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Biomedical subjects

Mark C P Haigney

Publications and source records attributed to Mark C P Haigney.

7 recordsLinked to original sources
PubMed2006

Intravenous cocaine and QT variability.

BACKGROUND: Dynamic instability in cardiac repolarization may contribute to drug-induced arrhythmogenesis. We hypothesized that intravenous cocaine would significantly destabilize repolarization as measured by QT variability. METHODS AND RESULTS: Twenty-nine cocaine-experienced volunteers not seeking treatment for cocaine addiction received randomized, sequential intravenous infusions of placebo or cocaine (20 and 40 mg). Five-minute epochs of digitized ECG were recorded 10 minutes before, during, and at intervals following the infusions. QT variability was measured using a semiautomated method and expressed as the log ratio of normalized QT variance to normalized heart rate variance (QTVI). Seventeen subjects received a repeat course of cocaine infusions 1 week later. Placebo infusion resulted in a small but significant increase in QTVI, while cocaine caused a highly significant, dose-dependent increase in QTVI that peaked at 10 minutes and dissipated by 45 minutes following infusion (P < 0.0001). The increase in QTVI was reproducible at 1 week (P = 0.8). CONCLUSIONS: Cocaine injection results in a significant dose-dependent increase in QT variability as indexed by QTVI. This destabilizing effect on repolarization may increase vulnerability to reentrant arrhythmias and may partially explain an increased risk of sudden cardiac death associated with cocaine use.

Adult↗
PubMed2005

Ciprofloxacin-induced torsade de pointes.

We report a rare case of torsade de pointes, a polymorphic ventricular tachycardia associated with QT interval prolongation, caused by intravenous ciprofloxacin given for pneumonia in a 22-year-old healthy Marine. Although the risk for quinolone-associated torsade de pointes appears to be low, caution is still warranted when given in the presence of pre-existing QT prolongation.

Adult↗
PubMed2003

Protein kinase A hyperphosphorylation increases basal current but decreases beta-adrenergic responsiveness of the sarcolemmal Na+-Ca2+ exchanger in failing pig myocytes.

The sodium-calcium exchanger (NCX) protein is the major cardiac calcium extrusion mechanism and is upregulated in heart failure (HF). NCX expression level and functional activity as regulated by beta-adrenergic receptor (beta-AR) stimulation in swine with and without tachycardia-induced heart failure were studied. The Ni2+-sensitive NCX current was measured in myocytes from HF and control animals in the basal state or in the presence of isoproterenol, forskolin, 8-Br-cAMP, okadaic acid, or protein phosphatase type 1. Western blot analysis revealed a significant increase in both the 120-kDa (29%) and 80-kDa (69%) fragments in HF (P<0.05 versus control). Despite this modest increase in protein, the basal peak outward NCX current was increased almost 5-fold in HF (P<0.05 versus control). Stimulation with isoproterenol, however, increased the control currents to a significantly greater extent than HF (500% increase in control versus 100% increase in HF, P<0.01); peak stimulated current was not different in HF and control. This reduction in responsiveness to beta-AR stimulation was refractory to forskolin, 8-Br-cAMP, or okadaic acid stimulation. In vitro protein kinase A back-phosphorylation revealed higher phosphorylation capacity of NCX protein in control versus HF, consistent with increased phosphorylation in vivo (hyperphosphorylation) in HF. Protein phosphatase type 1 exposure resulted in a significant reduction (73%) in peak basal current in HF (compared with no significant difference in controls), confirming that the increased basal NCX current in HF is predominantly attributable to hyperphosphorylation. NCX expression and activity are thus increased in HF, although beta-AR responsiveness is decreased because of NCX hyperphosphorylation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Cytosolic free magnesium modulates Na/Ca exchange currents in pig myocytes.

OBJECTIVE: Cardiac Na/Ca exchanger (NCX) protein is up-regulated and intracellular free magnesium ([Mg(2+)](i)) is significantly reduced in experimental heart failure. We asked whether changes in [Mg(2+)](i) in a physiologically relevant range could alter the I(NCX). METHODS: The nickel-sensitive current was measured in voltage-clamped myocytes (Yorkshire pig; left ventricular) exposed to ramp pulses at 37 degrees C in Tyrode's solution containing ouabain, nifedipine and +/- Ni(2+) (5 mmol/l). The intracellular free [Ca(2+)] and [Mg(2+)] concentrations were set at 50 nmol/l and 1.25 mmol/l (HiMg) or 0.13 mmol/l (LoMg), respectively, through pipette dialysis. RESULTS: Reducing [Mg(2+)](i) resulted in a significant increase in both outward and inward Ni-sensitive current without a shift in the reversal potential. This effect was not due to the inadvertent reduction of intracellular free [ATP] secondary to binding of ATP to Mg(2+); reducing intracellular [ATP] in LoMg cells from 1.35 mmol/l to 0.18 mmol/l did not affect I(NCX). The intracellular free [Ca(2+)] was raised from 50 to 200 nmol/l, resulting in augmented inward and outward current due to calcium activation. HiMg attenuated both inward and outward currents significantly compared to LoMg, suggesting that [Mg(2+)](i) competes with [Ca(2+)](i) at the allosteric regulatory site. CONCLUSION: Cytosolic free magnesium modulates the I(NCX) over a physiologic range independent of [ATP](i). Reduced [Mg(2+)](i) in heart failure could contribute to altered calcium regulation of the NCX, contributing to the altered heart failure phenotype through enhanced NCX activity.

Action Potentials↗
PubMed2002

Beta-adrenergic stimulation of pig myocytes with decreased cytosolic free magnesium prolongs the action potential and enhances triggered activity.

INTRODUCTION: Heart failure results in chronic beta-adrenergic stimulation, repolarization lability, and arrhythmias associated with early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). Having described a significant reduction in intracellular free magnesium ([Mg2+]i) in experimental heart failure, we asked whether a reduction in [Mg2+]i would delay repolarization or facilitate EADs and/or DADs. METHODS AND RESULTS: Left ventricular myocytes were isolated from Yorkshire swine. Cytosolic free [Mg2+] was set at 0.12 mM (LoMg) or 1.2 mM (HiMg) through pipette dialysis. Action potentials (AP), Ca current (I(Ca)), and sodium/calcium exchange current (I(NCX)) were measured in the presence or absence of isoproterenol (2 microM) at 37 degrees C. Under basal conditions (0.1-Hz stimulation, 2 mM external [Ca2+]), reducing [Mg2+]i had no effect on AP duration and I(Ca) but did significantly enhance I(NCX). In contrast, during superfusion with isoproterenol, reduced [Mg2+]i caused a significant increase in AP duration at both 50% and 90% repolarization (APD50 and APD90) compared with HiMg (P < 0.05). LoMg cells manifested a high incidence of triggered activities, including spontaneous AP, EADs, and DADs (83.3% in LoMg, n = 12 vs 38.3% in HiMg, n = 13; P < 0.05). I(Ca) and I(NCX) were significantly increased in LoMg cells compared with HiMg cells (P < 0.05). CONCLUSION: Decreased cytosolic free magnesium prolongs AP duration and increases the incidence of triggered activity during beta-adrenergic stimulation. These effects may be due to increased I(Ca) and I(NCX) in the presence of reduced intracellular [Mg2+]. A magnesium-dependent increase in triggered activity coupled with delayed repolarization during beta-adrenergic stimulation could contribute to the arrhythmogenic substrate in heart failure.

Action Potentials↗