Direct and autonomically mediated effects of oral quinidine on RR/QT relation after an abrupt increase in heart rate.

OBJECTIVES: This study evaluates the direct and autonomically mediated effects of oral quinidine on ventricular repolarization in humans. BACKGROUND: Interactions between quinidine-related vagolytic properties and autonomic modulation on ventricular repolarization are unknown. The relative role of the two components, if present, might improve our understanding of the therapeutic and proarrhythmic mechanisms of quinidine on the ventricular tissue. METHODS: Rate-related changes in the QT interval were investigated after an abrupt increase in heart rate in 15 patients during atrial pacing. In the control study, the QT interval was measured at six paced cycle lengths (600, 540, 500, 460, 430 and 400 ms) both in the basal state and after autonomic blockade (intravenous propranolol, 0.2 mg/kg, and intravenous atropine, 0.04 mg/kg); oral quinidine was then administered at a daily dosage of 1,200 mg for 3 to 4 days, after which the QT duration was reassessed using the same method in a second study. RESULTS: During the control study, the mean slope of the regression curve estimating the correlation between pacing cycle length and QT duration was significantly lower after autonomic blockade (0.14 +/- 0.05) than in the basal state (0.27 +/- 0.10, p < 0.05). Quinidine exhibited a prominent but opposite effect on the mean slope of the regression curves in basal conditions (from 0.27 +/- 0.10 to 0.20 +/- 0.07, p < 0.05) and after withdrawal of autonomic modulation (from 0.14 +/- 0.05 to 0.19 +/- 0.05, p < 0.05), thus annulling the differences observed between the two states in the control study. CONCLUSIONS: A quinidine-induced increase in QT duration as cycle length is prolonged is consistent with a reverse use dependence effect on ventricular repolarization. This effect is not evident in the basal state owing to interaction of quinidine-related vagolytic effect with the autonomic tone. Reverse use dependence and vagolytic activity on ventricular tissue indicate two potentially undesirable effects that could play a role in the lack of efficacy or proarrhythmic effect of quinidine.

Amiodarone and thyroid status in refractory arrhythmias.

Out of 20 subjects selected for refractory arrhythmias, amiodarone therapy (200 mg/day) was efficacious in 85%. No statistically significant variations in electrocardiographic parameters (QTc) were observed; similarly, there was little evidence of side effects 1 year after initiation of treatment. These results were most likely due to the low daily dosage administered. We observed: 1) a significant increase in rT3 levels; 2) a decrease in TT3; 3) a uniform homeostasis of free fraction (FT3;FT4) These effects are all characteristic patterns of a "Low T3 Syndrome". The dosage of circulating amiodarone in 6 patients with borderline hormonal status (3 hyper- and 3 hypothyroidism) was not found to be an efficacious test for therapeutic monitoring. Identification of a statistically significant linear regression relationship between cumulative dose of amiodarone and rT3 levels may be a useful test in clinical practise for establishing more appropriate therapeutic dosages. Furthermore, it provides a guideline for threshold levels (maximum rT3 = 100-110 ng/dl) which are in close association with several side effects.

Circadian variations of sinus rate in subjects with sinus node dysfunction.

Circadian variations of sinus rate (SR) are well described in subjects with normal sinus node (SN). On the other hand there are no data in literature concerning the SR daily variations in patients with SN dysfunction. In order to clarify this problem we studied the SR circadian variation in healthy subjects (12) and in patients with intermittent bradycardia (11), persistent bradycardia (9) and intermittent 2:1 sino-atrial block (7). Sr was recorded utilizing ECG Holter monitoring. By histograms obtained every 2 h, maximum, modal, and minimum SR were evaluated. Time series were analyzed with a computer program for cosinor method. In the patients with normal SN, circadian periodicity in SR was confirmed with acrophase at 16(26) (Maximum SR), 16(38) (minimum SR) and 16(31) (SR mode), respectively. In patients with intermittent bradycardia a circadian rhythm was detected only in minimum SR (Acrophase: 16(51)) and in SR mode (acrophase: 16(13)). No statistically significant circadian variations of the 3 parameters of SR were observed in patients with both persistent bradycardia and sino-atrial block. These data suggest that: 1. the disappearance of the circadian periodicity is proportional to the severity of SN dysfunction; 2. the patients with intermittent bradycardia show a more normal behavior at low rates than at high ones; 3. the disappearance of circadian rhythm in patients with marked SN dysfunction can be related to the SN intrinsic involvement and/or autonomic nervous system dysfunction.

Determination of the anaerobic threshold by a noninvasive field test in runners.

The relationship between running speed (RS) and heart rate (HR) was determined in 210 runners. On a 400-m track the athletes ran continuously from an initial velocity of 12-14 km/h to submaximal velocities varying according to the athlete's capability. The HRs were determined through ECG. In all athletes examined, a deflection from the expected linearity of the RS-HR relationship was observed at submaximal RS. The test-retest correlation for the velocities at which this deflection from linearity occurred (Vd) determined in 26 athletes was 0.99. The velocity at the anaerobic threshold (AT), established by means of blood lactate measurements, and Vd were coincident in 10 runners. The correlation between Vd and average running speed (mean RS) in competition was 0.93 in the 5,000 m (mean Vd = 19.13 +/- 1.08 km/h; mean RS = 20.25 +/- 1.15 km/h), 0.95 in the marathon (mean Vd = 18.85 +/- 1.15 km/h; mean RS = 17.40 +/- 1.14 km/h), and 0.99 in the 1-h race (mean Vd = 18.70 +/- 0.98 km/h; mean RS = 18.65 +/- 0.92 km/h), thus showing that AT is critical in determining the running pace in aerobic competitive events.

Unstable rest angina. Coronary anatomy and evaluation of medical therapy.

The results of beta blockers and nitrates therapy were evaluated in 100 consecutive patients with unstable angina (72 with previous stable angina, 28 with recent onset angina), 89 patients had also a history of effort angina and 11 patients had only rest angina. In 92 of 100 patients selective coronary arteriography revealed fixed obstructive coronary artery disease in 86 patients and coronary artery spasm with normal coronary arteries in 6 patients. In 58 of 100 patients beta blockers and nitrates effectively controlled angina, and immediate coronary artery bypass graft surgery was avoided. In 42 patients early and in 22 patients late surgery were needed. 29 patients remained stable on long term beta blockers and nitrates therapy. Thus, despite the possibility of increased coronary vasomotor tone as the mechanism of rest angina, beta blockers and nitrates remain effective immediate medical therapy.

[Antiarrhythmic treatment with mexiletine in acute myocardial infarction (author's transl)]. / Trattamento antiaritmico con mexiletina nell'infarto acuto.

The effect of an introduced i.v. bolus of 250 mg of mexiletine was checked in cases of acute myocardial infarction with ventricular premature beats. On the 19 observed subjects 17 are male and 2 female: 18 cases with acute myocardial infarction and 1 with acute coronary failure. The introduction of the bolus was followed by an infusion of 0.75 mg/m for the successive four days. After 60 m' no significant changes in arterial pressure and in the heart rate were recorded. The Extrasistolies decrease from 11 +/- 3 to 3 +/- 2/m' (-71%, p less than 0.01); PQ and QT variations were not significant. After four days of infusion, systolic arterial pressure decrease from 135 +/- 4 to 121 +/- 3 (-10%; p less than 0.01), sinusal rate drops from 90 +/- 4 to 80 +/- 3 (-12%, p less than 0.05). The changes of diastolic arterial pressure, PQ and QT were not significant. Extrasistolies disappears entirely. A comparison between a mexiletine and a xilocaine i.v. bolus showed that mexiletine performs a higher antiarrhythmic activity.

[Circadian variations of sinus rate in subjects with normal or pathological sinus node (author's transl)]. / Variazioni circadiane della frequenza sinusale in soggetti con nodo del seno normale e patologico.

Circadian variation of sinus rate (SR) is well described in subjects with normal sinus node (SN). On the other hand there are on data in literature concerning the SR daily variations in patients with SN disfunction. In order to clarify this problem we studied the SR circadian variation in normal subjects (12, and in patients with intermittent bradycardia (11), persistent bradycardia (9) and intermittent 2:1 seno-atrial block (7). SR was recorded utilizing ECG Holter monitoring. By histograms obtained every two hours, modal, maximum and minimum SR were evaluated. Time series were analyzed with a computer program for cosinor method. In the patients with normal SN, circadian periodicity in SR was confirmed with acrophase at 1626 (maximum SR), 1638 (minimum SR) and 1631 (SR mode), respectively. In patients with intermittent bradycardia a circadian rhythm was detected only in minimum SR (acrophase 1651) and in SR mode (acrophase: 1631). No statistically significant circadian variations of the 3 parameters of SR were observed in patients with both persistent bradycardia and sinoatrial block. These data suggest that: - the disappearance of circadian periodicity is proportional to the severity of SN dysfunction; - the patients with intermittent bradycardia show a more normal behavior at low rates than at high ones; - the disappearance of circadian rhythm in patients with marked SN disfunction can be related to SN intrinsic involvement and/or autonomic nervous system disfunction.

[Determination of the anaerobic threshold by a noninvasive field in man]. / Un test da campo per la determinazione della soglia anaerobica nell'uomo.

The relationship between running velocity and heart rate has been determined in 320 runners. A deflection from the expected linearity of this relationship has been observed at sub-maximal running speeds. Deflection velocity and anaerobic threshold (established through blood lactate determination) were coincident in 10 runners, thus showing that the increase in running speed exceeding the augmentation in heart frequency above Vd depends on anaerobic ATP production.

[The antiarrhythmic effect of metoprolol (author's transl)]. / L'azione antiaritmica del metoprololo.

The antiarrhythmic effect of metoprolol after chronic treatment has been evaluated by 24 hour Holter monitoring in 16 patients with several premature ventricular beats and in 14 patients with chronic atrial fibrillation and compared with the effect of a placebo. Metoprolol induced a mean decrease of heart rate of 14.5% in the 16 patients and reduced the mean value/min of the ventricular premature beats of the 51.2%. In addition the use of metoprolol abolished the ventricular premature beats in 9 cases, while in two cases there was an increase of their frequency. In the 14 patients with chronic atrial fibrillation metoprolol was able to reverse to sinus rhythm three of the patients and in the remaining 11 decreased the ventricular heart rate of the 33%.

Effects of dobutamine on electrophysiological properties of the specialized conduction system in man.

The electrophysiological effects of Dobutamine, a new beta adrenergic drug, were investigated using intracardiac electrograms and the extrastimulus method, in 19 patients with 1:1 AV conduction and in 10 other patients, five with second and five with third degree AV block. The electrophysiological effects were studied at three concentrations of the drug: 5, 10 and 15 micrograms/Kg/m'. Dobutamine induces: 1) an enhancement of SA node automaticity, showed by a decrease of the sinus cycle length (P less than 0.001 at the first concentration) and by a decrease in the corrected sinus node recovery time (P less than 0.001 at the second concentration); 2) a decrease in the effective atrial refractory period (P less than 0.001 at the first concentration); 3) an improvement of AV conduction, showed by a decrease in AH interval (P less than 0.001 at the first concentration) and by a shortening of functional and effective refractory periods (P less than 0.001 at the first concentration); 4) no change in the HV interval; 5) an improvement of conduction in patients with second degree AV block proximal to the His bundle; and 6) a minimal increase in the heart rate in patients with complete AV block distal to His bundle.

[Radioanalytical methods of determination in vitro of folates and vitamin B 12: diagnostic use in disorders of absorption and utilization]. / Le metodiche radioanalitiche di dosaggio "in vitro" dei folati e della vitamina B12: utilità diagnostica nei difetti di assorbimento ed utilizazione

The blood concentrations of vitamin B12 and folate, which are very useful in diagnosis of megaloblastic anemia and of these factors' dificiencies, are actually measured by precise, rapid, and specific competitive binding radioassays. Futher clinical advantages can be reached with the application of other in vitro radioisotope techniques, such as radioassay of IF, of antibodies anti-IF, of transcobalamins, and of FABP (folic acid binding protein). The major impact of the vitamin B12, folates and other related radioassays has been to permit more Hospitals and laboratories to do these determinations, replacing the more time-consuming, relatively imprecise, and often artifactual microbiological assays.