiovascular risk profile of water buffalo meat consumption

Background/Objectives:Meat is a good source of proteins and irons, yet its consumption has been associated with unfavorable cardiovascular effects. Whether this applies to all types of meat is unclear. We thus aimed to appraise the impact of water buffalo meat consumption on cardiovascular risk profile with an observational longitudinal study.Subjects/Methods:Several important cardiovascular risk features were appraised at baseline and at 12-month follow-up in 300 adult subjects divided in groups: recent consumers of water buffalo meat vs subjects who had never consumed water buffalo meat. In addition, long-standing consumers of water buffalo meat were evaluated.Results:Age, gender, height, body weight, and the remaining diet (with the exception of cow meat consumption) were similar across groups. From baseline to follow-up, recent consumers of water buffalo meat change their intake of water buffalo meat from none to 600±107 g per week (P<0.001), with ensuing reductions in cow meat consumption from 504±104 to 4±28 (P<0.001). At the end of the study, recent consumers of water buffalo meat showed a significant decrease in total cholesterol and triglycerides levels, lower pulse wave velocity, as well as a more blunted response to oxidative stress from baseline to follow-up in comparison with subjects who had never consumed water buffalo meat (all P<0.05).Conclusions:Consumption of buffalo meat seems to be associated with several beneficial effects on cardiovascular risk profile. Awaiting further randomized clinical trials, this study suggests that a larger consumption of water buffalo meat could confer significant cardiovascular benefits, while continuing to provide a substantial proportion of the recommended daily allowance of protein.

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.

Regional left ventricular mechanical function during isometric exercise in patients with coronary artery disease: Correlation with regional coronary blood flow changes

The effects of isometric exercise on regional left ventricular mechanical function and regional coronary blood flow were evaluated in 17 patients with significant proximal stenosis of the left anterior descending coronary artery and 10 patients with normal coronary arteriograms. All patients had normal myocardial contractility in the basal condition. All performed isometric handgrip exercise at 50% of the maximal voluntary contraction for 3 min during two-dimensional echocardiographic monitoring and hemodynamic evaluation of great cardiac vein flow by thermodilution technique. During isometric exercise, 7 of the 17 patients with left anterior descending coronary stenosis developed asynergy in the anterior territory (anterior or septal segment, or both) (group I); the remaining 10 showed normal myocardial contraction during the test (group II). The 10 normal subjects manifested no regional asynergy during the test (control group). The increase in great cardiac vein flow at peak isometric exercise was significantly smaller (p less than 0.01) in group I (+15 +/- 8%) than that in group II (+98 +/- 48%) and the control group (+64 +/- 22%). Anterior coronary vascular resistance decreased in group II (-32 +/- 13%) and in the control group (-25 +/- 8%) but increased in group I (+6 +/- 8%, p less than 0.01 versus group II and control group). These data demonstrate that handgrip-induced myocardial asynergy is associated, in our study patients, with an abnormal response of the regional coronary circulation. The increase in coronary vascular resistance in group I patients with asynergy demonstrates that functional mechanisms play a dominant role in left ventricular mechanical dysfunction induced by isometric exercise.

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

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