Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias.

The aim of this study was to test the hypothesis that some cases of drug-induced arrhythmias depend on genetic predisposition. Excessive prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some drug-induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of drug-induced QT prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause drug-induced life-threatening arrhythmias and allow early identification of individuals at risk.

[Cardiac troponin I and T in unstable angina: incidence, correlation, kinetics of release and prognostic value]. / Troponina i cardiaca e troponina T cardiaca nell'angina instabile: incidenza, correlazione, cinetica di rilasciamento e valore prognostico.

BACKGROUND: The aim of this study was to ascertain the incidence of altered serum cardiac Troponin-T (cTnT) and cardiac Troponin I (cTnI) in patients with unstable angina, the concordance between findings for the two proteins, their release kinetics and their utility in predicting coronary events. METHODS: We studied 32 consecutive patients (pts) admitted to the Coronary Unit with a diagnosis of unstable angina; following Braunwald classification criteria, 5 pts were in class I, 4 class II, 23 class III. A blood sample was taken on admission to hospital and subsequently every 8 hours for two days, a total of 7 samples being obtained per pt. Cardiac-TnT values ranging from 0-0.17 mugr/L (Boehringer Mannheim) were considered normal, as were cTnI values ranging from 0 to 0.7 mugr/L (Stratus-Dade). RESULTS: Among 218 samples, altered cTnT values (0.18-0.68 mugr/L) were found in 19 (3 pts), and 13 of these samples were positive for cTnI (0.8-5.5 mugr/L), while the remaining 6 showed borderline values for cTnI (0.5-0.7 mugr/L). No cTnT negative samples were found to be positive for cTnI. The release kinetics of cTnT and cTnI were comparable in all three cases, with a "plateau" pattern, unlike the kinetics in the course of acute myocardial infarction (AMI). The mean follow-up was 13 months on average (range 1-19). In two pts with altered cTnT and cTnI values, symptoms were controlled with medical therapy, while the remaining patient failed to respond to medical therapy and therefore underwent PTCA. Fifteen months later, they are alive and have not had myocardial infarction. Of the 29 pts with normal cTnT and cTnI values, three developed AMI, which in two cases was fatal. Seven pts were submitted PTCA, seven to aorto-coronary bypass surgery, two were subsequently rehospitalized for a recurrent angina symptoms. In 13 pts complete control of symptoms was achieved with medical therapy. CONCLUSIONS: Our findings demonstrate that the incidence of altered cTnT and cTnI values in pts with unstable angina is low; there is close agreement between findings for the two proteins; in cases of angina, the cTnT and cTnI release kinetics are different from those in AMI. The finding of altered cTnT and cTnI values in the serum of our pts with unstable angina does not appear to be of prognostic value for future coronary events.

[Cardiac troponin I in unstable angina]. / La troponina I cardiaca nell'angina instabile.

BACKGROUND: Unstable angina implies high risk of myocardial infarction and sudden death. Increased levels of cytoplasmatic enzymes and proteins (creatine phosphokinase, MB creatine phosphokinase troponin T, etc.) were described in unstable angina, providing information about incoming major coronary events. Cardiac troponin I (cTn-I) is a structural protein inhibiting the actinomyosine ATPase; it is only found in myocardial cells. Serum titration of cTn-I has been recently introduced into clinical practice as a sensitive and specific marker of myocardial cellular necrosis. OBJECTIVES: The aim of our prospective study was to assess the presence of cTn-I in blood samples of patients with unstable angina and no signs of myocardial necrosis. Furthermore we intended to test the possible use of cTn-I in unstable angina as a prognostic marker of major coronary events on short and middle term. METHODS: We studied 33 consecutive patients admitted to our CCU for unstable angina. According to unstable angina Braunwald's classification, 6 patients were included in the first class, 4 patients in the second class and 23 patients in the third class. We excluded patients with acute or recent myocardial infarction. Blood samples of all patients were obtained at the time of CCU admission and every eight hours in the first and second day. Serum cTn-I titration was performed with the sandwich immunoenzymometric method, recently introduced by Diagnostic Pasteur. Two months follow-up was carried out in order to survey major coronary events and revascularization procedures, either angioplasty or coronary artery bypass surgery. RESULTS: No patients with unstable angina exhibited cTn-I in their blood samples; accordingly, cTn-I was not found in the first blood sample of a patient who underwent myocardial infarction during hospitalization. During the follow-up 2 patients died of myocardial infarction, 9 patients had surgical revascularization and 5 patients angioplasty. CONCLUSIONS: CTn-I is a sensitive and specific marker of myocardial necrosis. It is not found in patients with unstable angina; therefore it has no role as a prognostic marker of major coronary events.

[The effect of gallopamil on myocardial perfusion in angina of effort]. / Influenza del gallopamil sulla perfusione miocardica nell'angina da sforzo.

To value stress tolerance and stress myocardial perfusion before and after a week of oral therapy with gallopamil 150 mg daily, we studied 10 patients suffering from stable effort angina. We performed bicycle exercise stress testing and thallium scintigraphy (Tl) with planar technique in 3 projections (anterior-posterior and oblique left anterior at 45 and 70 degrees) according to the current standards. We valued systolic and diastolic blood pressure (SBP-DBP), heart rate (HR) and HR-SBP product at rest, at symptoms stress-induced and at the end of the procedure. Moreover we valued work threshold of chest discomfort and ischemia, the maximal work capacity and the perfusion defects according to a Tl score obtained dividing the 3 projections in 5 segments and fixing a value according to the observed perfusion from 0 = normal perfusion to 3 absent perfusion. We observed a significant reduction of basal HR (77 vs 71, p = 0.05), SBP (147 +/- 15 vs 131 +/- 15 mmHg, p = 0.001), DBP (91 +/- 6 vs 83 +/- 6 mmHg, p = 0.002). Work threshold of chest discomfort and ischemia significantly arose (8 +/- 3 vs 11 +/- 4 min., p = 0.002; 6 +/- 3 vs 10 +/- 4 min., p = 0.001). The HR-SBP product at the maximal work capacity and the Tl score significant decreased (31650 +/- 6239 vs 29406 +/- 5418, p = 0.003; 8 +/- 2 vs 5 +/- 1, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Short- and long-term effects of propafenone in ventricular arrhythmias.

The effectiveness of short- (15 days) and long- (12 months) term propafenone treatment was assessed in 53 patients presenting with more than 30 premature ventricular complexes per hour as detected by 24-hour ambulatory Holter monitoring. Thirty-nine patients had no apparent concomitant heart disease while 14 had chronic coronary artery disease. The effects of propafenone were analysed by ambulatory Holter monitoring after 15 days and at 3, 6 and 12 months. The initial dose was 150 mg four times daily and was increased up to 300 mg four times daily when necessary. Favourable short-term effects were obtained in 39 patients (73.6%). After 12 months, 17 patients (32.1%) were still on propafenone treatment with good results. Treatment was discontinued on account of low compliance in 28.3%. This was because treatment was ineffective even at high doses in 15.2%, because of severe side effects in 13.2%, because of proarrhythmic effects in 5.6% and for other causes in 5.6%.