Biomedical subjects

P S Spector

Publications and source records attributed to P S Spector.

7 recordsLinked to original sources

PubMed2001

Ablation strategies reflect evolving concepts of atrial fibrillation mechanisms.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and results in the largest number of arrhythmia related hospital admissions. Despite the enormity of its impact on patients and the health care system, current medical therapy for AF is inadequate. Therapeutic approaches have been guided by understanding of fibrillation mechanisms. AF results from multiple simultaneous reentrant wavefronts. This is a diffuse and dynamic substrate with no discrete anatomic target. The catheter mediated "Maze" procedure employs creation of linear lesions to divide the atria into segments too small to support reentrant activation. Using current catheter technology this is a challenging procedure with low success rates and high complication rates. The observation that rapid focal firing of atrial myocytes within the pulmonary veins initiates fibrillation in the majority of paroxysmal AF patients has led to an entirely new ablation strategy. The sites of firing that initiate AF are targeted for ablation. Thus the paradigm for AF ablation has changed dramatically from altering the substrate of ongoing fibrillation to elimination of the triggers that initiate fibrillation. Initial experience revealed that multiple sites in the pulmonary veins are capable of rapid firing. Unfortunately not all sites fire during an ablation procedure. Sites that are quiescent during an ablation procedure may result in AF recurrence despite acute success. Ablation strategy has thus changed yet again to electrical isolation of all pulmonary venous tissue from the left atrium. The evolution of ablation strategies has paralleled our understanding of AF mechanisms. Elucidation of the mechanisms responsible for venous firing may lead to more specific therapy for the prevention of AF in the future.

Atrial Fibrillation↗

PubMed2000

Lidocaine-induced conduction disturbance in patients with systemic hyperkalemia.

We report 2 cases in which lidocaine, given for wide-complex tachycardia in the presence of hyperkalemia, precipitated profound conduction disturbance and asystole. The electrophysiologic effects of hyperkalemia and its interaction with lidocaine are reviewed. In patients with known hyperkalemia and wide-complex tachycardia, treatment should be directed at hyperkalemia, rather than following treatment algorithms for wide-complex tachycardia.

Adult↗

PubMed1997

Potassium channelopathies.

The molecular diversity of K(+)-selective channels far exceeds any other group of voltage- or ligand-gated channels, reflecting their early ancestral origin. This diversity is mirrored by the broad spectrum of physiological functions subserved by these proteins. Potassium channels modulate the resting potential and action potential duration of neurons, myocytes and endocrine cells and stabilize the membrane potential of excitable and nonexcitable cells. In addition to channel diversity, differential cellular expression of K+ channels determines the specific electrical responses to stimuli in a particular cell or tissue. This study reviews the recent genetic and physiological studies of congenital disorders caused by mutations in genes encoding K+ channels. These include the human disorders of episodic ataxia with myokymia, long QT syndrome and Bartter's syndrome, and weaver ataxia in mice. An understanding of the molecular basis of these diseases could facilitate the discovery and development of specific pharmacological therapies.

Action Potentials↗

PubMed1996

Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.

The slowly activating delayed-rectifier K+ current, I(Ks), modulates the repolarization of cardiac action potentials. The molecular structure of the I(Ks) channel is not known, but physiological data indicate that one component of the I(Ks), channel is minK, a 130-amino-acid protein with a single putative transmembrane domain. The size and structure of this protein is such that it is unlikely that minK alone forms functional channels. We have previously used positional cloning techniques to define a new putative K+-channel gene, KVLQT1. Mutations in this gene cause long-QT syndrome, an inherited disorder that increases the risk of sudden death from cardiac arrhythmias. Here we show that KVLQT1 encodes a K+ channel with biophysical properties unlike other known cardiac currents. We considered that K(V)LQT1 might coassemble with another subunit to form functional channels in cardiac myocytes. Coexpression of K(V)LQT1 with minK induced a current that was almost identical to cardiac I(Ks). Therefore, K(V)LQT1 is the subunit that coassembles with minK to form I(Ks) channels and I(Ks) dysfunction is a cause of cardiac arrhythmia.

Amino Acid Sequence↗

PubMed1996

Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia.

Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome 7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT.

Animals↗

PubMed1996

Fast inactivation causes rectification of the IKr channel.

The mechanism of rectification of HERG, the human cardiac delayed rectifier K+ channel, was studied after heterologous expression in Xenopus oocytes. Currents were measured using two-microelectrode and macropatch voltage clamp techniques. The fully activated current-voltage (I-V) relationship for HERG inwardly rectified. Rectification was not altered by exposing the cytoplasmic side of a macropatch to a divalent-free solution, indicating this property was not caused by voltage-dependent block of outward current by Mg2+ or other soluble cytosolic molecules. The instantaneous I-V relationship for HERG was linear after removal of fast inactivation by a brief hyperpolarization. The time constants for the onset of and recovery from inactivation were a bell-shaped function of membrane potential. The time constants of inactivation varied from 1.8 ms at +50 mV to 16 ms at -20 mV; recovery from inactivation varied from 4.7 ms at -120 mV to 15 ms at -50 mV. Truncation of the NH2-terminal region of HERG shifted the voltage dependence of activation and inactivation by +20 to +30 mV. In addition, the rate of deactivation of the truncated channel was much faster than wild-type HERG. The mechanism of HERG rectification is voltage-gated fast inactivation. Inactivation of channels proceeds at a much faster rate than activation, such that no outward current is observed upon depolarization to very high membrane potentials. Fast inactivation of HERG and the resulting rectification are partly responsible for the prolonged plateau phase typical of ventricular action potentials.

Animals↗

PubMed1996

Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.

We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oocytes revealed that this channel had biophysical properties nearly identical to a cardiac delayed rectifier K+ current I(Kr), but had dissimilar pharmacological properties. Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I (Kr) in cardiac myocytes. Our initial studies indicated that these compounds did not block HERG at a concentration of 1 micromol/L. In the present study, we used standard two-microelectrode voltage-clamp techniques to further characterize the effects of these drugs on HERG channels expressed in oocytes. Consistent with initial findings, 1 micromol/L MK-499 and E-4031 had not effect on HERG when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug. However, MK-499 did block HERG current if oocytes were repetitively pulsed, or clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that showed significant block of I(Kr) in isolated myocytes by similar drugs, even in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mouse I (Kr)), tissue (oocytes versus myocytes), or specific drugs. Under steady state conditions, block of HERG by MK-499 was half maximal at 123 +/- 12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did not affect the voltage dependence of activation and rectification nor the kinetics of activation and deactivation of HERG. These data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I(Kr) channels in cardiac myocytes.

Animals↗