Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

INTRODUCTION: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). METHODS AND RESULTS: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. CONCLUSIONS: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes.

OBJECTIVE: Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population. METHODS: Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy. RESULTS: In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15-20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (-22.3 ms). CONCLUSION: The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy.

Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes.

BACKGROUND: In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. METHODS AND RESULTS: Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. CONCLUSIONS: Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk.

Multifactorial QT interval prolongation.

Acquired long QT interval has been widely reported to be a consequence of drug therapy and electrolyte disturbances. We describe two cases of multifactorial acquired QT interval prolongation and torsades de pointes. In the first case, the drugs venlafaxine, amiodarone and domperidone may have contributed to QT interval prolongation in a patient with hypokalemia and hypomagnesaemia. In the second case, QT interval prolongation occurred in a patient taking quetiapine and citalopram, and whose use of hydrocholorothiazide and history of chronic alcohol abuse likely contributed by rendering the patient hypokalemic. These cases highlight the potential risks associated with polypharmacy and demonstrate that though torsades de pointes is an uncommon arrhythmia, the combination of multiple factors known to prolong QT interval may precipitate this life-threatening arrhythmia.

[Early onset of torsades de Pointes and elevated levels of serum troponin I due to acute arsenic poisoning]. / Torsades de Pointes precoces y elevación sérica de la troponina I debidas a intoxicación aguda por arsénico.

Most cases of acute arsenic poisoning occur through accidental or voluntary ingestion of pesticides or insecticides, and all body systems are affected. Arsenic can prolong the QT interval and lead to torsades of Pointes, a crucial type of arrhythmia characteristic of such QT interval prolongation. In our revision of the literature, there have been found only 5 cases of torsades of Pointes due to acute arsenic poisoning. Recently, there have been published four additional cases in patients with refractory or recurrent acute promyelocytic leukemia being treated with arsenic trioxide. In all nine cases, torsades of pointes appeared slowly after poisoning. Herein is described a case of acute arsenic poisoning which led to an early onset of torsades of Pointes, hypopotasemia and high levels of serum troponin I.

Torsades de pointes associated with high dose levomethadyl acetate (ORLAAM).

A patient undergoing management of heroin dependency with high dosages of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM; ORLAAM) developed a prolonged QTc interval and polymorphic QRS complexes on EKG consistent with torsades de pointes (TdP). The patient was taking other drugs known to prolong the QTc interval (fluoxetine and IV cocaine), and those known to antagonize the activity of the P450 enzymes responsible for the metabolism of LAAM and its active metabolite (fluoxetine, cocaine and marijuana). No previous reports have appeared in the literature attributing this adverse event to LAAM therapy; however, five similar cases have been reported to the manufacturer. Animal studies indicate that LAAM and metabolites prolong the action potential duration of myocardial cells. We propose that predisposed patients on high doses of LAAM may be at risk for developing TdP. Patients being treated with LAAM should receive dosages consistent with guidelines and be evaluated for concomitant diseases, interacting drug therapies, and EKG abnormalities.

Abnormal function of platelet G proteins in long QT syndrome.

Several hypotheses have been proposed for the pathophysiology of the congenital long QT syndrome, however, the underlying mechanism has not yet been elucidated. This study evaluated G protein function in patients with congenital long QT syndrome (LQTS) and compared it with that of normal subjects. Platelet-rich plasma was collected and the cyclic AMP (cAMP) level of platelets was measured in three conditions utilizing radioimmunoassay: the basal state (Basal cAMP), after stimulation by PGE1 (PGE1-cAMP), and after stimulation by PGE1 followed by inhibition by adrenaline (Adr-cAMP), and the results were compared between 7 LQTS patients and 10 healthy volunteers (control). Gs function was defined as (PGE1-cAMP)/(Basal cAMP) and Gi function as ¿(PGE1-cAMP)-(Adr-cAMP)¿/(PGE1-cAMP). Basal cAMP was lower in patients than in the controls: 2.9 +/- 0.6 pmol/ 10(8) cells vs. 4.2 +/- 0.7 pmol/10(8) cells (p < 0.05). The increase in cAMP after PGE1 was similar in the two groups but the peak was lower in the patients: 16.8 +/- 6.2 pmol/10(8) cells vs. 24.8 +/- 7.4 pmol/10(8) cells (PGE1-cAMP). After addition of adrenaline, cAMP decreased to 14.2 +/- 5.8 pmol/10(8) cells vs. 16.2 +/- 7.6 pmol/10(8) cells and the change was significantly smaller in the patients than in the controls: 0.17 +/- 0.12 vs. 0.38 +/- 0.16 (p < 0.05). Basal cAMP was weakly correlated with sinus cycle length (r = -0.48, p > 0.3) and QTc was correlated with Gs function (r = 0.52, p > 0.3) but not with Gi function. Patients with associated Torsade de Pointes had a significantly lower Gi function compared to those without (p < 0.05). In LQTS patients, G protein function was abnormal and the abnormality was associated with clinical characteristics of long QT syndrome. The relationship between the abnormal G protein function and the regulation of the repolarization of the ventricular myocardium needs to be studied further.