Left ventricular peak filling rate, heart failure and 1-year survival in patients with acute myocardial infarction

Radionuclide left ventricular (LV) peak filling rate (PFR) wasdetermined in 185 survivors of acute myocardial infarction (AMI)and expressed in units of (1) end-diastolic volume per second( EDV s^–1), (2) stroke volume per second (SV s^–1),or (3) actual millilitres of blood filled into the left ventricleper second (ml s^–1). The purpose of the study was to assessthe interrelationship between the three expressions of PFR,and to analyse their significance with regard to signs of congestiveheart failure and 1-year survival in patients with AMI. PFREDVs^–1, PFRSVs^–1 and PFR mis^–1 had a poorrelationship to each other, were all influenced by L V volumesand ejection fraction, and supplied contradictory informationwith regard to LV filling in patients with heart failure. Noneof the three expressions of LV peak filling rate had an associationto heart failure that was independent of LV volume and ejectionfraction. A low PFR EDVs^–1 in contrast to a high PFR SVs^–1 was associated with a high 1-year cardiac mortality,suggesting that these ‘normalized’ indices of LVpeak filling rate signalled LV size and stroke volume ratherthan actual LV filling behaviour. No association was presentbetween PFR mis^–1 and 1-year mortality. We conclude thatthe clinical use of radionuclide LV PFR in patients with AMImay lead to spurious results, unless the influence of LV sizeand ejection fraction is taken into consideration.     

The prognostic significance of post-infarction angina pectoris and the effect of verapamil on the incidence of angina pectoris and prognosis

The prognostic sign of angina pectoris and the effect of interventionwith verapamil on the incidence of angina pectoris were studiedin patients recovering from myocardial infarction and includedin the Danish Verapamil Infarction Trial II. During the secondweek after admission patients were double-blindly randomizedto treatment with verapamil 360 mg. day^–1 or placebo.Treatment was continued for up to 18 months. At discharge anginapectoris was reported in 11% of 869 patients randomized to verapamiland in 12% of 888 randomized to placebo (ns). One month afterdischarge a significantly increase in the prevalance of anginapectoris was reported in both the verapamil (33%) (P<0·001)and the placebo groups (39%) (P <0·001). The one monthprevalence of angina pectoris (P=0·03) and the 18 monthsoverall incidence of angina pectoris (P= 0·002) wereboth .sigificant lower in the verapamil group compared withplacebo. Stable angina pectoris during the first month of follow-upwas a significant predictor of major events (i.e. death or reinfarction)(hazard ratio = 1·45; 95% confidence limits: 1·101·89). As verapamil significantly reduced the incidenceof angina pectoris during daily activities, and thereby thenumber of patients at high risk, the beneficial effect of verapamilin reducing major events in patients recovering from myocardialinfarction is likely to be due to abolishing myocardial ischaemia.     

Changes in canine ventricular fibrillation threshold induced by verapamil, flecainide and bretylium

The changes produced by verapamil, bretylium and flecainidein both ventricular fibrillation threshold (VFT) and ventricularrepetitive response threshold (VRRT) were studied in 20 closed-chestdogs anaesthetized with pentobarbital. Right ventricle endocardium thresholds were determined usingbipolar electrode catheters. Increasing intensity stimulus trains(200ms, 4ms, 100 Hz, 1mA steps) were delivered 50 ms after QRS;VRRT and VFT were calculated before and after drug administration.Three study groups were considered according to the drug assayed:(1) verapamil 0.15 mg . kg^–1 n=6; (2) flecainide 2.0 mg.kg^–1 n=7, and (3) bretylium 10.0mg .kg^–1 n=7. Flecainidesignificantly increased VRRT (4.8±1.4 vs 9.4±1.5mA, P<0.05), but the latter failed to change in the othertwo groups. VFT remained unchanged with verapamil, increasedslightly post-flecainide (10.3±4.6 vs 12.4±4.1,P<0.05 mA) and markedly post-bretylium (10.3±4.;6vs 17.3 ± 7.5, P<0.05). VFT changes were significantlycorrelated (r=0.77, P<0.05) with the effective refractoryperiod changes in the bretylium group. Thus, of the three drugs tested, bretylium induced the greatestVFT increases without modifying VRRT, whereas flecainide affectedboth parameters. Only in the bretylium series were ERP changessignificantly correlated to the corresponding VFT changes. Thissuggests that ventricular fibrillation threshold increase isnot a non-specific property of antiarrhythmic drugs. Changesin ventricular repetitive response threshold may provide additionalinformation     

Radionuclide assessment of a normal left ventricular response to exercise in patients without evidence of heart disease

The aim of this study was to define normal left ventricularperformance at rest and during supine bicycle exercise withequilibrium radionuclide ventriculography in a normal populationother than young healthy volunteers. Thirty-one patients (meanage 45 years ± 9 SD) with chest pain of varying originandno evidence of heart disease proven by means of noninvasiveand invasive techniques were studied. Left ventricular ejectionfraction (LVEF) at rest averaged 0.64 ± 007 SD and increasedwith peak exercise to 0.73 ± 008 SD (P<0.005). Changein LVEF from rest to maximum exercise ranged within 0–0.19.Six patients (19%) failed to augment LVEF with exercise to morethan 0.05; none of the patients dropped LVEF during exercise.Multivariate analysis revealed no significant predictors ofLVEF response to exercise. However, there was a tendency thatresting LVEF and enddiastolic volume index with exercise mightinfluence LVEF response to exercise. Peak left ventricular ejectionrate (LVER) at rest averaged 3.3s^–1 ± 0.6 SD andincreased to 51 s^–1 ± 11 SD (P<0.005) with exercise.Peak left ventricular early filling rate (LVFR) was 2.8s^–1± 0.6 SD at rest and was measured 5.5 s^–1 ±l.3 SD at maximum exercise (P<0.005). Left ventricular enddiastolicvolume (EDV) did not change significantly from rest to maximumexercise, whereas left ventricular endsystolic volume (ESV)decreased to 79% ± 19 SD (P<0.01) of the value atrest. In conclusion, in a normal population other than healthy youngvolunteers LVEF does not necessarily have to increase with exercise.Moreover, besides an augmentation of heart rate a normal leftventricular response to supine exercise is associated with anincrease of LVER and LVFR, a decrease in ESV and no significantchange in EDV, suggesting augmented contractility and a virtuallynegligible role of the Frank-Starling mechanism during exercise.     

Experience with flecainide for the treatment of cardiac arrhythmias in children

We treated 22 children, aged 3 days to 16 years 6 months (medium11 years 1 month), with flecainide for a variety of aryhythmiaswhere a Class I agent was indicated in 16, conventional antiarrhythmictreatment had failed. Structural heart disease was present innine. The arrhythmia was paroxysmal re-entry atrioventriculartachycardia in five and frequent ventricular extrasystoles (withcouplets) in three. Sinas rhythm was achieved in all four childrenwho received flecainide during tachycardia (three received intravenousflecainide during tachycardia (three received intravenous flecainide,one oral). During follow-up of 3–24 months (median 12months), arrhythmia control was obtained in 13 children (59%).Combination therapy was used in seven of these; with digoxinin four and a beta blocker in three. Flecainide doses used inthis study ranged from 1–11 mg kg^–1 day^–1(median 4 mg kg^–1 day^–1), 25–297 mg m^–2day^–1).The medium, pre-dose flecainide concentration inthose responding to therapy was 225 µgl^–1 and inthose failing to respond was 417 µgl^–1. An arrhythmogeniceffect occured in one child.     

Effect of flecainide on left ventricular ejection fraction

Antiarrhythmic agents may depress cardiac contractility andworsen heart failure. Flecainide is an effective antiarrhythmicdrug, but when administered orally in patients with left ventricular(LV) dysfunction, its effect on LV function is unknown. To assessthe effects of flecainide on cardiac function, LV ejection fraction(LVEF) was measured by radionuclide ventriculography in 36 patientswith LV dysfunction (LVEF 40%), prior to and 7 days after drugtherapy was initiated. To analyse the possibility of a dose-dependenteffect on LVEF, 18 patients received 200 mg day^–1 of flecainideand 18 patients with an identical initial LVEF (27±8vs 27±9) (NS) received 300 mg day^–1. The studywas stopped in 7 patients because of severe cardiac adverseeffects; in these patients the LVEF was significantly lower(15±7) than that of the 29 patients who completed theprotocol (27±8) (P<0.01). In patients who completedthe protocol, there was no significant change in LVEF eitherwith a daily dosage of flecainide of 200 mg day^–1 (27±8vs 27±8) or with 300 mg day^–1 (27±9 vs 28±13).Thus, in the patients with LV dysfunction studied, oral flecainidedid not significantly affect LV function either with a low orwith the ususal daily dosage. However in patients with severeimpairment of LV function (LVEF<30%) flecainide must be usedcarefully owing to a higher incidence of adverse effects oncardiac rhythm.     

Determinants of exercise capacity in patients with coronary artery disease and mild to moderate systolic dysfunction: Role of heart rate and diastolic filling abnormalities

BACKGROUND: To test the hypothesis that diastolic filling abnormalitiesare an important cause of exercise limitation in some patientswith coronary artery disease we assessed the factors limitingexercise capacity in a group of patients with coronary arterydisease in whom exercise limitation was greater than expectedfrom the degree of resting left ventricular systolic dysfunction. METHODS AND RESULTS: We assessed the relationship between exercise capacity (maximaloxygen consumption) during erect cycle ergometry, heart rate,radionuclide indi ces of left ventricular systolic function(ejection fraction) and diastolic filling (peak filling rate,and time to peak filling) during semi-erect cycle ergometryin 20 patients (15 male, five female) who were aged 42–72years (mean 61 years) and had angiographically proven coronaryartery disease and evidence of reversible myocardial ischaemiaon thallium scintigraphy. All patients exhibited marked exerciselimitation (maximal oxygen consumption 8.7–22.4 ml. min^–1.kg^–1— mean 15.9 ml. kg^–1. min^–1, whichwas 611 ± 16% of age and gender predicted maxi mum) dueto breathlessness or fatigue rather than angina, in spite ofa mean ejection fraction for the group of 465% (range 30–67%).We also compared the diastolic filling characteristics of thesepatients during exercise with 10 healthy controls (age 38–66,mean 58 years; eight male, two female). Comparing diastolicfilling characteristics, peak filling rate was higher and timeto peak filling shorter both at rest and peak exercise in controlsthan patients (peak filling rate 3.1± 0.5 vs 2.2±0.9 EDV. s^–1 P =0.01 at rest and 8.3± 0.8 vs 5.2±1.9 EDV. s^–1 , P< 0.0000l on exercise; time to peakfilling 115.2± 29.8 vs 228.9± 71.7 ms, p< 0.0001.atrest and 52.8± 16.2 vs 139.6± 4.48 ms, P<0.0000lon exercise respectively). On univariate analysis in the patientsstudied, maximal oxygen consumption was correlated with peakheart rate (r=0.45 P=0.04), peak exercise time to peak filling(r=– 0.85 P< 0.0001 peak exercise peak filling rate(r = 0.58, P=0.019), and the relative increase in cardiac outputi.e. cardiac output peak/cardiac output rest (r=0.58, P=0.008).There was no correlation between maximal oxygen consumptionand resting indices of diastolic filling (peak filling rateand time to peak filling) or with resting or peak exercise ejectionfraction. On multiple regression analysis, only peak exercisetime to peak filling was significantly related to maximal oxygenconsumption. CONCLUSION: We have observed a strong correlation between exercise capacityand indices of exercise left ventricular diastolic filling,and have confirmed previous studies showing a poor correlationwith resting and exercise indices of systolic function and restingdiastolic filling, in patients with coronary artery disease.     

The use of propafenone in the treatment of tachyarrhythmias in children

Propafenone was given to 60 children (mean age 4.5 years) withparoxysmal re-entrant supraventricular tachycardia (rSVT: 41cases), postoperative automatic junctional tachycardia (JET:eight cases), automatic atrial tachycardia (AT: four cases),ventricular tachycardia (VT: four cases) and atrial flutter(AF: three cases). In acute cases (29) propafenone was administered intravenously(mean dose 1.3±0.5 mg . kg^–1) chronic oral treatment(mean dose of either 11±3.3 mg . kg. day^–1 or 265±78mg . m^–2 . day^–1) was given to 48 children, in 2–3divided doses. Overall efficacy was 76% for acute and 69% forchronic treatment, with best results in paroxysmal rSVT. Itwas effective in 89% acutely of those treated acutely and in69% of those administered chronically. The efficacy of propafenonein the prevention of rSVT was strictly related to the incidenceof attacks before treatment. propafenone was indeed inefficaciousin 6/11, 6/14 and 0/12 of patients with daily, weekly and monthlyattacks respectively. Side effects were observed in 25% of patients: 6% required suspensionof therapy due to pro-arrhythrnic effects in one patient onintravenous administration, peripheral neuropathy in one caseand hypotension in two postoperative JET patients. In conclusion, its efficacy and limited side effects make propafenonea relatively safe and very useful drug in the treatment of varioustachyarrhythmias. However, risk of unpredictable toxic levelsrequires careful use of the drug especially in the first daysof treatment, when a daily monitoring of ECG is strongly recommended.     

A comparison of verapamil and digoxin in the treatment of atrial fibrillation

Twelve patients (including 2 females) with chronic atrial fibrillationwere entered into a randomized, double blind crossover studyto compare the effects of digoxin and verapamil upon heart rate,exercise tolerance and symptom control. The dose of digoxinwas adjusted so as to give serum concentrations within the range1.3 to 2.6 nmol ^l–1 between four and six hours after dosing,and was continued for six weeks. The dose of verapamil was increasedfrom 40 mg tds to 80 mg tds to 120 mg tds at fortnightly intervals.Three patients did not complete the study; two because of adverseeffects attributable to verapamil. In the remaining nine patients,mean post exercise heart rates were significantly lower duringtreatment with verapamil 80 mgs tds (126.7bpm) than with verapamil40 mg tds (148.6 bpm) or digoxin (146.7 bpm). However, exercisetolerance was similar with both verapamil and digoxin and thesuperior control of exercise induced tachycardia achieved withhigher doses of verapamil was not associated with improved exerciseendurance. Visual analogue scale scores for constipation weresignificantly higher during treatment with verapamil; scoresfor other possible side effects and for overall wellbeing weresimilar. The results do not confirm the findings of others whohave reported that verapamil is superior to digoxin in the treatmentof atrial fibrillation.     

A clinical study of amiodarone as a single oral dose in patients with recent-onset atrial tachyarrhythmia

Forty-five patients with recent-onset sustained atrial tachyarrhythmia(mean heart rate at entry; 140.0± 3.5 beats. min^–1)associated with various cardiovascular diseases were treatedby oral amiodarone, given as a single loading dose of 25.7±0.9 mg. kg–1 body weight. Conversion to sinus rhythm wasobserved in 29 patients during the first 24 h of treatment,leading to a success rate of 64.4%. Five additional patientsconverted to sinus rhythm with continuation of oral amiodarone,(10–15 mg. kg^–1 by day) with a mean delay of 4.2days. A similar population of 27 patients (mean heart rate atentry; 140 ± 3 beats. min^–1) was treated by intravenousamiodarone, given as a bolus infusion of 3–5mg. kg^–1over 30min (mean; 41±02 mg. kg^–1), followed bya continuous infusion of 10–15mg. kg^–1 for 24 h(mean; 11.1±0.7 mg. kg^–1). Eighteen patients convertedto sinus rhythm during the first 24 h of therapy, leading toa success rate of 66.7%. Minor adverse effects of therapy wereobserved in two patients given oral amiodarone, and in sevengiven intravenous amiodarone. No major effect was observed.We suggest that amiodarone given as a single oral loading doseof 25–30mg. kg^–1 body weight is an effective, simpleand well-tolerated therapy, suitable for most patients withrecent-onset ATA.     

Acute and chronic effects of molsidomine on pulmonary artery pressure and work capacity in patients with coronary heart disease

To test the clinically supposed development of tolerance duringchronic molsidomine therapy we studied a total of 11 patientswith angiographically-proven coronary heart disease at restand during ergometric exercise (supine position; submaximal,i.e. 50 W for 3 min, and maximal exercise). pulmonary arterialpressure (PAP_mean, floating catheter), arterial blood pressure(RR, cuff method). work capacity (W x min) and duration of exerciseloading (sec) were measured at rest and on exercise before andduring chronic (4 weeks) oral therapy with 3 x 4mg day^-1 ofmolsidomine. Acute administration of 4 mg molsidomine reducedthe mean arterial resting pressure by 12% and under submaximalexercise loading by 8%. After molsidomine, the PAP_mean was reducedby 35% at rest; following a period of treatment of 4 weeks nosignificant decrease in efficacy could be discerned (PAP_meanreduction by 31%). Under submaximal and maximal exercise thePAP_mean dropped by 44% and 37%. respectively (35.5±6.7cf. 19.9±4.5 mm Hg: 39.2±6.5 cf. 24.8±7.0mm Hg). whilst simultaneously the work capacity increased by93% (281±108 cf. 545±254 W x min). After 4 weekstreatment with 12 mg day^-1 of molsidomine, the PAP_mean of 22.4±6.6mm Hg and 30.1±9.9 mm Hg under identical exercise loadingconditions. remained significanty below the exercise load valueprior to the onset of the medication. The molsidomine-inducedincrease in the exercise tolerance was maintained throughoutthe long-term medication (537±268 W x min). With a fourweek treatment with daily doses of molsidomine there was a persistenteffect on the pulmonary arterial pressure and the work capacity.Thus development of tolerance during high dose, long-term molsidominetherapy is not to be expected.     

More favourable haemodynamic effects from metoprolol than from captopril in patients with dilated cardiomyopathy

AIM: The object of this study was to investigate and compare thehaemodynamic effects of treatment with a beta receptor blocker(metoprolol) or an angiotensin-converting-enzyme inhibitor (captopril)in 54 patients with idiopathic dilated cardiomyopathy. METHOD: All patients had cardiac catheterization performed at rest andduring exercise, before and after 3 months of treatment. RESULTS: The mean dose of metoprolol was 135 mg.day^–1 and of captopril98 mg. day^–1. After treatment there was a significantreduction in left ventricular filling pressure both at rest(from 16 to 12 mmHg) and during exercise (from 27 to 20 mmHg)in the metoprolol group. In the captopril group a significantreduction was seen only during exercise (25 to 20 mmHg), comparedto baseline. The stroke volume increased significantly after3 months of therapy in the metoprolol group, both at rest (53to 70 ml) and during exercise (56 to 79 ml). In the captoprilgroup the increase reached significance only during exercise(72 to 79 ml). Cardiac output was maintained in both groups. CONCLUSION: There were positive effects on left ventricular function inthe metoprolol group as well as in the captopril group. Metoprololreduced left ventricular filling pressure at rest and increasedstroke volume both at rest and during exercise signficantlymore than captopril.     

Dose-response scrutiny of coronary vasodilation after intracoronary verapamil in man. A quantitative cineangiographic study

The effect of various doses of intracoronary verapamil on thediameter of angiographically normal left coronary artery segmentswas investigated in 22 patients with and without coronary atherosclerosisby quantitative angiography. Very low doses (50 µg) weregiven in 3 patients; doses of 250 µg, 350 µg and500 µg were administered in 7,6 and 13 patients, respectively.A single dose was administered in 15 patients, while two increasingdoses of verapamil were tested in 7. The effect of verapamilwas compared in each patient with that of nitroglycerin (NG;0.6 mg), administered sublingually in all as the last step ofthe study. An additional group of 8 patients served as the control. Thesepatients received 4 intracoronary injections of contrast mediumwithout drugs and a fifth injection following 0.6 mg of sublingualNG. In the control group no significant changes in coronary arterydiameter were observed following the four control injectionsof contrast medium, while a 18±9% increase in vasculardiameter was observed following NG. When verapamil was injecteda dose-dependent vasodilation was observed, which began to besignificant with doses higher than 250 µg. Mean percentvariations of coronary artery diameter relative to control were–0·2±3.6%, 4.6±5.5%, 11.4±7.5%and 19.9±10.7%, in response to verapamil doses of 50,250, 350 and 500 µg, respectively. Subsequent nitroglycerininduced a 21.5±10.7% mean percent coronary artery dilation(NSvs verapamil 500 µg and vs NG in the controlgroup).Thus, verapamil induced a dose-dependent coronary vasodilationwhich at a dose of 500 µg was comparable to that inducedby NG. Both with verapamil and NG the smallest vessels exhibitedthe greatest vasodilation. It is concluded that at the dosesused in this study, injection of verapamil into the left coronaryartery is safe and markedly decreases tone in the large coronaryarteries. This finding supports the use of verapamil in clinicalconditions in which the role of coronary vasoconstriction provenor thought to be relevant.     

Influence of verapamil therapy on left ventricular performance at rest and during exercise in hypertrophic cardiomyopathy

To determine the hemodynamic effect of verapamil at rest and during exercise, 18 patients with hypertrophic cardiomyopathy were studied before and after 7 weeks of treatment with oral verapamil (maximal dose, 720 mg/day). At rest and at peak exercise, verapamil produced a significant increase in left ventricular (LV) systolic performance in terms of stroke volume index (rest, from 43 ± 11 to 53 ± 11 ml/m², p < 0.001; exercise, from 46 ± 11 to 51 ± 10 ml/m², p < 0.01), whereas heart rate decreased (rest, from 81 ± 14 to 70 ± 11 min^?1, p < 0.001; exercise, from 150 ± 21 to 141 ± 18 min^?1, p < 0.01). Cardiac index at rest and during exercise remained unchanged. Systolic vascular resistance did not change at rest, but decreased significantly during exercise (974 ± 243 to 874 ± 174 dynes s cm^?5; p < 0.05). After verapamil administration, pulmonary artery pressures did not change at rest, but decreased significantly during exercise. This was probably due to a shift in the LV pressure-volume relation. The improvement in LV hemodynamics was associated with a significant increase in exercise capacity. The findings of this study indicate that in patients with hypertrophic cardiomyopathy, hemodynamic improvement at rest and during exercise can be achieved by chronic administration of verapamil.     

Microalbumin excretion in patients with positive exercise electrocardiogram tests

Thirty-three subjects underwent exercise electrocardiogram testing,20 had a history of myocardial infarction and 13 were age-matchedvolunteers. Exercise electrocardiograms were positive in 15subjects, negative in 12 and anomalous in six. Urinary microalbuminexcretion was measured at rest, 30 and 60 min after exercise.Urinary microalbumin excretion was expressed as the albumin-creatinineratio in mg. mmol^–1. In the positive exercise electrocardiogramgroup median albumin-creatinine ratio increased from 10 mg.mmol^–1 (95% CI 0.94-1.49) at rest to 20 mg. mmol^–1(95% CI 1.51–3.94) 30 min after exercise, whilst in thenegative electrocardiogram group median resting and 30 min postexercise albumin-creatinine ratio values of 0.85 (95% CI 0.53–1.32)and 1.80 (95% CI 0.63-2.32) mg. mmol^–1 respectively werenot significantly different. These results suggest that exercise-inducedmyocardial ischaemia is associated with increased urinary microalbuminexcretion.     

Effects of sympathetic activation on ventricular ectopic beats in subjects with and without evidence of organic heart disease

In a selected group of 10 apparently healthy subjects and 22patients with organic heart disease, all with frequent ventricularectopic beats on Holter monitoring, we assessed the influenceof sympathetic activation by comparing the arrhythmogenic effectsof a symptom-limited bicycle exercise stress test and 90°head up tilt. Tilting reduced ventricular arrhythmias in thenormal subjects (–48±18% from 9±2 beatsmin^-1, P<0.05). Exercise stress testing caused small andinsignificant changes in arrhythmias during the early (50–75W) phases and an almost complete suppression of ventricularectopic beats in the final stages (–99±1%, P<0.01).In six of the 10 subjects, ventricular arrhythmias reappearedin the early recovery phase. In the 22 patients with organicheart disease, tilting increased ventricular ectopic beats (43±17%from 9±3 beats min^-1, P<0.05); augmented repetitiveforms in 12 patients (179±88% from 1.4±0.6 per3 min) and produced repetitive forms in six of the 10 remainingpatients who did not show repetitive forms during control conditions.Exercise stress testing caused a marked increase in ectopicactivity in the early phase (84±35%) while the responseduring the maximal phase of exercise as well as during recoverywas related to the effort capabilities. Arrhythmias were increasedin 12 patients with limited exercise duration and were reducedin 10 patients with good exercise tolerance. These data indicatethat sympathetic activation has different effects on ventriculararrhythmias depending on the clinical setting and that tiltingis a useful manoevre to evaluate the arrhythmogenic effectsof increased sympathetic activity.     

Comparison of the effects of intravenous and oral betaxolol on antegrade and retrograde conduction in patients with atrioventricular nodal reentrant and atrioventricular reentrant tachycardia.

The electrophysiologic effects of intravenous (015 mg kg^–1)and oral (20 mg day^–1) betaxolol have been investigatedin 11 patients with atrioventricular (A-V) nodal reentrant tachycardiaand eight patients with orthodromic A-V reentrant tachycardia.Betaxolol significantly (P > 001) prolonged sinus cycle length,sinus node recovery time, intranodal conduction time, and theantegrade functional refractory period of the A-V node. Whenthe effective refractory period of the A-V node could be determinedit was increased by betaxolol, whereas no significant electrophysiologiceffects were observed in the atrium, the ventricle or the accessorypathway. Intravenous betaxolol prevented tachycardia in 8 outof 11 patients with A-V nodal reentrant tachycardia, whereasoral betaxolol was effective in 10 patients, primarily by actingon the antegrade limb in two patients and on the retrogradelimb in eight patients. In those with A-V reentrant tachycardia,intravenous betaxolol did not prevent tachycardia in any patient,while it was effective after oral treatment in two patients.When the tachycardia remained inducible, cycle length of thetachycardia increased in all patients, due to prolongation ofthe antegrade and retrograde conduction time in patients withA-V nodal reentrant tachycardia, and due to an increase in theantegrade conduction time, i.e. the A-V node, in the patientswith A-V reentrant tachycardia. In conclusion, betaxolol provedto be effective in the treatment of supraventricular tachycardia;for chronic treatment, a single oral dose (20 mg) seems to suffice.     

Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function

The adequacy, selectivity and long-term persistence of inhibitionin cyclooxygenase-dependent platelet function by a daily low-dose(0.45 mg kg^–1 day^–1) aspirin treatment have beenevaluated in 15 patients after a recent (less than 17 days)acute myocardial infarction. Serum thromboxane (TX) B₂, an indexof platelet TXA₂ production, was decreased by 94–98% (P<0.001)by aspirin, while urinary excretion of 6-keto-prostaglandinF^la, as an index of extraplatelet cyclooxygenase activity, remainedunchanged. Compared to placebo, aspirin induced a persistentincrease in bleeding time (% difference 45.6±21.4, mean± SD) and a decrease in platelet aggregation by ADP,epinephrine, collagen and arachidonic acid. No tendency towardsan attenuation of the effects was apparent for the period ofaspirin administration (4 weeks). Aspirin 0.45 mg kg^–1 day^–1 is adequate and selectivein the long-term inhibition of TX-related platelet functionin patients after acute myocardial infarction. The clinicaleffectiveness of such a regimen remains to be proven in clinicaltrials.     

Efficacy of flecainide in pacing-induced sustained ventricular tachyarrhythmias: correlation to clinical parameters and tachycardia-characteristics

Seventy-two patients with sustained ventricular tachycardiaor syncope of unknown origin underwent electrophysiologic evaluationbefore and after therapy with flecainide (200–300 mg day^–1).In all patients, sustained ventricular tachycardia or ventricularfibrillation was inducible during control electrophysiologicstudy. During flecainide therapy, sustained ventricular tachycardia(VT) was no longer inducible in 18 patients (25%) whereas in54 patients, VT was still inducible. In five of the latter patients,VT became more difficult to induce (overall efficacy 32%). Therate of VT decreased from 214±49 beats min^–1 duringthe control electrophysiologic study to 178±48 beatsmin^–1 during flecainide (P<0.01). The ERP of the rightventricle increased from 251±27 ms during the controlstudy to 267±34 ms on flecainide (P<0.01). Mean ejectionfraction and mean LVEDP did not differ between responders andnon-responders, yet the presence of a left ventricular aneurysmcorrelated with a lack of antiarrhythmic response to flecainide.VT rate as well as VT morphology during the control study discriminatedbetween responders and non-responders; 11% of patients withVT-rate 230 beats min^–1 responded to oral flecainidecompared with 31% with a VT rate > 230 beats min^–1at control. 26% with induced monomorphic VT responded, comparedwith 100% with induced VF during the control study. 18 of 23responders were discharged on flecainide. During a mean follow-upof 26±18 months, two patients experienced a recurrenceof VT and in one patient, flecainide had to be discontinueddue to side-effects. Thus, the acute efficacy of flecainide, evaluated by serialdrug testing, correlates with haemodynamic parameters and thecharacteristics of tachycardia.     

Clinical relevance of verapamil plasma levels in stable angina pectoris

Plasma levels of verapamil and norverapamil were evaluated in 77 patients who received oral verapamil for treatment of angina pectoris. There was a sixfold interpatient variation in verapamil plasma concentrations, but plasma concentrations were linearly related to doses of the drug (240 to 480 mg/day) in the same patient (r = 0.81). Plasma concentrations of norverapamil, the major active metabolite of verapamil, were similar to those of verapamil.Although verapamil produced a significant improvement in exercise tolerance in most patients, the increase in exercise time was not related to plasma levels of the drug; however, most patients with improvement had plasma levels exceeding 100 ng/ml. An increase in the dose of verapamil from 320 to 480 mg daily produced a substantial (71 %) increase in plasma levels of the drug but no significant increase in exercise tolerance (4%).The average increase in the P-R interval with 480 mg of verapamil in these 77 patients was small (8%) (161 ± 18 to 174 ± 22 ms); only six patients had first-degree heart block. These minor effects on atrioventricular conduction were noted despite plasma verapamil concentrations in 76 patients that exceeded 100 ng/ml, a level that successfully converts supraventricular tachycardias after intravenous drug administration. The differences between the effects of oral and intravenous verapamil on atrioventricular conduction may be the result of stereoselective hepatic inactivation of verapamil's /-isomer.Determination of plasma levels of verapamil is of limited value in the management of patients with angina pectoris, but may be useful in the identification of nonresponders with plasma levels less than 100 ng/ml who may benefit from a further increment in drug dose.