Lasting alterations of the sodium current by short-term hyperlipidemia as a mechanism for initiation of cardiac remodeling.

Clinical and animal studies indicate that increased fatty acid delivery to lean tissues induces cardiac electrical remodeling and alterations of cellular calcium homeostasis. Since this may represent a mechanism initiating cardiac dysfunction during establishment of insulin resistance and diabetes or anaerobic cardiac metabolism (ischemia), we sought to determine if short-term exposure to high plasma concentration of fatty acid in vivo was sufficient to alter the cardiac sodium current (INa) in dog ventricular myocytes. Our results show that delivery of triglycerides and nonesterified fatty acids by infusion of Intralipid + heparin (IH) for 8 h increased the amplitude of INa by 43% and shifted its activation threshold by -5 mV, closer to the resting membrane potential. Steady-state inactivation (availability) of the channels was reduced by IH with no changes in recovery from inactivation. As a consequence, INa "window" current, a strong determinant of intracellular Na+ and Ca2+ concentrations, was significantly increased. The results indicate that increased circulating fatty acids alter INa gating in manners consistent with an increased cardiac excitability and augmentation of intracellular calcium. Moreover, these changes could still be measured after the dogs were left to recover for 12 h after IH perfusion, suggesting lasting changes in INa. Our results indicate that fatty acids rapidly induce cardiac remodeling and suggest that this process may be involved in the development of cardiac dysfunctions associated to insulin resistance and diabetes.

Central sleep apnea after acute coronary syndrome and association with ticagrelor use.

STUDY OBJECTIVES: By modifying the apneic threshold, the antiplatelet agent ticagrelor could promote central sleep apnea hypopnea syndrome (CSAHS). We aimed to assess the association between CSAHS and ticagrelor administration. METHODS: Patients were prospectively included within 1 year after acute coronary syndrome (ACS), if they had no heart failure (and left ventricular ejection fraction ≥ 45%) and no history of sleep apnea. After an overnight sleep study, patients were classified as "normal" with apnea hypopnea index (AHI) < 15, "CSAHS patients" with AHI ≥ 15 mostly with central sleep apneas, and "obstructive sleep apnea hypopnea syndrome (OSAHS) patients" with AHI ≥ 15 mostly with obstructive sleep apneas. RESULTS: We included 121 consecutive patients (mean age 56.8 ± 10.8, 88% men, mean body mass index 28.3 ± 4.4 kg/m2, left ventricular ejection fraction 56 ± 5%, at a mean of 67 ± 60 days (median 40 days, interquartile range: 30-80 days) after ACS. In total, 49 (45.3%) patients had AHI ≥ 15 (27 [22.3%] CSAHS %, 22 [18.2%] OSAHS). For 80 patients receiving ticagrelor, 24 (30%) had CSAHS with AHI ≥ 15, and for 41 patients not taking ticagrelor, only 3 (7.3%) had CSAHS with AHI ≥ 15 (chi-square = 8, p = 0.004). On multivariable analysis only age and ticagrelor administration were associated with the occurrence of CSAHS, (p = 0.0007 and p = 0.0006). CONCLUSION: CSA prevalence after ACS is high and seems promoted by ticagrelor administration. Results from monocentric study suggest a preliminary signal of safety. CLINICAL TRIALS. GOV ID: NCT03540459.

Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis.

OBJECTIVE: Hypofibrinolysis promotes atherosclerosis progression and recurrent ischemic events in premature coronary artery disease. We investigated the role of fibrin physical properties in this particular setting. METHODS AND RESULTS: Biomarkers of recurrent thrombosis and premature coronary artery disease (CAD) were measured in 33 young post-myocardial infarction patients with angiographic-proven CAD and in 33 healthy volunteers matched for age and sex. Ex vivo plasma fibrin physical properties were assessed by measuring fibrin rigidity and fibrin morphological properties using a torsion pendulum and optical confocal microscopy. The fibrinolysis rate was derived from continuous monitoring of the viscoelastic properties after addition of lytic enzymes. Young CAD patients had a significant increase in plasma concentration of fibrinogen, von Willebrand factor, plasminogen activator inhibitor type 1, and lipoprotein(a) as compared with controls (P<0.05). Fibrin of young CAD patients was stiffer (P=0.002), made of numerous (P=0.002) and shorter fibers (P=0.04), and lysed at a slower rate than that of controls (P=0.03). Fibrin stiffness was an independent predictor for both premature CAD and hypofibrinolysis. CONCLUSIONS: This first detailed study of clot properties in such a group of patients demonstrated that abnormal plasma fibrin architecture is an important feature of both premature CAD and fibrinolysis rate. The determinants of this particular phenotype warrant further investigation.

Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.

The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.

Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome.

OBJECTIVE: Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias. METHODS: We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells. RESULTS: Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a "hump" like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes. CONCLUSIONS: Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium.

Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles.

OBJECTIVE: To determine the presence and the potential contribution of neuronal sodium channels to dog cardiac function. METHODS: We used a combination of electrophysiological (patch clamp), RT-PCR, biochemical and immunohistochemical techniques to identify and localize neuronal Na(+) channels in dog heart and determine their potential contribution to the fast sodium current. RESULTS: In all cardiac tissues investigated, Na(v)1.1, Na(v)1.2 and Na(v)1.3 transcripts were detected. In immunoblots, we found Na(v)1.1 and Na(v)1.2 proteins in the ventricle (V) and in Purkinje fibers (PF). Na(v)1.3 immunoblots suggested strong proteolytic activity against this isoform in the heart. Na(v)1.6 was not found in any of the tissues tested. Confocal immunofluorescence on cardiac myocytes showed that Na(v)1.1 was predominantly localized at the intercalated disks in V and PF and around the nucleus (V). Na(v)1.2 was only present at the Z lines (V). Consistent with the immunoblot data, an intense but diffuse intracellular staining was observed for Na(v)1.3. Na(v)1.6 fluorescence staining was faint and diffuse. Surprisingly, immunoblots indicated the presence of two Na(v)beta 2 variants: a 42-kDa protein that co-localized with Na(v)1.2 at the Z lines in V and a 34-kDa protein that co-localized with Na(v)1.1 at the intercalated disks in PF. In agreement with the biochemical data, electrophysiological results suggest that neuronal sodium channels generate 10+/-5% and 22+/-5% of the peak sodium current in dog ventricle and Purkinje fibers, respectively. CONCLUSIONS: Our results suggest that neuronal NaChs are more abundant in Purkinje fibers than in ventricles, and this suggests a role for them in cardiac conduction.

Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin.

BACKGROUND: Low-molecular-weight heparin (LMWH) is recommended in the treatment of unstable angina (UA)/non-ST-segment-elevation myocardial infarction (NSTEMI), but no relationship has ever been shown between anticoagulation levels obtained with LMWH treatment and clinical outcomes. METHODS AND RESULTS: In all, 803 consecutive patients with UA/NSTEMI were treated with subcutaneous enoxaparin and were followed up for 30 days. The recommended dose of enoxaparin of 1 mg/kg BID was used throughout the population except when physicians decided on dose reduction because of a history of a recent bleeding event or because of a high bleeding risk. Anti-factor Xa activity was >0.5 IU/mL in 93% of patients; subtherapeutic anti-Xa levels (<0.5 IU/mL) were associated with lower doses of enoxaparin. The 30-day mortality rate was significantly associated with low anti-Xa levels (<0.5 IU/mL), with a >3-fold increase in mortality compared with the patients with anti-Xa levels in the target range of 0.5 to 1.2 IU/mL (P=0.004). Multivariate analysis revealed low anti-Xa activity as an independent predictor of 30-day mortality at least as strong as age, left ventricular function, and renal function. In contrast, anti-Xa activity did not predict major bleeding complications within the range of anti-Xa levels observed in this study. CONCLUSIONS: In this large unselected cohort of patients with UA/NSTEMI patients, low anti-Xa activity on enoxaparin treatment is independently associated with 30-day mortality, which highlights the need for achieving at least the minimum prescribed anti-Xa level of 0.5 IU/mL with enoxaparin whenever possible.

[Antithrombotics in pre-hospital phase of acute coronary syndromes]. / Antithrombotiques durant la phase préhospitalière des syndromes coronaires aigus.

Antithrombotic therapies are the corner stone of acute coronary syndrome management. We have the proof that many of them should be initiated during the prehospital care because their clinical benefit is time-dependent. The hypothesis that anticoagulation therapy is an effective treatment of STEMI, which benefit is time-dependent, is now validated. It is also fair to affirm that GP lIb/IIIa receptor inhibitors are the adjuvant therapy of choice for primary PCI. Indeed, these medications reduce short-term and long-term mortality. This clinical benefit is time dependent. Clopidogrel therapy is probably also a medication of the prehospital phase. It is well established now that the biological efficacy of this pro drug is loading dose dependent. It is also demonstrated that its clinical efficacy depends on the time delay between symptom onset and initiation of the therapy. However, the clinical benefit of prehospital administration remains to be established.

Taurine depresses INa and depolarises the membrane but does not affect membrane surface charges in perfused rabbit hearts.

STUDY OBJECTIVE: The aim was to determine whether taurine influences the membrane surface charges in cardiac muscle. DESIGN: Screening of the negative charges at the outside surface of the membrane results in a shift of the steady state inactivation of the sodium system towards less negative potentials. This feature was used to study eventual effects of taurine on surface charges and the data were compared to the known influence of varying extracellular calcium. EXPERIMENTAL MATERIAL: New Zealand rabbits (6-7 weeks, 1.25-1.75 kg) were anesthetised and the hearts were rapidly excised and perfused with the Langendorff technique. MEASUREMENTS AND MAIN RESULTS: Standard microelectrodes were used to determine the effects of 20 mM taurine and varying Ca concentrations (from 0.3 to 5.0 mM) on action potential parameters. The resting potential was varied by changing extracellular K between 2.5 and 10 mM. Taurine significantly depolarised the membrane by about 3 mV between 5 and 10 mM Ko but not at 2.5 mM; the maximum rate of depolarisation (dV/dTmax) decreased significantly at all Ko except at 10 mM where taurine caused arrhythmias or cardiac arrest. The dV/dTmax upsilon resting potential relationship (a measure for the steady state sodium current inactivation) was not changed by taurine, but the current was depressed as a function of membrane potential, the depression being more pronounced at more positive membrane potentials. An increase in Cao from 0.3 to 5.0 mM displaced the half maximal value of the dV/dtmax upsilon resting potential relationship from -79 to -67 mV, showing that the screening effect of Ca on the negative charges at the outside surface of the membrane could be detected with this experimental approach. CONCLUSIONS: The decrease of the fast Na current by taurine can explain the arrhythmias observed at 10 mM external potassium, whereas the surface charges of the glycocalix were not affected.

Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of I(Ks) in canine hypertrophied hearts.

OBJECTIVE: In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (I(Ks)) of the delayed rectifier potassium current (I(K)), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in I(Ks) by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel. METHODS AND RESULTS: Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in I(Ks) density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog. CONCLUSIONS: Our results indicate that the CAVB-induced reduction in I(Ks) is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of I(K) and may potentiate the action of Class III antiarrhythmic agents.

Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development.

The repolarization phase of the cardiac action potential is dependent on transmembrane K(+) currents. The slow (I(Ks)) and fast (I(Kr)) components of the delayed-rectifier cardiac K(+) current are generated by pore-forming alpha subunits KCNQ1 and KCNH2, respectively, in association with regulatory beta-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the beta-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that alpha subunits are homogeneously distributed within the myocardium, whereas the beta subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K(+) currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential beta-subunit distribution.

[Biological markers for acute phase hemostasis in coronary thrombosis]. / Les marqueurs biologiques de l'hémostase à la phase aiguë de la thrombose coronaire.

Associated with rheological conditions, multiple factors regarding haemostasis and fibrinolysis contribute to the instability and rupture of atherosclerotic plaque. Various biological parameters are modified during the occurrence of a coronary thrombotic episode, but do these increasingly identified alterations constitute a cause or a direct consequence of this accident? With the increasing identification of markers more and more sensitive but of limited specificity, the relative abundance of studies in the literature contrasts with the paucity of effective assets for everyday clinical practice. In fact, the potential use of these indicators in the evaluation of the pathogenesis of vascular accident, their eventual prognostic value, their predictive nature in therapeutic strategy, and their relevance for patient classification and follow up remain to be established on a wider scale. There is growing interest in the detection of evidence of cellular cooperation or a vascular compartment lesion thanks to the development of new diagnostic tools such as flux cytometry or immunoenzymology. While advances in biology have allowed undeniable clarifications of the physiopathology of coronary accidents and in the management of thrombotic pathology, it must nevertheless be endeavoured to give a practical response to the numerous questions where doubt remains, and to pursue the search for markers or tests clinically relevant.

The promiscuous nature of the cardiac sodium current.

Voltage-gated sodium channels (Na(V)s) are essential in propagating neuronal electrical impulse and triggering muscle contraction. In the heart, the Na(+) channel isoform Na(V)1.5 is strongly expressed and in the past was thought to be solely responsible for generating the cardiac Na(+) current (I(Na)). Recent studies, however, revealed that neuronal and skeletal muscle Na(+) channel isoforms are also expressed in the heart and contribute to cardiac I(Na). Amongst the findings is that many neuronal type Na(V)s are expressed in specific areas of the conduction system and ventricles. The contribution of these TTX-sensitive channels to normal cardiac function remains unclear but these data raise the possibility of a more prominent role of TTX-sensitive channels in conduction. Moreover, cardiac arrhythmias are commonly observed in many neuronal and musculoskeletal diseases despite their exclusive linkage to mutations in the neuronal and skeletal muscle sodium channel isoforms. The cause for these arrhythmias remains poorly understood. These recent findings indicate that neuronal and skeletal muscle sodium channels are expressed in areas of the heart that may be involved in the clinical phenotypes observed. The purpose of this review is to give an overview of the evidence for the presence of TTX-sensitive Na(V) isoforms in the heart and present the hypothesis brought forward so far for their direct role in cardiac function. These data demonstrate the promiscuous nature of the cardiac sodium current at the molecular level and should help us to bridge the gap that exists between our understanding of cardiac physiology and arrhythmias associated to brain and myotonic diseases.

Two conformational states involved in the use-dependent TTX blockade of human cardiac Na+ channel.

We used a fast inactivation-deficient mutant (QQQ) of the human heart Na+ channel alpha-subunit (hH1a) to assess the influence of the inactivation gate on tetrodotoxin (TTX) use-dependent block (UDB) and postrepolarization block (PRB). PRB had similar time courses in both channels, suggesting no direct interaction of the inactivation gate with the TTX binding site. The UDB saturated with high concentrations of TTX in hH1a but not in QQQ, revealing the modulatory action of fast inactivation on UDB. TTX did not stabilize the inactivated states of QQQ, and the extra block developing during long depolarizations suggests a higher-affinity site involved in the gating of the channel. These results cannot be solely explained by a slow recovery from the block in the inactivated states. They suggest a common use-dependent block mechanism for hH1a and QQQ involving a high-affinity site. We propose that an activated state is primarily responsible for UDB during short depolarization in the range of the action potential plateau and that fast inactivation modulates the accessibility of the toxin to this site.

Interaction of taurine with the fast Na-current in isolated rabbit myocytes.

We studied in whole cell configuration with the patch clamp method the effect of taurine on the macroscopic Na current in adult ventricular rabbit myocytes. Because these cells have a large surface [13,750 +/- 704 microns2 (19), mean +/- S.E.M. (n)], we reduced [Na]o to 45 mM and worked at room temperature to obtain acceptable voltage control. When the cells were held at -80 mV, taurine (20 mM) had the following effects: 1) The current voltage relationships crossed over so that taurine increased INa at potentials negative to -45 mV, and at more positive potentials it depressed the current; 2) taurine reduced the maximal Na conductance from 536.3 +/- 72.2 to 253.6 +/- 33.6 microS.cm-2; 3) the crossing over of the I/V curves was mainly caused by a hyperpolarizing shift of V1/2 of the steady-state activation by 6.3 mV; 4) the crossing over was independent of a -4.6 mV shift of V1/2 of the steady-state inactivation and 5) taurine increased significantly the time constant of reactivation between -90 and -70 mV, but we did not find evidence that taurine changed the time constant of inactivation between -40 and +20 mV. We conclude that positive to -45 mV taurine causes a block of INa channels that resembles that of local anesthetic antiarrhythmic drugs. Negative to -45 mV taurine counteracts the local anesthetic effect causing increased excitability and improved conduction in the range of the threshold potential and -45 mV.

Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels.

Inherited long Q-T syndrome is a ventricular arrhythmia associated with delayed repolarization and the risk of sudden death. The chromosome 3-linked form of the disease (LQT3) is associated with mutations in the cardiac Na+ channel (N1325S or R1644H; or deletion of residues 1,505-1,507, delta KPQ) that increase late inward currents and may cause delayed repolarization. Late currents arise from dispersed reopenings (N1325S and R1644H) or from reopenings combined with prolonged bursts (delta KPQ). Therefore, we tested whether lidocaine blockade of late current varied among the different LQT3 mutant channels. We found that lidocaine preferentially blocked late over peak current and that the blockade was equally effective in all three channels, expressed in Xenopus oocytes. Lidocaine inhibited both dispersed reopenings and bursting in single channels without affecting mean open times. In the absence of drug, inactivating prepulses inhibited bursting but not dispersed reopenings. We suggest that lidocaine block of late current in LQT3 channels acts via a common mechanism involving stabilization of inactivation. Therefore, blockers that target the inactivated state may be effective therapeutic agents in all three biophysical phenotypes of LQT3.

Blockade of HERG and Kv1.5 by ketoconazole.

Ketoconazole, a widely used fungicide in patients, has been associated with Q-T prolongation and torsade de pointes when co-administered with terfenadine (Seldane). Both compounds use the same cytochrome-P450 metabolic pathway, resulting in an increase in plasma concentration of terfenadine. We previously showed that terfenadine blocked HERG (Human Ether-a-Gogo Related Gene), an important component of the repolarizing cardiac delayed rectifier IK with concentration needed to obtain 50% of the block (IC50) in the therapeutic range (300 nM). Another target is Kv1.5 (delayed outward rectifier potassium current), an important component of human atrial ultrarapid delayed rectifier current. Whether Kv1.5 and HERG proteins are direct targets for ketoconazole has yet to be addressed. We heterologously expressed HERG and Kv1.5 in Xenopus oocytes and compared their sensitivities to ketoconazole. HERG and Kv1.5 currents were reduced comparably with apparent IC50 values of 49 microM and 107 microM, respectively, when measured using the two-microelectrode recording technique. The differences in the IC50 may help explain the preferential ventricular origin of the ketoconazole-associated arrhythmias during overdose. The mechanism of block was different between Kv1.5 and HERG. Cumulative application of terfenadine and ketoconazole at their respective IC50 concentrations resulted in current reductions that suggest an additive rather than a competitive type of block by the two drugs. We conclude that ketoconazole may potentiate the effects of terfenadine first by an indirect pharmacokinetic action to elevate plasma levels and second by a direct pharmacodynamic action on HERG currents. These potential dual actions on HERG currents suggest that precautions should be taken in long-term ketoconazole treatment, particularly for patients who have decreased liver function or are on a drug regimen requiring simultaneous medications that use cytochrome-P450 for breakdown, such as terfenadine or erythromycin, or Class III antiarrhythmic drugs.

HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.

BACKGROUND: Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K+ current (Ikur) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go-related gene that expresses a delayed rectifier current (IKr) in human ventricle and produces hereditary long QT syndrome when defective. METHODS AND RESULTS: We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range. CONCLUSIONS: Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.

Multiple mechanisms of Na+ channel--linked long-QT syndrome.

Inheritable long-QT syndrome (LQTS) is a disease in which delayed ventricular repolarization leads to cardiac arrhythmias and the possibility of sudden death. In the chromosome 3-linked disease, one mutation of the cardiac Na+ channel gene results in a deletion of residues 1505 to 1507 (Delta KPQ), and two mutation result in substitutions (N1325S and R1644H). We compared all three mutant-channel phenotypes by heterologous expression in Xenopus oocytes. Each produced a late phase of inactivation-resistant, mexiletine- and tetrodotoxin-sensitive whole-cell currents, but the underlying mechanisms were different at the single-channel level. N1325S and R1644H showed dispersed reopenings after the initial transient, whereas Delta KPQ showed both dispersed reopenings and long-lasting bursts. Thus, two distinct biophysical defects underlie the in vitro phenotype of persistent current in Na+ channel-linked LQTS, and the additive effects of both are responsible for making the Delta KPQ phenotype the most severe.