Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone: A randomized, digoxin-controlled study

A 24 h intravenous dosing regimen of amiodarone was designedto reach a peak plasma concentration at 1 h and to maintainthe concentration above a certain level during the infusionperiod A randomized, open-label, digoxin-controlled study wasundertaken to observe the efficacy and safety of the dosingregimen of amiodarone in treating recent-onset, persistent,atrial fibrillation and flutter with ventricular rates above130 beats. min^–1. Fifty patients with a mean age of 70± 7 (SD) years were enrolled and randomly assigned toreceive either amiodarone intravenously (n=26) or digoxin (n=24).Amiodarone HCl was infused over 24 h according to the followingregimen: 5 mg. min^–1, 3 mg. min^–1, 1 mg. min^–1and 0.5 mg. min^–1 for 1, 3, 6 and 14 h, respectively,for a 70-kg subject. Digoxin (0.013 mg. kg^–1) was infusedin three divided doses, each dose 2 h apart and infused over30 min. The mean heart rates in the amiodarone group decreased significantlyfrom 157 ± 20 beats. min^–1 to 122 ± 25 beats.min^–1 after 1 h (P<005 vs baseline), and then decreasedfurther to stabilize at 96 ± 25 beats. min^–1 after6 h (P<0.05). The digoxin group had fewer dramatic alterationsin heart rates, compared to the amiodarone group, in the first8h (P<0.05, respectively). Maximum reduction was reachedonly after 8 h. The amiodarone infusion was prematurely abortedin two patients due to severe bradycardia and death after conversionin one patient and aggravation of heart failure in the other.Overall, 24 of 26 patients (92%) in the amiodarone group and17 of 24 (71%) in the digoxin group were restored to sinus rhythmwithin 24 h. The accumulated rates of conversion over 24 h weresignificantly different between the two groups (P=0.0048). Digoxin,while not as effective as amiodarone in the treatment of recent-onsetatrial fibrillation and flutter, appears to be safer. Therefore,we suggest the use of digoxin as the first line drug for thetype of patients that formed the basis of the current studyand reserve amiodarone for refractory cases or those in whomdigoxin is not suitable.     

Increased cardiac sympathetic nervous activity in patients with unstable coronary heart disease

We have evaluated overall and cardiac sympathetic activity in47 patients undergoing coronary angiography, 27 with stableangina of at least 3 months duration, and 20 with unstable ischaemicsymptoms within this period. Cardiac and overall sympatheticactivity were assessed using radiotracer noradrenaline kinetictechniques to measure cardiac and total noradrenaline spilloverto plasma. Overall sympathetic activity (whole body noradrenaline spillover)was similar in the two groups, whereas cardiac sympathetic activity(cardiac noradrenaline spillover) was strikingly increased inthe patients with unstable ischaemic symptoms (102 ±23 pmol . min^–1 vs 34 ± 4 pmol . min^–1, P< 0.001), as was the cardiac to whole body noradrenalinespillover ratio (0.043 ± 0.008 vs 0.021± 0.005,P < 0.01). Coronary sinus bloodflow (50 ± 4 ml . min^–1vs 38 ± 4 ml . min^–1 P < 0.05) and coronarysinus noradrenaline concentration (2.60±0.38 nmol . 1^–1vs 1.41±0.17 nmol . 1^–1, P<0.01) were also increasedin the patients with unstable ischaemic syndromes. Left ventricularejection fraction was similar in the two groups (63 ±2% vs 62 ± 2%). Patients with unstable ischaemic symptoms within the previousthree months have increased cardiac sympathetic nervous activitycompared to patients with stable angina. This may in part explainwhy patients with unstable ischaemic syndromes are at increasedrisk of sudden cardiac death.     

Influence of the force--frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy

In isolated human myocardium it was shown that a positive force-frequencyrelationship occurs in non-failing myocardium; however, theforce-frequency relationship was found to be inverse in myocardiumfrom failing human hearts. In order to investigate the clinicalrelevance of these experimental findings, the influence of heartrate changes on haemodynamics and left ventricular functionwas studied in eight patients without heart failure and in ninewith failing dilated cardiomyopathy (NYHA II–III). Rightventricular pacing was performed at a rate slightly above sinusrate and at 100, 120 and 140 beats. min^–1 Haemodynamicparameters were obtained by right heart catheterization andby high-fidelity left ventricular pressure measurements. Leftventricular angiography was performed at basal pacing rate andat 100 and 140 beats. min^–1 With increasing heart rate,cardiac index increased in patients with normal left ventricularfunction from 2·9 ± 0·2 to 3·5 ±0·21. min^–1. m^–2 (P<0·01) and decreasedcontinuously in patients with dilated cardiornyopathy from 2·6± 0·1 to 2·2 ± 0·11. min^–1. m^–2 (P<0·05). With increasing heart rate,the maximum rate of left ventricular pressure rise increasedin non-failing hearts from 1388 ± 86 to 1671 ±88 mmHg. s^–1 (P<0·01) and did not change infailing hearts. Ejection fraction decreased from 27 ± 3% to 19 ±2% in patients with dilated cardiomyopathy (P<0·05)when the pacing rate was changed from 84 ± 2 beats. min^–1to 140 beats. min^–1, which was associated with a significantlyincrease in end-systolic volume without significantly changesin end-diastolic volume. In patients with normal left ventricularfunction, when the pacing rate was changed from 85 ±3 beats. min^–1 to 140 beats. min^–1, end-diastolicvolume decreased significantly by 13%, whereas left ventricularend-systolic volume and ejection fraction did not significantlychange. Left ventricular systolic and end-diastolic pressuresdid not significantly change with pacing tachycardia in eithergroup. The frequency-related changes in left ventricular volumesand pressures indicate that the differrent haemodynamic effectsof pacing tachycardia in both groups of patients result predominantlyfrom frequency effects on myocardial function and not from frequencyeffects on preload or afterload. These data indicate that recentexperimental findings of positive force-frequency effects innon-failing and negative force-frequency effects in failinghuman myocardium are relevant for the intact heart.     

Lipid peroxidation and antioxidant status following thrombolytic therapy for acute myocardial infarction

We have investigated the timescale of increased lipid peroxidationfollowing successful early thrombolytic therapy for acute myocardialinfarction and report for the first time reciprocal changesin plasma chain-breaking antioxidants. Sixty-seven patientswere recruited following a first acute myocardial infarctionwithin 6 h of the onset of symptoms and received 70 or 100 mgof recombinant tissue plasminogen activator (Actilyse) as twointravenous bolus injections 30 min apart. Serial blood sampleswere taken before administration of thrombolytic therapy andafter 30 min, 60 min, 90 min, 6 h and 24 h. Coronary arterypatency was assessed at 90 min by coronary angiography. Malondialdehyde(MDA), a marker of lipid peroxidation, and the chain-breakingantioxidants alpha-tocopherol, retinol and ascorbate were measuredby high performance liquid chromatography. When the coronaryartery was patent there was an early rise in plasma MDA (time0.091 ± 0.05 µmol.l^–1) with levels peakingat 90 min (1.02 ± 0.06, P<0.05) and returning to baselineby 6 h (0.85 ± 0.06), accompanied by reciprocal decreasesin alpha-tocopherol (time 0 7.13 ± 0.34 µmol.mmol^–1cholesterol, 90 min 6.64±0.33, P<0.05) and retinol(time 0 1.99±0.10 µmol.l^–1, 90 min 1.81 ±0.08, P<0.05). Ascorbate levels did not change significantlyuntil 24 h (time 0 29.5 ± 4.9 µmol.l^–1, 24h 22.6 ± 4.4, P<0.05). Where the coronary artery wasoccluded no changes in these parameters were found except fora late (24 h) fall in ascorbate (time 0 18.5 ± 2.0 mol.l^–1,24 h 12.2 ± 2.2, P<0.05). The timescale of changesin MDA and antioxidants supports a role for increased free radicalproduction following successful early thrombolytic therapy foracute myocardial infarction.     

Differential effects of tissue plasminogen activator and streptokinase on infarct size and on rate of enzyme release: influence of early infarct related artery patency: The GUSTO Enzyme Substudy

BACKGROUND: The recent international GUSTO trial of 41 021 patients withacute myocardial infarction demonstrated improved 90-mm infarctrelated artery patency as well as reduced mortality in patientstreated with an accelerated regimen of tissue plasminogen activator,compared to patients treated with streptokinase. A regimen combiningtissue plasminogen activator and streptokinase yielded intermediateresults. The present study investigated the effects of treatmenton infarct size and enzyme release kinetics in a subgroup ofthese patients. METHODS: A total of 553 patients from 15 hospitals were enrolled in thestudy. Four thrombolytic strategies were compared: streptokinasewith subcutaneous heparin, streptokinase with intravenous (iv.)heparin, tissue plasminogen activator with iv. heparin, andstreptokinase plus tissue plasminogen activator with i.v. heparin.The activity of alpha-hydroxybutyrate dehydrogenase (HBDH) inplasma was centrally analysed and infarct size was defined ascumulative HBDH release per litre of plasma within 72 h of thefirst symptoms (Q(72)). Patency of the infarct-related vesselwas determined by angiography in 159 patients, 90 mm after treatment. RESULTS: Infarct size was 3·72 g-eq . 1^–1 in patients withadequate coronary perfusion (TIMI-3) at the 90 mm angi-ogramand larger in patients with TIMI-2 (4·35 g-eq . 1^–1)or TIMI 0–1 (5·07 g-eq . 1^–1)flow (P=0·024).In this subset of the GUSTO angiographic study, early coronarypatency rates (TIMI 2+3) were similar in the two streptokinasegroups (53 and 46%). Higher, but similar, patency rates wereobserved in the tissue plasminogen activator and combinationtherapy groups (87 and 90%). Median infarct size for the fourtreatment groups, expressed in gram- equivalents (g-eq) of myocardium,was 4·4, 4·5, 3·9 and 3·9 g-eq perlitre of plasma (P=0·04 for streptokinase vs tissue plasminogenactivator). Six hours after the first symptoms, respectively5·3, 6·6, 14·0 and 13·6% of totalHBDH release was complete (P<0·000l for streptokinasevs tissue plasminogen activator). CONCLUSIONS: Rapid and complete coronary reperfusion salvages myocardialtissue, resulting in limitation of infarct size and acceleratedrelease of proteins from the myocardium. Treatment with tissueplasminogen activator, resulting in earlier reperfusion wasmore effective in reducing infarct size than the streptokinaseregimens, which contributes to the differences in survival betweentreatment groups in the GUSTO trial.     

Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy: A study with positron emission tomography

Objectives Coronary vasodilator reserve is reduced in hypertrophiccardiomyopathy and secondary left ventricular hypertrophy despiteangiographically normal coronaries. The aim of the present studywas to assess whether quantitative differences exist betweenthese conditions. Methods Using positron emission tomography with H₂¹⁵O, myocardialblood flow was measured at baseline and following intravenousdipyridamole (0·56 mg. kg ^–1) in 12 hypertrophiccardiomyopathy patients (age 34 (11) years, mean (SD), all male),16 secondary left ventricular hypertrophy patients (age 58 (20)years, P<0·01 vs hypertrophic cardiomyopathy; 10 female)and 40 normal controls (age 54 (20), 13 female). In view ofthe known decline of post-dipyridamole myocardial blood flowwith age, myocardial blood flow was compared between the patientgroups and appropriately matched subsets of the total controlgroup. Results Baseline myocardial blood flow in the hypertrophic cardiomyopathypatients was 0·82 (0·23) ml. min^–1 . g^–1vs 0·94 (0·14) ml. min^–1 . g^–1 inits matched control group, P=ns. For the secondary left ventricularhypertrophy patient group, baseline myocardial blood flow was1·17 (0·40) ml . min^–1 . g^–1 vs 1·06(0·28) ml . min^–1 . g^–1 for the secondaryleft ventricular hypertrophy matched control group, P=ns. Followingdipyridamole, myocardial blood flow was 1·64 (0·44)ml . min^–1 . g^–1 in hypertrophic cardiomyopathypatients vs 3·50 (0·95) ml . min^–1 . g^–1forthe hypertrophic cardiomyopathy matched control group, P=0·0001.For the left ventricular hypertrophy patients, post-dipyridamolemyocardial blood flow was 2·27 (0·60)ml . min^–1. g^–1 vs 2·94(1·29) ml . min^–1 . g^–1for the left ventricular hypertrophy controls, P 0·06.Coronary vasodilator reserve (dipyridamole-myocardial bloodflow/baseline-myocardial blood flow) was 2·05 (0·61)for hypertrophic cardiomyopathy patients vs 3·81 (0·98)for the hypertrophic cardiomyopathy controls (P=0 0001, patientsvs controls) and 2·06 (0·62) for left ventricularhypertrophy patients vs 2·90 (1·38) for the leftventricular hypertrophy controls, P<0·03 patientsvs controls. After correction of baseline myocardial blood flowfor baseline heart rate x systolic pressure product, coronaryvasodilator reserve for the hypertrophic cardiomyopathy patientswas 2·06 (1·06) vs 4·34 (1·54) forthe hypertrophic cardiomyopathy controls, P=0·0002 andin the secondary left ventricular hypertrophy patients, thevalues were 2·13 (0·64) vs 2·89 (1·42)in the secondary left ventricular hypertrophy controls, P<0·05. Conclusions In both hypertrophic cardiomyopathy and secondaryleft ventricular hypertrophy, the computed coronary vasodilatorreserve is impaired, even after correction for baseline cardiacwork. However, the extent of the reduction is greater in thehypertrophic cardiomyopathy patients. In the blunting of vasodilatorreserve of secondary left ventricular hypertrophy, the patients'greater hyperaemic response is partly offset by the higher baselinemyocardial blood flow.     

Cardioprotection by nisoldipine: role of timing of administration

Nisoldipine was administered at 10^–9M, a dose lackingnegative inotropism, to isolated and perfused rabbit heartssubmitted to 60 min ischaemia (1 ml.min^–1) followed by30 min reperfusion. The drug was delivered either 30 min beforeischaemia, at the onset and after 30 min of ischaemia and duringreperfusion only. Cardiac protection was evaluated in termsof recovery of left ventricular pressure during reperfusion,release of creatine phosphokinase (CPK), mitochondrial function,tissue content of adenosine triphosphate (ATP) and creatinephosphate (CP), calcium homeostasis and the occurrence of oxidativestress, established measuring content and release of reducedand oxidized glutathione. The cytoprotective action of nisoldipine occurs in the absenceof negative inotropism and is closely related to the time ofadministration. Optimal myocardial preservation is achievedwhen nisoldipine is given before or at the onset of ischaemia.Prophylactic administration of nisoldipine improved the recoveryof the developed pressure from 159±10 (SE) mmHg to 478±19mmHg, P<0.01 and reduced the release of CPK from 830±29to 229±27 mU. min^–1 g^–1 wet wt, P<0.01.The accumulation of tissue and mitochondrial calcium was reducedfrom58±11 and49±9 to 14±6 and 10±4 mmol.kg^–1 dry wt respectively, P<0.01. This resulted ina signficant (P<0.01) preservation of all indices of mitochondrialfunction, allowing a higher recovery of ATP and CP after reperfusion(from 4.1±0.7 and 10.0±0.6 to 16.1±1.0and 29.9±0.2 µmol.g^–1 dry wt respectively,P<0.001). Reperfusion-induced myocardial accumulation and release of oxidizedglutathione were reduced from 0.493±0.07 nmol.mg^–1protein and 0.768±0.063 nmol.min^–1g^–1 wetwt to 0.225±0.07 and 0.157±0.038 respectively,P<0.01. Similar data were obtained when nisoldipine was givenat the time of ischaemia, while administration 30 min afterthe onset of ischaemia showed only a trend towards protection.Nisoldipine lost its protective effect when given on reperfusion. A multifactorial analysis of the data suggest that the cardioprotectiveeffect of nisoldipine is related to the maintenance of membraneintegrity, possibly since nisoldipine is highly lipophilic.     

An evaluation of nebulized prostacyclin in patients with primary and secondary pulmonary hypertension

AIMS: To investigate the response to inhaled prostacyclin in patientswith primary and secondary pulmonary hypertension and to compareits effects to those of intravenous prostacyclin and inhalednitric oxide. METHODS AND RESULTS: Twelve patients with pulmonary hypertension (seven primary andfive secondary) were studied. All patients had a pulmonary arteryballoon flotation catheter inserted into the proximal pulmonaryartery and radial arterial line. Prostacyclin was nebulizedwith 81. min^–1 of oxygen and administered in doses increasingfrom 15 to 50 ng. kg^–1. min^–1 via a facemask. Eightof these patients also received intravenous prostacyclin indoses of 1 to 5 ng.kg^–1.min^–1 and nitric oxide indoses of 10 to 100 ppm via a facemask. Haemodynamic measurementswere taken during each treatment. In the 12 patients, nebulizedprostacyclin produced a significant reduction in mean pulmonaryartery pressure from 56±5 to 45±4 mmHg (P=0·0001).The pulmonary vascular resistance decreased by 38% from 964±169to 595±116 dyne s^–1.cm^–5 (P=0·0001).Direct comparison with inhaled nitric oxide and intravenousprostacyclin in eight patients demonstrated that nebulized prostacyclinproduced a greater fall in mean pulmonary artery pressure thanthe other two agents without any significant effect on systemicarterial pressure. CONCLUSION: Nebulized prostacyclin appears to be more effective at reducingpulmonary artery pressure in patients with pulmonary hypertensionwhen compared to intravenous prostacyclin and inhaled nitricoxide. This could have important clinical implications for themanagement of patients with pulmonary hypertension.     

The use of esmolol to attenuate the haemodynamic response when extubating patients following cardiac surgery -- a double-blind controlled study

We have assessed the cardiovascular changes associated withemergence from anaesthesia, reversal of neuromuscular blockadeand extubation in a group of 14 patients immediately after coronaryartery bypass graft surgery had been completed. Patients wererandomly allocated to receive either esmolol 500µg. kg^–1over 1 min followed by 100 µg . kg^–1. min^–1or placebo starting prior to reversal. Significant hypertensionand tachycardia occurred in the placebo group, whilst thesechanges were prevented by the administration of esmolol.     

Clinical, adrenergic and heart endocrine measures in chronic atrial fibrillation as predictors of conversion and maintenance of sinus rhythm after direct current cardioversion

The aim of this study was to evaluate clinical, adrenergic andendocrine factors that could predict sinus rhythm maintenanceafter direct current cardioversion in chronic atrial fibrillation. Nineteen patients with chronic non-rheumatic atrial fibrillation(mean duration 6±5 months) were studied. They were exercised24 h before cardioversion at maximum effort with the Naughtonprotocol. Heart rate and blood pressure at rest and exercisewere recorded and blood samples were taken for the assessmentof adrenergic activity, by measuring cyclic adenosine monophosphate,heart endocrine function, atrial natriuretic peptide and itssecond messenger, cyclic guanosine monophosphate. Fifteen ofthe 19 patients were initially converted to sinus rhythm (eightpatients with external and seven patients with internal DC shocks).After 3 months eight patients remained in sinus rhythm and 11had relapsed, most of them within the first month. On exercisethe chronotropic response was lower in the group who remainedin sinus rhythm than in the group in atrial fibrillation (peakheart rate 147±11 beats.min^–1 vs 165±24beats.min^–1 p=0·02). During exercise, the systolicblood pressure in the sinus group reached higher values thanin the group who relapsed (192±17 mmHg vs 176±18mmHg, p=0·03). Cyclic adenosine monophosphate increasedsignificantly from rest to peak exercise in the sinus rhythmgroup (from 23±9 pmol.ml^–1 to 31±15 mol.ml^–1,p=0·02) while it remained unchanged in the atrial fibrillationgroup (25±10 pmol.ml^–1 to 24±8 pmol.ml^–1,p=0·02). For all 19 patients the differ ence in cyclicadenosine monophosphate between rest and exercise was negativelycorrelated with maximum heart rate (r=0·58, p=0·009).Atrial natriuretic peptide increased from rest to peak exercisein the sinus rhythm group (from l29±58 fmol.ml^–1to 140±66fmol.ml^–1 while it remained unchangedin the group in which atrial fibrillation persisted or recurred(from 112±58 fmol.ml^–1 to 111±53 fmol.ml^–1p=0· A significant correlation between atrial natriureticpeptide and cyclic guanosine monophosphate levels at exercisebefore cardioversion was found for the sinus rhythm group only(r=0·76, p=0·02). In patients with non-rheumatic chronic atrial fibrillation evaluationof clinical parameters such as heart rate and blood pressurechanges during maximal exercise can be useful in the choiceof suitable therapy. An inadequate increase in plasma cyclic-adenosinemonophosphate and atrial natriuretic peptide on exercise couldpredict patients with more severe underlying disease, wherecardioversion should not be recommended.     

Reversal of ischaemic systolic and diastolic left ventricular dysfunction by successful coronary angioplasty in patients with non-Q wave anterior myocardial infarction

The effect of PTCA on global and regional left ventricular systolicfunction, isovolumic relaxation, chamber and muscle stiffnesswere studied in 30 patients with angina pectoris, previous non-Qwave anterior myocardial infarction (AMI) and significant stenosisof the left anterior descending coronary artery (LAD). In 11of the 30 patients the condition was stable, but it was unstablein 19. Left ventricular angiograms were obtained before and4. 85± 3.67 months after PTCA. The RAO was in the 30^°projection, with the silhouette of the left ventricle slicedinto 90 regions; changes in left ventricular volume, pressureand anterior wall thickness during the full cardiac cycle, togetherwith dpldt were demonstrated. After PTCA, global ejection fractionincreased from 68. 77 ± 5.96% to 76.57 ±3.18%,P<0.001. Impaired contractility was found in 29190 (32.2%)regions before PTCA and in 5190 (5.6%) after PTCA, P<0.001.The time constant of the isovolumic pressure fall decreasedafter PTCA (52.56 ± 17. 40 ms vs 39. 61 ± 11.26ms, P<0.01). Elastic chamber stiffness coefficient decreased(0.022 ± 0.003 vs 0.008 ± 0.004, P<0001) andpeak rate of left ventricular filling increased (319.0 ±107.9 ml. min^–1 vs 396.8 ±201.4 ml. min^–1,P<0.05) after PTCA. The muscle stiffness coefficient waswithin normal values before and did not change after PTCA. Thestudy findings show that in patients with persistent anginapectoris after non-Q wave AMI, complex systolic and diastolicischaemic dysfunction occurs. This dysfunction can be reversedafter successful PTCA of LAD.     

Additive haemodynamic effects of piroximone and prostacyclin in severe chronic heart failure

This study was undertaken to assess the haemodynamic effectsof the combined infusion of prostacyclin and piroximone, a phosphodiesteraseinhibitor, in 18 patients with severe congestive heart failure.Right heart catheterization was performed with a Swan-Ganz thermodilutioncatheter and arterial blood pressure was monitored using a radialline. After baseline haemodynamic measurements, prostacyclinwas administered in all patients at the incremental infusionrate of 2, 4, 6 and 8 and 10 ng. kg^–1. min^–1 during15min each. After recovery of baseline haemodynamics, patientswere randomly assigned to the piroximone infusion rate of 5or 10µg. kg^–1. min^–1 or placebo. After 24h piroximone or placebo infusion, the same prostacyclin protocolwas applied. Prostacyclin infusion added to piroximone resultedin a significant improvement in haemodynamics, as compared tothe group receiving prostacyclin added to placebo. As comparedto the curve observed with the placebo infusion, 10 ng. kg^–1.min^–1 prostacyclin infusion resulted in a further increasein cardiac index, by 41 and 38% (P<0·01) at the piroximone-infusionrates of 5 and 10 ng. kg^–1. min^–1, respectively,whereas systemic vascular resistance decreased by 25 and 21%,respectively (P<0·01). Additionally, a further decreasein pulmonary capillary wedge pressure by 13 and 11% (P<0·05)and in pulmonary vascular resistance by 21 and 19% (P<0·05)was observed at the piroximone-infusion rates of 5 and 10µig.Kg^–1. min^–1, respectively. Consequently, strokework index increased significantly, as compared to the groupreceiving prostacyclin added to placebo. This haemodynamic improvementoccurred without significant changes in heart rate and meanarterial pressure. Thus, this study shows that in patients withsevere congestive heart failure, short-term infusion of prostacyclinis safe and has additive haemodynamic effects on phosphodiesteraseinhibitors.     

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.     

Comparison of flecainide and procainamide in cardioversion of atrial fibrillation

In this prospective, controlled and randomized cross-over studywe tried to establish the efficiency and safety of flecainidevs procainamide for the treatment of acute atrial fibrillation.Eighty patients (30 females, 50 males, mean age: 55 ±14 years) were included. Patients entered into the study ifthey had atrial fibrillation of recent onset (<24 h) witha ventricular rate >100 beats. min^–1 at rest and were<75 years of age. Exclusion criteria were any sign of heartfailure, conduction disturbances, sick sinus syndrome or acuteischaemic events. Randomly 40 patients received flecainide and40 procainamide as the first treatment. There were no significantclinical dfference between the two groups. Procainamide wasgiven at a dose of 1 g infused over 30 min, and followed byan infusion of 2 mg.min^–1 over 1 h. Flecainide was givenat a dose of 1.5 mg.kg^–1 over 15 min followed by an infusionof 1.5 mg.kg^–1 over 1 h. Drug infusion was continued untilmaximal dose, intolerance or reversion to sinus rhythm. After1 h of wash out, patients remaining in atrial fibrillation werestarted on the second drug. Left atrial size was measured byecho. Serum levels of drug and atrial size did not dffer betweenpatients who returned to sinus rhythm and those who remainedin atrial fibrillation. Conversion to sinus rhythm was achieved in 37 (92%) of the 40patients treated with flecainide and 25 (65%) of those treatedwith procainamide (P<0.001). The time required for reversionto sinus rhythm was similar between the two groups. Flecainideis a highly effective drug, superior to procainamide, for thetreatment of paroxysmal atrial fibrillation.     

Coronary reserve, extent of coronary disease, recurrent angina and ECG changes during pain in the in-hospital prognosis of acute coronary syndromes

The prognostic value of recurrent angina, severity of coronarydisease, ECG changes during pain and coronary reserve (ischaemicthreshold measured by atrial pacing: heart rate with ST segmentshift = 1 mm), was evaluated in 383 consecutive patients withacute coronary syndromes. Univariate analysis showed a significantrelationship between occurrence of complications (death, infarctionor coronary surgery) and number of anginal episodes, extentof coronary disease, ischaemic threshold and ST depression withpain. A multivariate analysis indicated that the first threeparameters were the main independent predictors. Coronary reservewas reduced (threshold 150 beats. min^–1) in 83% of patientswho had a myocardial infarction (40), in 91% of those who died(11), in 87% of those who underwent coronary surgery (52) andin 47% of uncomplicated cases (301). Also, a low ischaemic thresholdwas associated with a larger number of anginal episodes thana high threshold ( 130 beats. min^–1, 6.1 ± 5.6vs > 150 beats. min^–1, 2.9± 4.1, P<0.0001),and in complicated patients with one-, two- or three-vesseldisease ischaemic threshold (137.3± 21.2, 133.3 ±18.9, and 135.1 ± 21.2 beats. min^–1, respectively)was lower than in the uncomplicated ones (153.4±20.1,P < 0.005; 148.2± 19.1 P < 0.005; and 139.2 ±23.0 ns, beats, min^–1). A threshold <150 beats. min^–1and ECG changes during pain identified the subset with the highestrisk for complications (59/137, 45%), whereas a threshold >150 beats. Min^–1 and absence of pain or ECG changes duringpain identified those with the lowest risk (5/109, 5%, p <0.001). Thus, our findings document the prognostic significance of coronaryreserve for in-hospital complications in patients with acutecoronary syndromes and confirm the prognostic value of previouslyknown risk markers. They also indicate that some of them maybe significantly influenced by the status of coronary reserve.     

The effect of simvastatin on progression of coronary artery disease: The Multicenter Coronary Intervention Study (CIS)

BACKGROUND: In several angiographic trials, HMG-CoA reductase inhibitorshave shown a beneficial effect on the progression of coronaryartery disease. Using 20 mg simvastatin day^–1, a treatmentperiod of up to 4 years was necessary to show a significantreduction in coronary artery disease progression. The questionremains however, whether higher dosages of simvastatin wouldbe more advantageous in respect to the magnitude of the effectand the required time interval to demonstrate treatment efficacy. METHODS AND RESULTS: In the Coronary Intervention Study (CIS), a multicentre randomizeddouble-blind placebo-controlled study, the effects of lipid-loweringtherapy with simvastatin on progression of coronary artery diseasein 254 men with documented coronary artery disease and hypercholesterolaemiawere investigated. Following a period of lipid-lowering diet,treatment with 40 mg simvastatin or placebo was maintained foran average of 2·3 years. Two primary angiographic endpointswere chosen: the global change score (visual evaluation accordingto the method of Blankenhorn) and the per patient mean changeof minimum lumen diameter (evaluated by the CAAS I system). The mean simvastatin dose was 34·5 mg day^–1. Inthe placebo group, the serum lipids remained unchanged; in comparisonto the placebo group the simvastatin group showed a 35% LDL-cholesteroldecrease. Coronary angiography was repeated in 205 patients(81%) and 203 film pairs (80%) were evaluable by quantitativecoronary angiography. In the simvastatin and placebo groups,the mean global change scores were +0·20 and +0·58respectively, demonstrating a significantly slower progressionof coronary artery disease in the treatment group (P=0·02).The change in minimum lumen diameter assessed by computer-assistedquantitative evaluation with the CAAS I system was –0·02mm in the simvastatin group and –0·10 mm in theplacebo group (P=0·002). In the simvastatin group, therewas a significant correlation between the LDL cholesterol levelsachieved therapeutically and the per patient mean loss of minimumlumen diameter (r=0·29; P=0·003). During the studyperiod, there was no significant difference in the incidenceof serious cardiac events (15 of 129 patients in the simvastatingroup and 19 of 125 patients in the placebo group, ns). CONCLUSION: Treatment with 40 mg simvastatin day^–1 reduces serum cholesteroland slows the progression of coronary artery disease significantlywithin a short period of treatment time. In the treatment group,retardation of progression is inversely correlated to the LDL-cholesterollevels achieved.     

Vasodilator reserve in collateral-dependent myocardium as measured by positron emission tomography

Myocardial blood flow can be accurately quantitated in patientsusing positron emission tomography and oxygen-15 labelled water.The purpose of this study was to determine the vasodilator reservein myocardium completely perfused by intramyocardial collateralblood flow. We hypothesized that altered relative flow reservein such regions would correlate with the degree of ischaemiaobserved in these patients during exercise. The technique involves the inhalation of the positron emittingtracer C¹⁵O₂ which is converted to freely diffusible H₂¹⁵O bythe lung. With rapid dynamic scanning, arterial and regionalmyocardial tissue concentrations can be obtained and time activitycurves generated. With a two-compartment kinetic model, myocardialblood flow can be accurately quantitated over a wide range ofblood flows. Five patients with stable exertional angina andnormal ventricular function studies and who had an occludedmajor epicardial artery which completely opacified via intramyocardialcollateral blood flow were studied. Myocardial blood flow (MBF)was measured both at rest and following an infusion of intravenousdipyridamole (0.56 mg. kg^–1) and the results were comparedwith measurements obtained from a group of eight normal volunteers.During resting conditions, MBF in the control group was 0.86±0.10ml.g^–1. min^–1 and in the patient group was 0.99±0.10ml. g^–1. min^–1 in normally perfused myocardium (ns)and 0.86±0.14 ml. g^–1. min^–1 in collateral-dependentmyocardium (ns). Following dipyridamole, MBF increased to 3.58±0.89ml. g^–1. min^–1 in the control group and to 2.97±0.94ml. g^–1. min^–1 in the normal regions of the patients(ns). In the collateralized regions of the patients, the increasewas less than that observed in the control group (1.66±1.02,P <0.005). Absolute coronary flow reserve (ACFR) (dipyridamoleMBF/resting MBF) in the control group was 4.1±0.8 andin the patient group was 3.1±1.1 (ns) in normal regionsand 1.9± 1.0 (P <0.001) in collateralized regions.Relative coronary flow reserve, the ratio of ACFR in collateralizedvs that of normally perfused myocardium was determined in eachpatient and correlated well with total exercise time (r = 0.98;P <0.01) and peak double product (r = 0.85; P = 0.06) observedduring a symptom-limited modified Bruce treadmill test. These studies support the hypothesis that vasodilator reservein the distribution of non-infarcted collateral-dependent myocardiumis abnormal compared with normally perfused myocardium. Thedegree of altered flow reserve correlates well with the degreeof ischaemia during symptom-limited exercise, and may explainwhy these patients experience angina at high work loads.     

Intravenous digoxin in acute atrial fibrillation: Results of a randomized, placebo-controlled multicentre trial in 239 patients

AIMS: The DAAF Trial was designed to investigate whether digoxin,within 16 h of its use, increases the rate of conversion tosinus rhythm in patients with acute atrial fibrillation. METHODS AND RESULTS: In a randomized, double-blind multicentre trial the effectsof intravenous digoxin and placebo, (mean dose 0·88±0·35mg and 0·96±0·37 mg) were compared in 239patients with a mean age of 66·2±13·0 yearsand atrial fibrillation of, at most, 7 days' duration. The meanarrhythmia duration was 21·7±30·4 h andbaseline heart rate 122·0±23·0 beats. min^–1.At 16 h, 46% of the placebo group and 51% of the digoxin grouphad converted to sinus rhythm, (ns). Time to sinus rhythm wasshorter in the digoxin group, but the difference was not significant.Digoxin had a pronounced and rapid effect on heart rate, whichwas already significant at 2 h; 104·6±20·9beats. min^–1 vs 116·8±22·5 beats.min^–1 (P=0·0001). CONCLUSION: Acute intravenous treatment with digoxin does not increase therate of conversion to sinus rhythm, but has a fast acting andclinically significant effect on heart rate and should remainan alternative in haemodynamically stable patients     

Serum triglycerides and HDL cholesterol -- major predictors of long-term survival after coronary surgery

The influence of pre-operative serum lipid levels on late clinicaloutcome after coronary artery bypass surgery was analysed in83 patients undergoing coronary bypass surgery for stable anginapectoris. The mean follow-up period for surviving patients was105±33 months (range 65–133). Twenty-two patients(27%) had died during follow-upt of whom 14 had sustained afatal myocardial infarction and four had succumbed to othercardiovascular causes. Thirty-one patients sustained 35 cardiacevents, defined as either fatal or non-fatal myocardial infarction,or reoperation, or PTCA during the follow-up period. With univariateanalysis, pre-operative serum levels of total cholesterol andtriglycerides were significantly related to cardiac events,P<0.05 and P<0.05, respectively. In a Cox proportionalanalysis, cardiac mortality and total mortality were relatedto serum triglycerides and HDL cholesterol (P<0.05 and P<0.01respectively). Eighty-five percent of the patients with triglycerides<2.0 mm. l^–1 survived for 10 years, while only 48%of patients with triglycerides >2.0 mM. 1^–1 remainedalive for that period. Figures were similar for subjects withHDL cholesterol >1.0mM. I^–1 or HDL cholesterol <1.0mM. I^–1, at 89 and 38%, respectively. Only 28% of the patients with the combination triglycerides>2.0 mM. I^–1 and HDL cholesterol <1.0 mM. I^–1were alive 10 years after surgery. These data suggest that dyslipidaemia,especially the combination of high serum triglycerides and lowHDL cholesterol, is an important factor influencing long-termclinical outcome after coronary bypass surgery.     

Effect of magnesium sulphate in patients with unstable angina: A double blind, randomized, placebo-controlled study

AIM: Administration of intravenous magnesium sulphate has been shownto be protective during acute myocardial ischaemia and it maytherefore have beneficial effects in unstable angina. The purposeof this study was to assess the effects of a 24-h infusion ofmagnesium in patients with unstable angina. METHODS AND RESULTS: Patients who presented with unstable angina with electrocardiographicchanges were randomized to receive a 24-h intravenous infusionof magnesium or placebo within 12 h of admission. The primaryendpoint was myocardial ischaemia, as assessed by 48 h Holtermonitoring. Resting 12-lead ECGs, creatine kinase-MB releaseand urinary catecholamines were also assessed. Patients werefollowed for 1 month. Thirty-one patients received magnesiumsulphate and 31 placebo. Baseline characteristics and extentof coronary disease were similar in both groups. On 48 h Holtermonitoring, 14 patients (50%) had transient ST segment shiftsin the magnesium group vs 12 patients (46%) in the placebo group.However, there were fewer ischaemic episodes in the magnesiumgroup (51 vs 101, P<0·001) and there was a trend towardsan increase in the total duration of ischaemia in the placebogroup compared to the magnesium group in the second 24 h (2176min vs 719 min respectively, P=0·08). Regression of Twave changes on the 24 h ECG occurred more frequently in patientswho received magnesium compared to those treated with placebo(11 patients vs 0 patients respectively, P<0·005).Creatine kinase-MB release was significantly less at 6 and 24h in patients who received magnesium compared to those treatedwith placebo. Catecholamine excretion was lower in patientstreated with magnesium than in those treated with placebo (adrenaline:1·05±0·16 vs 1·61±0·32ng . mmol^–1 creatinine; noradrenaline: 9·99±1·82vs 18·48±2·41 ng.mmol^–1 creatininerespectively in the first 12 h sample, P<0·05). CONCLUSION: Intravenous magnesium reduces ischaemic ECG changes, creatinekinase-MB release and urinary catecholamine excretion in theacute phase of unstable angina. Thus, magnesium may be a beneficialadditional therapy for these patients. Further studies are requiredto confirm these findings.