Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: a possible 'anti-proarrhythmic' role for amlodipine.

Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 µM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD90). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I(Kr)-blocking (dofetilide) and I(Ks)-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.

Middle-aged men with increased waist circumference and elevated C-reactive protein level are at higher risk for postoperative atrial fibrillation following coronary artery bypass grafting surgery.

INTRODUCTION: We recently demonstrated that metabolic syndrome (MetS) is an independent risk factor for postoperative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG). In the present work, we sought to determine which feature of the MetS is associated with POAF. METHODS AND RESULTS: We retrospectively analysed the association between metabolic features and the incidence of new-onset POAF in a total of 2214 male patients <65 years who underwent first isolated CABG. Anthropometric data including waist circumference (WC) and complete preoperative lipid profile were available. We also conducted a nested case-control substudy including 147 patients who developed POAF, and were matched for age with a control population. In these patients, C-reactive protein, interleukin-6 (IL-6), and thiobarbituric acid-reactive substances (TBARS; evaluating the oxidative stress) blood levels were determined. In the whole cohort, 19.6% of patients developed POAF. On univariate analysis, body mass index (BMI; P = 0.002) and WC (P = 0.001) were the only anthropometric variables significantly associated with increased incidence of POAF. In the multivariable logistic model, the only independent predictors of POAF were a WC > 102 cm [odds ratio (OR) = 1.40, P = 0.04)] and older age (OR = 1.08, P < 0.001). In the nested case-control substudy C-reactive protein, IL-6, and TBARS levels were not significantly different in patients with or without POAF. Of particular significance, patients with elevated WC > 102 cm and C-reactive protein > 1.5 mg/L or IL-6 >2.2 pg/mL were at a high risk of developing POAF (respectively, OR = 2.32, P = 0.02 and OR = 2.27, P = 0.03). CONCLUSION: Patients with increased WC combined with elevated C-reactive protein levels are at higher risk for POAF. Thus, interventions targeting inflammation related to visceral obesity might help reducing the incidence of POAF.

Obesity and metabolic syndrome are independent risk factors for atrial fibrillation after coronary artery bypass graft surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a highly prevalent complication after cardiac surgery with substantial effects on outcomes. Previous studies have reported that obesity is a risk factor for POAF after cardiac surgery. However, it is unknown whether the metabolic syndrome (MS) also increases the risk of postoperative atrial fibrillation. METHODS AND RESULTS: We retrospectively analyzed the association between obesity and MS and the incidence of new-onset POAF in a total of 5085 patients who underwent isolated coronary artery bypass grafting surgery with no concomitant valvular surgery. Of these patients, 1468 (29%) were obese (body mass index > or = 30 kg/m2) and 2320 (46%) had a MS as defined by the NCEP-ATPIII. POAF occurred in 1374 (27%) of the patients. Obesity was associated (P<0.001) with increased incidence of POAF in the whole cohort as well as in patients > 50 years old but not in patients < or = 50 years old. In these patients, MS was the only metabolic factor to be significantly associated with higher incidence of POAF (12% versus 6%, P=0.01). In > 50-year-old patients, mild (30 < or = body mass index < 35 kg/m2) and moderate-severe (body mass index > or = 35 kg/m2) obesity were independently associated with a 1.4-fold (95% CI: 1.10 to 1.71; P=0.004) and 2.3-fold (95% CI: 1.71 to 3.13; P<0.0001) increase in the risk of POAF, respectively. In < or = 50-year-old patients, MS (relative risk [RR]: 2.36; 95% CI: 1.10 to 5.12; P=0.02) but not obesity was independently associated with POAF. CONCLUSIONS: This study demonstrates that obesity is a powerful risk factor for the occurrence of POAF after isolated coronary artery bypass grafting surgery in patients older than 50 years. However, in the younger population, this association is not observed and MS is the only metabolic risk factor to be independently associated with POAF.

Ischemic, genetic and pharmacological origins of cardiac arrhythmias: the contribution of the Quebec Heart Institute.

Research in the field of basic electrophysiology at the Quebec Heart Institute (Laval Hospital, Quebec City, Quebec) has evolved since its beginning in the 1990s. Interests were focused on cardiac arrhythmias induced by drugs, allelic variants and metabolic factors produced during ischemia. The results have contributed to the creation of new standards in drug development, more specifically, testing all new drugs for their potential effects on cardiac potassium currents, which could produce life-threatening proarrhythmic effects. In a French-Canadian population, three heterozygous single nucleotide polymorphisms in hK(v)1.5, a gene encoding for a major atrial repolarizing current, were found. These variants affect the expression level of the hK(v)1.5 channel and change the inactivation process in the presence of its accessory beta subunit. Because these effects could shorten atrial action potential, their presence was tested in postcoronary bypass patients and a higher prevalence was found in patients with postoperative atrial fibrillation. Finally, three potentially proarrhythmic factors characteristic of ischemia were identified: pH decrease; oxygen free radicals, which both increase the flow of K(+) ions through human ether-a-go-go-related gene and hK(v)1.5, producing a reduction in action potential duration, frequently leading to cardiac arrhythmias; and lysophosphatidylcholine, a metabolite involved in the production of cardiac arrhythmias early during ischemia that was shown to be a major cause of electrical uncoupling. Over the past decade, the Quebec Heart Institute has provided a significant amount of original data in the field of basic cardiac electrophysiology, specifically concerning arrhythmias originating from pharmacological agents, genetic background and cardiac ischemia.

New epilepsy seizure at high altitude without signs of acute mountain sickness or high altitude cerebral edema.

Neurological disturbances may be present at high altitude independently of high altitude cerebral edema. We report here the case of a patient who experienced for the first time generalized seizures after spending a night at an altitude of 5200 m, with no preceding symptoms of acute mountain sickness. An initial CT scan performed 12 hours after his loss of consciousness and an MRI scan performed 2 months later were normal. An EEG, obtained 2 months after the event, showed epileptiform discharges triggered by hyperventilation. The description of the clinical event obtained from the witness and the presence of a positive family history strongly support a high altitude-triggered new epileptic seizure. This report suggests that at high altitudes seizure risks in a seizure-prone person may be higher than for normal individuals.

Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line.

Reactive oxygen species have been implicated in different types of cardiac arrhythmias including human atrial fibrillation. Kv1.5, the presumed molecular correlate of I(Kur), is an important determinant of human atrial repolarization. The aim of this study was to assess the effects of H(2)O(2), at pathophysiologically relevant concentrations (20-1,000 microM), on Kv1.5 expressed in Chinese hamster ovary cell line. Kv1.5 cDNA in pcDNA3 expression vector and CD8, a surface marker protein, were cotransfected in cells by calcium phosphate precipitation. Kv1.5 activation kinetics were significantly accelerated while the activation curve was negatively shifted by 10 mV (V(1/2) changed from -9.3 to -19.0 mV) in the presence of 100 microM H(2)O(2). The shift in Kv1.5 peak current I-V curve was voltage-dependent, the current amplitude being increased for voltages <+20 mV but decreased for high depolarizing voltages. The rapid activation time constant obtained from a bi-exponential fitting was decreased from 16.1+/-3.4 ms to 8.8+/-1.5 ms for a -20 mV depolarization ( n=9; P=0.01) and from 4.3+/-2.1 ms to 2.3+/-0.4 ms when cells were depolarized to +20 mV ( P<0.05). Kv1.5 steady-state inactivation was not modified by H(2)O(2). Intracellular application of SOD or catalase reduced the H(2)O(2) induced shift of activation I-V curve and SOD significantly decreased Kv1.5 amplitude at +40 mV ( n=9; P<0.05). In conclusion, H(2)O(2) increased Kv1.5 current amplitude at voltages corresponding to the action potential repolarization phase and accelerated Kv1.5 channel opening. These changes can reduce the action potential duration, leading to a shortening of the atrial effective refractory period. H(2)O(2)-induced changes in Kv1.5 properties could thus be involved in initiation or perpetuation of AF.

Statins reduce short- and long-term mortality associated with postoperative atrial fibrillation after coronary artery bypass grafting: impact of postoperative atrial fibrillation and statin therapy on survival.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a frequent complication of coronary artery bypass grafting (CABG) surgery. The objective of this study was to determine the impact of POAF on both short- and long-term mortality following isolated CABG. HYPOTHESIS: POAF is associated with a poorer short and long-term mortality following CABG. METHODS: We retrospectively analyzed the preoperative and operative data of 6728 consecutive patients undergoing a first isolated CABG. RESULTS: The incidence of POAF was 27.8%. Operative mortality was higher in patients with POAF compared to those without POAF (2.3% vs 0.9%, P < 0.001). On multivariate analysis, POAF remained an independent predictor of operative mortality (odds ratio [OR]: 1.78, P = 0.01). Patients with POAF also had reduced long-term survival (6-year survival: 85.3% vs 89.2%, P < 0.001). After adjusting for other predictors of mortality, POAF was significantly associated with increased long-term mortality (hazard ratio [HR]: 1.35, P = 0.04). Of note, after adjustment for potential confounders, statin treatment had a highly protective effect in POAF patients for both operative mortality (OR: 0.38, P = 0.003) and long-term mortality (HR: 0.62, P = 0.03), whereas it had no significant effect in patients without POAF. CONCLUSIONS: POAF is an independent predictor of both short- and long-term mortality following CABG. Moreover, statin therapy was independently associated with better survival in patients with POAF.

QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile.

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the I(Kr) -, I(Ks) -, and I(Na) -blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD(90) -, MAP amplitude-, phase 0 dV/dt-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an I(Kr) blocker. IC(50) was estimated at 34 µm. In contrast, bupropion had hardly any effect on I(Ks) and I(Na) . Bupropion had no significant MAPD(90) -modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its I(Kr) -blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 dV/dt -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.

A pilot study to estimate the feasibility of assessing the relationships between polymorphisms in hKv1.5 and atrial fibrillation in patients following coronary artery bypass graft surgery.

BACKGROUND: Postoperative atrial fibrillation (AF) is a frequent complication following cardiac surgery. Risk factors leading to the development of postoperative AF are not well known and may be influenced by mutations of specific channels involved in atrial repolarization. Recently, the authors have identified three single nucleotide polymorphisms (SNPs) (R87Q, A251T and P307S) in the voltage-gated potassium channel hKv1.5 in a French-Canadian population. Two of these, R87Q and P307S, modified the gating process and the expression level of the hKv1.5 channel. OBJECTIVES: Considering that these SNPs may accelerate atrial repolarization, it was hypothesized that they may predispose patients to postoperative AF. METHODS: The authors tested the presence of SNPs in the hKv1.5 channel among 185 patients undergoing coronary artery bypass graft surgery. RESULTS: In the postoperative period, 96 patients (52%) developed a new onset of AF. A higher prevalence of SNPs was found among patients who developed postoperative AF than in the population without this postoperative arrhythmia (6.25% versus 3.37%; P=0.42). Respective allelic frequencies for R87Q and P307S were 0.52% and 1.56% in the postoperative AF group versus 0% and 0.56% in the non-AF group. Families of the carrier patients were also screened, and several members were found who carried the SNPs but did not have AF. The A251T SNP is not likely to be responsible for AF because it does not modify hKv1.5 channel functions. CONCLUSIONS: A genetic background that may be involved in the occurrence of postoperative AF was identified. Therefore, R87Q and P307S polymorphisms in hKv1.5, possibly in combination with other risk factors, may influence the development of postoperative AF.

Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs.

OBJECTIVES: This open-label canine study assessed whether n-3 polyunsaturated fatty acids (PUFAs) prevent vagally induced atrial fibrillation (AF) and influence atrial tissue expression levels of connexins (CXs). BACKGROUND: n-3 polyunsaturated fatty acids in fish oils protect against sudden cardiac death and reduce postoperative AF. Changes in spatial organization of gap junctions or cellular CX levels have been linked to arrhythmogenesis. METHODS: Vagally induced AF was studied. Eight dogs were given fish oil daily for 14 days. Eight control dogs had reproducibly induced AF and were re-evaluated after intravenous administration of fish oil. Atrial fibrillation was compared, and n-3 PUFA, CX40, and CX43 protein levels were assessed in atrial biopsies. RESULTS: Atrial tissue n-3 PUFA levels increased in oral treatment dogs (5.78 +/- 0.71% vs. 2.49 +/- 0.46% in control animals, p < 0.001). No difference was observed for atrial refractory periods or hemodynamic or electrocardiographic parameters. Incidence of AF in oral treatment dogs decreased 79% with the extra stimulus technique (10.5% vs. 48.9%, p = 0.003) and 42% with burst induction (22.5% vs. 38.8%, p = 0.038). Both CX40 and CX43 levels were lower in oral treatment dogs (60% [p = 0.019] and 42% [p = 0.038] lower, respectively); protection against AF was mostly related to reduced CX40 expression levels (p = 0.02). In dogs that were given intravenous n-3 PUFAs, AF inducibility by the extra stimulus technique was reduced from 75.0% to 28.6% (p = 0.002). CONCLUSIONS: Oral treatment with fish oils increased atrial n-3 PUFA levels and reduced vulnerability to induction of AF in this dog model. Modulation of cardiac CX by n-3 PUFAs probably contributes to the antiarrhythmic effects of fish oils.

Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation.

Activation of nicotinic acetylcholine receptors (nAChRs) on inflammatory cells induces anti-inflammatory effects. The intracellular mechanisms that regulate this effect are still poorly understood. In neuronal cells, nAChRs are associated with phosphatidylinositol 3-kinase (PI3K). This enzyme, which can activate phospholipase C (PLC), is also present in monocytes. The aim of this study was to assess the role of these proteins in the signaling pathways involved in the anti-inflammatory effect of dimethylphenylpiperazinium (DMPP), a synthetic nAChR agonist, on monocytes and macrophages. The results indicate that PI3K is associated with alpha3, -4, and -5 nAChR subunits in monocytes. The PI3K inhibitors wortmannin and LY294002 abrogated the inhibitory effect of DMPP on LPS-induced TNF release by monocytes. Treatment with DMPP for 24 and 48 h provoked a mild PLC phosphorylation, which was blocked by the nAChR antagonist mecamylamine and reversed by PI3K inhibitors. Treatment of monocytes and alveolar macrophages with DMPP reduced the inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium mobilization induced by platelet-activating factor (PAF), an effect that was reversed by mecamylamine in alveolar macrophages. DMPP did not have any effect on PAF receptor expression. DMPP also inhibited the thapsigargin-provoked calcium release, indicating that the endoplasmic reticulum calcium stores might be depleted by treatment with the nAChR agonist. Taken together, these results suggest that PI3K and PLC activation is involved in the anti-inflammatory effect of DMPP. PLC limited, but constant activation could induce, the depletion of intracellular calcium stores, leading to the anti-inflammatory effect of DMPP.

Electrophysiological characterization of three non-synonymous single nucleotide polymorphisms (R87Q, A251T, and P307S) found in hKv1.5.

Non-synonymous single nucleotide polymorphisms (SNPs) in the KCNA5/hKv1.5 gene, which encodes for a voltage-gated K+ channel responsible for the I (Kur) current in the human atria, have been recently reported. To gain further knowledge on potential influence of hKv1.5 SNPs, we searched for their presence in a specific population of 96 French-Canadians and characterized electrophysiological properties of the variants in two cell lines. The presumed promoter (-83 bp) and coding regions were sequenced. We found three heterozygous SNPs: R87Q, A251T, and P307S. Functional analysis of SNPs transfected in Chinese hamster ovary (CHO) cells showed that both R87Q and P307S diminished the inactivation amplitude (e.g., at +60 mV, amplitudes were 89+/-26, 23+/-4, and 22+/-7 pA/pF for the wild type, R87Q and P307S, respectively; n=8, 6, and 8, respectively). Inactivation was slowed with these variants (e.g., tau (fast) at +50 mV were 270+/-48, 490+/-66, and 340+/-45 ms for the wild type, R87Q, and P307S, respectively) while R87Q additionally accelerated the rate of hKv1.5 channel opening. A dominant-negative effect was observed for R87Q but not for P307S. SNPs properties were not reproduced when expressed in the HEK293 cell line, suggesting that the regulatory beta-subunit present in CHO cells (and the human heart) is essential for the SNPs effects that we have observed.

Cut-off phenomenon in the protective effect of alcohols against lysophosphatidylcholine-induced calcium overload.

We studied the effect of chain length on the protective effect of alcohols against lysophosphatidylcholine (LPC)-induced Ca2+ overload in neonatal rat cardiomyocytes. We previously found that ethanol retards Ca2+ elevation. Cells were loaded with the Ca2+-sensitive fluorophore fura-2, and changes in fluorescence were followed. The addition of 10 microM LPC increased Ca2+, which reached a plateau after an 8-10 min delay. The presence of 88 mM n-propanol, n-butanol, tert-butanol, or 2,2-dimethylpropanol significantly increased the delay by 94-213%. However, n-pentanol at 2 mM or 88 mM had no protective effect. Among n-alcohols, the increase in lag time was inversely proportional to the length of the carbon chain. Chain length, rather than molecular weight determines the effect, because 2,2-dimethylpropanol had a protective effect. The influence of alcohols on LPC micelle formation was estimated from the increase in octadecyl rhodamine B fluorescence; the increase by n-alcohols was directly proportional to chain length, indicating that micelle formation was not involved in the extension of lag time. The absence of the protective effect when the alcohol aliphatic chain exceeds four carbons suggests that the effect of ethanol may be mediated via a small lipophilic pocket on a protein, or to lateral pressure perturbation in the membrane.

Ethanol protects against lysophosphatidylcholine-induced uncoupling of cardiac cell pairs.

Moderate alcohol consumption is related to a reduction in cardiovascular deaths. Lysophosphatidylcholine (LPC) produces arrhythmias similar to those induced by ischemia most likely due to its uncoupling properties. We assessed effects of LPC in the presence of ethanol in cardiac myocyte pairs using the double whole-cell voltage-clamp technique. Ethanol 11, 22 and 44 mmol.l(-1) did not change junctional conductance for up to 25 min but postponed the time for total uncoupling induced by 20 micromol.l(-1) LPC from 11.3+/-3.0 min ( n=4), respectively, to 16.0+/-0.5 ( n=3; P=0.05), 20.5+/-1.9 min ( n=4; P<0.05) and 27.0+/-3.5 min ( n=3; P=0.01; mean+/-SEM). LPC-induced uncoupling which might occur during ischemia may be counteracted by ethanol.

Risperidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

Cases of QT prolongation and sudden death have been reported with risperidone, a neuroleptic agent increasingly prescribed worldwide. Although hypokalemia was present in some of these events, we hypothesized that risperidone may have unsuspected electrophysiologic effects predisposing patients to proarrhythmia. In six isolated guinea pig hearts, risperidone elicited prolongation of cardiac repolarization: action potential duration increased from a baseline value of 128 ms +/- 5 to 147 ms +/- 5 (15%) with risperidone 1 microM during pacing at 250-ms cycle length, whereas the increase was only 10%, from 101 ms +/- 2 to 111 ms +/- 4, with pacing at a cycle length of 150 ms. In human ether-a-go-go (HERG)-transfected Chinese hamster ovary cells (n = 16), risperidone caused concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current with an IC(50) for tail block of 261 nM. Risperidone did not block I(Ks). Risperidone exerts cardiac electrophysiologic effects similar to those of Class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations. Because risperidone is metabolized primarily by CYP2D6, these actions likely enhance risk for risperidone-related QT prolongation and proarrhythmia in specific patient subsets (e.g., poor metabolizers and those taking interacting drugs).

Biophysical characteristics of a new mutation on the KCNQ1 potassium channel (L251P) causing long QT syndrome.

The congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by prolonged ventricular repolarization, syncope, and sudden death. Mutations causing LQTS have been identified in various genes that encode for ionic channels or their regulatory subunits. Several of these mutations have been reported on the KCNQ1 gene encoding for a potassium channel or its regulatory subunit (KCNE1). In this study, we report the biophysical characteristics of a new mutation (L251P) in the transmembrane segment 5 (S5) of the KCNQ1 potassium channel. Potassium currents were recorded from CHO cells transfected with either wild type or mutant KCNQ1 in the presence or in the absence of its regulatory subunit (KCNE1), using the whole-cell configuration of the patch clamp technique. Wild-type KCNQ1 current amplitudes are increased particularly by KCNE1 co-expression but no current is observed with the KCNQ1 (L251P) mutant either in the presence or in the absence of KCNE1. Coexpressing KCNE1 with equal amount of cDNAs encoding wild type and mutant KCNQ1 results in an 11-fold reduction in the amplitude of potassium currents. The kinetics of activation and inactivation and the activation curve are minimally affected by this mutation. Our results suggest that the dominant negative effect of the P251L mutation on KCNQ1 channel explains the prolonged repolarization in patients carrying this mutation.